Anti-PD-L1 Antibody MEDI4736 in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non-small Cell Lung Cancer (NSCLC). A Multicenter Single-arm Phase II Trial.
Phase: PHASE2
Conditions: NSCLC Non-small Cell Lung Cancer
Sponsor: Swiss Cancer Institute

 
 
 
 
 
SAKK CC 
Effingerstrasse 33 
CH – 3008 Bern 
Phone: +41 31 389 91 91 
Fax: +41 31 508 41 42 
E-mail: trials@sakk.ch 
Web: www.sakk.ch 
SAKK - SWISS GROUP FOR CLINICAL CANCER RESEARCH 
 
Protocol SAKK 16/14 
Anti-PD-L1 antibody MEDI4736 in addition to 
neoadjuvant chemotherapy in patients with stage 
IIIA(N2) non-small cell lung cancer (NSCLC). 
A multicenter single-arm phase II trial. 
 
Protocol version: 
Version 3.0, including amendments 1 and 2, 04.08.2017 
 
SNCTP No.: 
SNCTP000001480 
Study type: 
Clinical trial with Investigational Medicinal Product (IMP)  
Categorization: 
Risk category C according to the Human Research Act (HRA) and its 
ordinance KlinV/Oclin 
 
Coordinating Investigator: 
Sacha Rothschild, MD PhD 
Phone: +41 61 265 50 74 
 
Medical Oncology 
Fax: +41 61 265 53 16 
 
University Hospital, Basel 
sacha.rothschild@usb.ch 
 
 
 
 
CONFIDENTIALITY 
The information contained in this document is confidential and the property of SAKK (or “sponsor”). 
The information may not - in full or in part - be transmitted, reproduced, published, or disclosed to 
others than the applicable Competent Ethics Committee(s) and Regulatory Authorities, involved 
pharmaceutical companies and any other stakeholders without prior written authorization from the 
sponsor except to the extent necessary to obtain informed consent from those who will participate 
in the study. The study is performed along applicable transparency rules and is published on 
publicly available registries (Swiss National Clinical Trials Portal at kofam.ch; clinicaltrials.gov).  
 
Copyright © 2015 by SAKK 
 

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GENERAL INFORMATION 
Supporting Coordinating 
 
 
Investigators: 
Alfred Zippelius, MD PhD 
Phone: +41 61 328 60 16 
 
Medical Oncology 
Fax: +41 61 265 53 16 
 
University Hospital, Basel 
alfred.zippelius@usb.ch 
 
Miklos Pless, MD 
Phone: +41 52 266 36 40 
 
Medical Oncology 
Fax: +41 52 266 45 20 
 
Cantonal Hospital, Winterthur 
miklos.pless@ksw.ch 
Supporting surgeon: 
Michel Gonzalez, MD 
Phone: +41 21 314 31 58 
 
Thoracic Surgery 
Fax: +41 21 314 23 58 
 
University Hospital, Lausanne 
michel.gonzalez@chuv.ch 
Senior supporting surgeon: Walter Weder, MD 
Phone: +41 44 255 88 02
 
Thoracic Surgery 
Fax: +41 44 255 88 05 
 
University Hospital, Zürich 
walter.weder@usz.ch 
Central Pathologist: 
Spasenija Savic Prince, MD 
Phone: +41 61 328 78 37
 
Institute of Pathology 
Fax: +41 61 265 31 94
 
University Hospital, Basel 
spasenija.savicprince@usb.ch 
Statistician: 
Alexandros Xyrafas, MSc  
Phone: +41 31 508 42 13 
 
SAKK CC, Bern  
alexandros.xyrafas@sakk.ch 
Clinical Project Manager: 
Corinne Rusterholz, PhD 
Phone: +41 31 508 41 53 
 
SAKK CC, Bern  
corinne.rusterholz@sakk.ch 
Clinical Research 
Associate: 
Michelle Schaffer, PhD 
Phone: +41 508 42 03
 
SAKK CC, Bern  
michelle.schaffer@sakk.ch  
 
 
Internet-based registration: 
www.sakk.ch/edc 
Fax-based registration:  
+41 31 508 41 42 
Information: 
SAKK CC 
Phone: +41 31 389 91 91  
 
Effingerstrasse 33 
Fax: +41 31 508 41 42 
 
CH – 3008 Bern 
sakkcc@sakk.ch 
 
Opening hours: 
Mon.-Fri. 8:00 a.m. to 5:00 p.m. 
Website: 
www.sakk.ch 
Sponsor:  
Swiss Group for Clinical Cancer Research 
 
Bern, Switzerland

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PROTOCOL SIGN-OFF PAGE PROTOCOL VERSION 3.0 FOR THE 
PRINCIPAL INVESTIGATOR 
 
 
SAKK 16/14. Anti-PD-L1 antibody MEDI4736 in addition to neoadjuvant chemotherapy in 
patients with stage IIIA(N2) non-small cell lung cancer (NSCLC). A multicenter single-arm 
phase II trial. 
 
Principal Investigator in:  ___________________________________________________  
Having read and understood protocol VERSION 3.0 including amendments 1 and 2, I agree to 
conduct the trial as specified in the protocol.  
Name:  ________________________  
Title: 
 __________________________  
Date: 
 ________________________  
Signature:  __________________________  
 

 
 
Anti-PD-L1 in stage IIIA(N2) NSCLC 
 
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ABBREVIATIONS 
ADA 
Antidrug antibodies  
AE 
Adverse event 
AESI 
AE of special interest 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
AST  
Aspartate aminotransferase 
AUC  
Area under the curve 
CD  
Cluster of differentiation 
CI 
Confidence interval 
CR 
Complete response 
CrCl  
Creatine clearance 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CTLA-4 
Cytotoxic T-lymphocyte-associated protein 4 
DLCO  
Diffusing capacity of the lung for carbone monoxide 
DSUR 
Development Safety Update report 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic CRF 
EDC 
Electronic data capture 
EFS 
Event-free survival 
FAS 
Full analysis set 
FDG 
Fludeoxyglucose (18F) 
FEV1  
Force expiratory volume in 1 s 
FFPE  
Formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
G-CSF  
Granulocyte-colony stimulating factor 
GGT  
Gamma-glutamyltransferase  
HE 
Hematoxylin and eosin  
HFV 
Humanforschungsverordnung 
HR 
Hazard ratio 
HRA 
Human research act 
IB 
Investigator’s Brochure  
ICH 
International Conference on Harmonization 
IDMC  
Independent data monitoring committee  
Ig 
Immunoglobulin 
IHC  
Immunohistochemistry 
ILD 
Interstitial lung disease 
IMP 
Investigational medicinal product 
INR  
International normalized ratio 
irAE  
Immune-related AE 
i.v. 
Intravenous 
KlinV 
Verordnung über klinische Versuche in der Humanforschung  
KOFAM 
Koordinationsstelle Forschung am Menschen 
mAb 
Monoclonal antibody 
MRI 
Magnetic resonance imaging 
LLN 
Lower limit of normal 

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NCI 
National Cancer Institute  
NE  
Non-evaluable 
NGS 
Next-generation sequencing  
NSCLC  
Non-small cell lung cancer 
NTL  
Non-target lesions 
OClin 
Ordonnance sur les essais cliniques dans le cadre de la recherche sur l’être humain 
OR 
Objective response 
ORH  
Ordonnance relative à la recherche sur l'être humain 
ORR 
Objective response rate  
OS  
Overall survival 
OV-HFG 
Organisationsverordnung zum Humanforschungsgesetz  
pCR 
Pathological complete response 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed cell death ligand 1 
PET 
Positron emission tomography 
PIS/IC  
Patient information sheet and informed consent form 
PK 
Pharmacokinetics 
p.o. 
Per os (orally) 
PP  
Per protocol 
ppo 
Predictive postoperative  
PQC 
Product quality complaint 
PR 
Partial response 
PT  
Prothrombin time 
PTT  
Partial thromboplastin time  
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAR 
Serious adverse reaction 
SAKK 
Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung / Swiss Group for Clinical 
Cancer Research 
SAKK CC 
SAKK Coordinating Center 
SAP 
Statistical analysis Plan 
SD 
Stable Disease 
SDV 
Source data verification 
SNCTP 
Swiss National Clinical Trials Portal 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
SUVA 
Schweizerische Unfallversicherungsanstalt 
TB 
Total bilirubin 
TL 
Target lesions 
TNF-α  
Tumor necrosis factor-α 
TSH  
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
UPN 
Unique patient number 
VO2 
Oxygen consumption 
WBC  
White blood cells 
WHO 
World Health Organization 

 
 
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TABLE OF CONTENTS 
ABBREVIATIONS 
5 
TABLE OF CONTENTS 
7 
1 TRIAL OVERVIEW SAKK 16/14 
10 
2 INTRODUCTION AND BACKGROUND 
14 
2.1 
Disease background 
14 
2.2 
Therapy background 
14 
2.3 
Cancer immunotherapy 
16 
2.4 
Novel investigational product 
17 
2.5 
Rationale for performing the trial 
22 
2.6 
Choice of design 
24 
2.7 
Choice of trial population 
24 
3 OBJECTIVES AND ENDPOINTS 
25 
3.1 
Objective 
25 
3.2 
Endpoints 
25 
3.3 
Additional research questions 
25 
4 TRIAL DESIGN 
26 
5 TRIAL DURATION AND TERMINATION 
26 
6 SELECTION OF PATIENTS 
27 
6.1 
Inclusion criteria 
27 
6.2 
Exclusion  criteria 
27 
7 REGISTRATION 
29 
7.1 
Pre-registration procedure 
29 
7.2 
Registration procedure 
29 
7.3 
After registration 
30 
8 DRUG SUPPLY AND HANDLING 
31 
8.1 
Drugs in protocol 
31 
8.2 
Drug supply and handling of MEDI4736 
31 
8.3 
Drug supply and handling of cisplatin and docetaxel 
32 
8.4 
Product quality complaint handling 
32 
9 TRIAL TREATMENT 
33 
9.1 
Treatment overview 
33 
9.2 
Chemotherapy with cisplatin/docetaxel 
33 
9.3 
Immunotherapy with MEDI4736 
34 
9.4 
Surgery 
36 
9.5 
Postoperative radiotherapy 
36 
9.6 
General remarks on dose modifications and delays 
37 
9.7 
Treatment duration 
37 
9.8 
Treatments not permitted during trial treatment phase 
38 
9.9 
Precaution 
38 
10 ADVERSE 
EVENT 
REPORTING, 
DOSE 
MODIFICATIONS 
AND 
SUPPORTIVE 
TREATMENT 
39 
10.1 Definition of AE 
39 
10.2 Reporting of AEs 
39 
10.3 Definition of AE of special interest (AESI) 
40 
10.4 Reporting of AESI 
41 

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10.5 Drug-related AEs 
41 
10.6 Safety parameters 
43 
10.7 Dose modifications and supportive treatment during treatment with cisplatin/docetaxel 44 
10.8 Toxicity management guidelines during MEDI4736 therapy 
46 
11 SAFETY REPORTING 
61 
11.1 Definition of serious adverse event (SAE) 
61 
11.2 Definition of serious adverse reaction (SAR) 
62 
11.3 Definition of suspected unexpected serious adverse reactions (SUSARs) 
62 
11.4 Reporting of individual SAEs by the investigator 
62 
11.5 Reporting of individual SAEs and SUSARs by the sponsor 
62 
11.6 Reporting of safety signals 
62 
11.7 Pregnancy 
62 
11.8 Periodic reporting on safety 
63 
12 EVALUATIONS AND INVESTIGATIONS BEFORE, DURING AND AFTER TRIAL 
TREATMENT 
64 
12.1 Pretreatment evaluations and procedures 
64 
12.2 Evaluations during neoadjuvant chemotherapy 
65 
12.3 Evaluations during neoadjuvant MEDI4736 therapy 
66 
12.4 Evaluations at surgery 
66 
12.5 Evaluations during adjuvant MEDI4736 therapy 
67 
12.6 Evaluations at the end of treatment 
68 
12.7 Evaluations at recurrence 
68 
12.8 Evaluations in the follow-up phase 
68 
13 CRITERIA OF EVALUATION AND DEFINITION OF ENDPOINTS 
69 
13.1 Criteria of evaluation 
69 
13.2 Definition of Endpoints 
69 
14 DOCUMENTATION 
71 
14.1 CRFs and reports 
71 
14.2 Notes for special handling of CRFs 
71 
14.3 Source data 
71 
15 STATISTICAL CONSIDERATIONS 
72 
15.1 Introduction 
72 
15.2 Sample size estimation 
72 
15.3 Interim safety analysis 
72 
15.4 Statistical analyses 
72 
15.5 Handling of missing data and drop-outs 
73 
16 QUALITY OF LIFE 
73 
17 PATHOLOGY 
74 
17.1 Local pathology 
74 
17.2 Central pathology 
76 
17.3 Pathology samples banking 
76 
18 TRANSLATIONAL RESEARCH 
77 
18.1 Determination of a pre- and post-therapeutic „Tumor Immune Profile“ (mandatory) 
77 
18.2 Re-biopsies/cytologies in patients with tumor progression  or relapse during adjuvant 
MEDI4736 treatment (optional) 
79 
18.3 Microbiome (optional) 
79 
18.4 Samples and scheduling of sampling 
79 

 
 
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18.5 Handling and labeling 
80 
18.6 Shipment 
80 
18.7 Sample biobanking 
81 
19 ECONOMIC EVALUATION 
81 
20 ETHICAL CONSIDERATIONS 
82 
20.1 Risks/benefits 
82 
20.2 Trial categorization 
82 
20.3 Patient information and informed consent 
82 
20.4 Premature withdrawal 
83 
21 ADMINISTRATIVE CONSIDERATIONS 
84 
21.1 Insurance 
84 
21.2 Financing and support 
84 
21.3 Monitoring and auditing 
84 
21.4 IDMC 
84 
21.5 Quality control and quality assurance 
84 
21.6 Trial activation procedure 
85 
21.7 Local trial records 
85 
21.8 Trial registration 
85 
21.9 List of participating sites 
85 
21.10 Modifications of the protocol 
85 
21.11 Trial termination 
86 
22 PUBLICATION 
86 
23 CONFIDENTIALITY 
86 
23.1 Copyright 
86 
23.2 Confidentiality 
86 
24 REFERENCES 
87 
APPENDICES 
92 
Appendix 1 
Tumor response assessment according to RECIST 1.1 
92 
Appendix 2 
TNM Classification 
95 
Appendix 3 
Calculation of creatinine clearance 
96 
Appendix 4 
WHO performance status 
96 
Appendix 5 
New York Heart Association (NYHA) classification 
96 
Appendix 6 
Process chart for mediastinal lymph node staging 
97 
Appendix 7 
Process chart for lung function tests 
98 
Appendix 8 
Schedule of assessments and treatments 
99 
 
 
 

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1 
TRIAL OVERVIEW SAKK 16/14 
 
SAKK 16/14. Anti-PD-L1 antibody MEDI4736 in addition to neoadjuvant chemotherapy in 
patients with stage IIIA(N2) non-small cell lung cancer (NSCLC). A multicenter single-arm 
phase II trial. 
 
Sponsor: Swiss Group for Clinical Cancer Research (SAKK) 
Trial registry No.:  SNCTP No.: SNCTP000001480 
 
Clinicaltrials.gov No.: NCT02572843 
Coordinating investigator: Sacha Rothschild, MD PhD, University Hospital, Basel, Switzerland  
TRIAL PHASE AND CATEGORY 
This is a phase II clinical trial with IMP.  
The IMP MEDI4736 (durvalumab) is an investigational product without marketing authorization for 
any indication in any country. MEDI4736 is currently under investigation in ten clinical trials either 
as monotherapy or as combination therapy for advanced stage solid tumors. According to the 
Swiss Human Research Act (HRA) and its corresponding ordinance KlinV/Oclin on clinical trials, 
this trial is classified as category C. 
OBJECTIVE(S) 
Trial objective(s): 
The objective of the trial is to demonstrate that the addition of perioperative immunotherapy (with 
the anti-programmed cell death ligand 1 (PD-L1) antibody MEDI4736) to standard chemotherapy 
(with cisplatin/docetaxel) in primary resectable stage IIIA(N2) NSCLC is efficacious and feasible. 
ENDPOINTS 
Primary endpoint: 
• Event-free survival (EFS) at 12 months 
An event is defined as relapse or progression according to RECIST 1.1 criteria, secondary 
tumor or death due to any cause. 
Secondary endpoints: 
• EFS 
• Overall survival (OS) 
• Objective response (OR) after neoadjuvant chemotherapy 
• OR after neoadjuvant immunotherapy 
• Pathological complete response (pCR) 
• Major pathological response (10% or less residual viable tumor) 
• Rate of nodal down-staging to < ypN2 
• Complete resection  
• Pattern of recurrence (local, loco-regional, distant) 
• Adverse events (AEs) 
• Postoperative 30-day mortality 
 

 
 
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Additional research questions: 
Patient participation is mandatory 
• Comparison of the tumor immunome at the time of diagnosis (treatment-naive) and at the time 
of tumor resection (after neoadjuvant chemo- and immunotherapy) 
• Investigation of efficacy outcome parameters (EFS, OR, OS) in relation to tissue expression of 
PD-L1 (tumor and immune cells)     
• Investigation of biomarkers for anti-PD-L1 treatment and their relation to efficacy outcome 
parameters of interest (EFS, OS and OR after neoadjuvant immunotherapy) 
 Patient participation is optional 
• Investigation of the effect of the intestinal microbiota on the response to immunotherapy  
TRIAL DESIGN 
Multicenter, single-arm, phase II trial  
 
SELECTION OF PATIENTS  
Refer to section 6 for the full list of inclusion/exclusion criteria 
• 
Pathologically proven NSCLC (adeno-, squamous-, large cell carcinoma or NSCLC not 
otherwise specified) irrespective of genomic aberrations or PD-L1 expression status. 
• 
Tumor tissue is available for the mandatory translational research (preferably histology, 
cytology allowed). 
• 
Tumor stage T1-3N2M0 (stage IIIA(N2) according to the 7th edition of the TNM classification; 
October 2009).  
• 
Tumor is considered resectable based on a multidisciplinary tumor board decision made 
before neoadjuvant treatment. 
• 
Age 18-75 years. 
• 
WHO performance status 0-1. 
• 
Adequate lung, cardiac, hepatic and renal functions. 
• 
Adequate hematological values. 
• 
No previous or concomitant malignancy within 5 years prior registration (see exceptions). 
• 
No previous therapy for NSCLC; no previous treatment with a PD-1 or PD-L1 inhibitor; no 
previous radiotherapy to the chest. 
• 
No preexisting peripheral neuropathy. 
• 
No active autoimmune disease requiring systemic treatment within the past 3 months; no 
documented history of clinically severe autoimmune disease (see exceptions). 
• 
No history of primary immunodeficiency, allogeneic organ transplant or previous clinical 
diagnosis of tuberculosis; no known evidence of acute or chronic hepatitis B, hepatitis C or 
human immunodeficiency virus (HIV) infection. 
INVESTIGATIONAL MEDICINAL PRODUCT 
For this trial MEDI4736 (durvalumab) is the IMP.  
MEDI4736 is a human monoclonal antibody (mAb) of the immunoglobulin (Ig)G1 kappa subclass 
against PD-L1.  

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TRIAL TREATMENT 
The trial investigates the addition of pre- and post-operative immune checkpoint inhibition with the 
anti-PD-L1 antibody MEDI4736 to the previously established standard of care for stage IIIA(N2) 
patients, which is based on the trials SAKK16/96 and SAKK16/00. Patients whose tumor is 
deemed resectable at diagnosis will receive 3 cycles (21 days each) of standard chemotherapy 
with cisplatin/docetaxel followed by 2 cycles (14 days each) of neoadjuvant immunotherapy with 
MEDI4736 750 mg. Following surgery, patients with complete resection (R0) of their tumor will be 
administered adjuvant treatment with MEDI4736 750 mg for up to one year or until recurrence, 
death, unacceptable toxicity or consent withdrawal (whichever occurs first). Patients with 
incomplete R1/R2 resection, including patients with extracapsular spread of mediastinal lymph 
node metastases, may undergo standard radiotherapy prior to adjuvant treatment with MEDI4736. 
MEASUREMENTS AND PROCEDURES  
Baseline assessments before trial therapy comprise a positron emission tomography/computed 
tomography (PET/CT) with contrast enhanced CT scan of thorax and upper abdomen, a brain 
magnetic resonance imaging (MRI) or CT, echocardiography and electrocardiogram (ECG), 
pulmonary function tests, physical examination and blood and urine testing for safety parameters 
(hepatic, renal, metabolic and thyroid function, hematology). A pregnancy test for women in child-
bearing age will also be performed. 
During neoadjuvant chemotherapy, regular physical examination and blood testing for safety 
parameters (hepatic, renal, metabolic function, hematology) will be performed. A PET/CT with 
contrast enhanced CT scan of thorax and upper abdomen is to be done at the end of the last 
(third) cycle of chemotherapy.  
Prior to neoadjuvant treatment with MEDI4736, patients will undergo an ECG and thyroid function 
analysis, as well as blood and urine testing for safety parameters (hepatic, renal, metabolic 
function, hematology). During the course of the treatment, regular physical examination and blood 
testing for safety parameters will be performed. Besides, vital signs will be monitored during each 
infusion of MEDI4736 and also post-infusion for the first cycle of treatment. 
Assessments prior to surgery comprise a PET/CT with contrast enhanced CT scan of thorax and 
upper abdomen, ECG or echocardiography, pulmonary function tests, physical examination and 
blood testing for safety parameters (hepatic, renal, metabolic, thyroid function, hematology and 
coagulation factors). In case post-surgery radiotherapy is administered, patients will be assessed 
for AEs during the course of the radiation therapy.   
During adjuvant immunotherapy until and including at the end of the treatment, physical 
examinations and laboratory investigations for safety parameters (hepatic, renal, metabolic and 
thyroid function, hematology) will take place at regular intervals. An ECG is to be performed at 
cycle 1, cycle 9 and at the end of treatment. Contrast enhanced CT scans of thorax and upper 
abdomen will be performed 1 month after surgery and every 3 months thereafter. 
In addition, tumor material (histology preferred, cytology accepted) will be collected prior to the 
start of trial therapy and a resected tumor specimen will be collected at surgery. Peripheral blood 
will be collected at baseline, prior to the start of neoadjuvant MEDI4736 therapy, prior to surgery, 
prior to the 5th application of adjuvant MEDI4736 therapy and at the end of trial treatment (whether 
completed as per protocol or prematurely discontinued due to recurrence or any of the listed 
events). Stool samples at baseline and during aduvant MEDI4736 therapy will be collected from 
patients who consent to give such a sample. A tumor biopsy or cytology specimen may be 
optionally collected at recurrence. 
The patients will be followed up lifelong. Visits, involving physical examination and contrast 
enhanced thorax CT scan alternating with chest X-ray will take place every 3 months for 2 years 
after the end of trial therapy, every 6 months during the years 3 to 5 and once a year thereafter. 
The frequency of follow-up visits and of medical assessments is in line with the international 
guidelines for the diagnosis and treatment of locally advanced NCSLC. 
 

 
 
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NUMBER OF PARTICIPANTS 
It is planned to include 68 patients in ca. 20 participating sites. 
TRIAL DURATION 
Duration of accrual: 3 years  
Duration of trial therapy (per patient): 16 to 18 months  
Duration of follow-up (per patient): lifelong 
Duration of trial in total: unknown (lifelong follow-up) 
The trial may be stopped early based on the results of an interim safety analysis or if new scientific 
data become available which change the assessment of risk/benefit. 
TRIAL SCHEDULE 
First patient in:  Q1 2016 (planned) 
Last patient in:  Q1 2019 (planned) 
End of trial therapy:  Q3 2020 (planned) 
Last patient, last visit:  unknown (lifelong follow-up) 
STATISTICAL CONSIDERATIONS 
The sample size is based on the EFS at 12 months after registration. A rate ≤ 48% of EFS at 12 
months after registration is considered uninteresting while a rate ≥ 65% is considered promising. 
According to a single-stage phase II design based on survival rate at a specific time-point, 64 
patients are needed to obtain a power of 80% with a significance level of 5%. Assuming a 5% rate 
of non-evaluable patients for the primary endpoint due to non-compliance to the criteria for the full 
analysis set (FAS; see section 13), the target sample size is increased to 68 patients. 
GCP STATEMENT 
This study will be conducted in compliance with the protocol, the current version of the Declaration 
of Helsinki, the guidelines of Good Clinical Practice (GCP) issued by the International Conference 
on Harmonization (ICH), as well as national legal and regulatory requirements. 
 

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2 
INTRODUCTION AND BACKGROUND 
2.1 
Disease background 
Lung cancer is the most common cancer both in incidence and in mortality globally with 1.35 
million deaths annually [1]. In Europe lung cancer is predicted to cause nearly 280’000 deaths 
(both sexes combined) in 2015, corresponding to over 20% of total cancer deaths [2]. In 
Switzerland 3’700 patients are diagnosed yearly with lung cancer [3]. 
Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers. Overall, the 5 
year survival rate in NSCLC is about 14% and mainly depends on the stage at diagnosis [4]. About 
one fourth of patients with NSCLC initially present with locally advanced stage III disease [5]. 
Locally advanced disease has traditionally been one of the major challenges due to its broad 
heterogeneity and, most importantly, a possibility for cure in selected subgroups of the patients. 
Historically, stage III NSCLC was defined as loco-regionally advanced disease with extra-
pulmonary invasion into surrounding organs (T3/T4) and/or malignant involvement of ipsilateral 
(N2) or contralateral (N3) lymph nodes but no evidence of distant metastasis. Stage IIIA includes 
T1-3 tumors with mediastinal lymph node involvement (N2), T3 tumors with ipsilateral hilar (N1) or 
mediastinal (N2) lymph node involvement and T4 tumors in the absence of nodal metastases (N0) 
or with hilar lymph node metastases (N1) [6]. From a therapeutic point of view patients with locally 
advanced NSCLC are divided into a subgroup deemed potentially resectable at disease diagnosis 
and a group of patients with disease deemed non-resectable.  
2.2 
Therapy background 
Stage IIIA(N2) is deemed resectable if a complete tumor resection may be achieved. Resectability 
is determined irrespective of any pre-operative treatment. Evaluation of resectability includes 
radiographic imaging techniques (computed tomography (CT), positron emission tomography–
computed tomography (PET/CT) or magnetic resonance imaging (MRI)) and, in case of centrally 
located tumors, more invasive staging procedures as video-mediastinoscopy in order to exclude a 
more advanced stage disease (e.g. infiltration of the contralateral main bronchus). The suspicion of 
an involvement of several mediastinal lymph nodes or mediastinal lymph node stations is not an 
exclusion criterion if the thoracic surgeon assesses the mediastinal lymph nodes as resectable. 
Role of pre- or post-operative chemotherapy 
Many phase II trials demonstrated the safety and efficacy of preoperative chemotherapy [7-11]. 
Randomized trials suggested an additional benefit when neoadjuvant chemotherapy was added to 
surgery [12-15]. The results were consistently in favor of primary chemotherapy prior surgery 
compared to surgery alone. However, these trials enrolled small number of patients and the 
differences in outcome were not statistically significant in most cases. 
A recently updated Cochrane meta-analysis (evaluating 11,107 patients in 47 trials) reported a 
clear benefit of the addition of platinum-based chemotherapy, either as adjuvant or neoadjuvant, 
over surgery alone in stage IB-III [16]. In particular, the meta-analysis showed that among the 35 
trials (8447 enrolled patients) which evaluated surgery plus adjuvant chemotherapy versus surgery 
alone, the addition of chemotherapy to surgery resulted in an absolute increase in survival of 4% at 
five years (HR 0.86, 95% CI 0.81-0.92, p<0.0001). 
Another meta-analysis, using data from 16 trials with 3728 patients, evaluated the role of pre-
operative chemotherapy in comparison to surgery alone for resectable NSCLC [17]. The pooled 
hazard ratio for overall survival was 0.84 (95% CI 0.77-0.91, p<0.001). Seven of these trials (1447 
patients) were limited to stage III disease. The pooled HR for these 7 trials was 0.77 (95% CI 0.68-
0.87, p<0.001).  
Hence, neoadjuvant or adjuvant chemotherapy for stage IIIA NSCLC is now considered standard 
of care. Encouragingly, preoperative chemotherapy appears to be better tolerated than adjuvant 
chemotherapy, with a high compliance of 90-95% [15, 18].  

 
 
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In the three-arm NATCH trial from the Spanish Lung Cancer Group, 624 patients with stages IA-II 
were randomly assigned to receive induction chemotherapy with carboplatin/paclitaxel followed by 
surgery or surgery followed by adjuvant chemotherapy or surgery alone [19]. Although the majority 
of patients had stage IA disease there was a non-significant trend for improved 5-year disease-free 
survival rates with neoadjuvant chemotherapy. In the subgroup of stage II (T3N1) patients disease-
free survival rates favored the neoadjuvant arm. A significantly greater proportion (90%) of patients 
in the neoadjuvant group received the planned three cycles of neoadjuvant chemotherapy 
compared with the adjuvant group (66%).  
Role of surgery 
A second question for stage IIIA disease is whether surgery leads to a better prognosis compared 
to definitive combined chemo-radiotherapy. Several randomized trials investigated the role of 
surgery with slightly different trial design. Postoperative morbidity and mortality is an important 
issue in this setting. In the RTOG 89-01 trial surgery did not increase the mortality rate [20]. The 
EORTC trial [21] and the US Intergroup trial [22] showed an increased morbidity and mortality rate 
for patients undergoing pneumonectomy compared to more limited surgical approaches 
(lobectomy, bilobectomy). An exploratory matching analysis of the US Intergroup trial showed a 
benefit of the addition of surgery if pneumonectomy is avoided. In the SAKK trials, the 
perioperative mortality was 0-3% [23, 24]. 
In summary, these trials showed that surgery after neoadjuvant therapy is feasible in selected 
patients with N2 disease at experienced centers with recorded low perioperative mortality and 
results in median and 5 years overall survival which were comparable to those obtained after 
definitive chemo-radiotherapy (Table 1).  
Table 1. Randomized phase III studies comparing neoadjuvant therapy and surgery to definitive chemo-
radiotherapy. 
Study 
(year) 
N 
Induction 
therapy/Surgery 
Chemo-
Radiotherapy 
(CRT) 
Median OS 
(months) 
5-year OS (%) 
Log-
rank 
test p-
value 
 
 
 
 
Induction CRT Induction CRT  
Johnstone 
(2002) [20] 
45 
Cis/Vinblastine 
Chemo → RT 
19.4 
17.4 
22* 
22* 
0.46 
Van 
Meerbeeck 
(2007) [21] 
332 Platinum-based 
Chemo → RT 
16.4 
17.5 
15.7 
14 
0.60 
Albain 
(2009) [22] 
396 Cis/Eto/RT (45 
Gy) 
Cis/Eto/RT 
(61 Gy) 
23.6 
22.2 
27 
20 
0.24 
* at 4 years 
Cisplatin/Docetaxel as chemotherapy backbone 
Docetaxel has been extensively tested in the metastatic setting in patients with NSCLC as 
monotherapy [25] or in combination with cisplatin [26, 27] and other agents [28, 29], either in first-
line or in second-line treatment after failure of a cisplatin-based chemotherapy [30, 31]. The 
combination of cisplatin with docetaxel can be considered one of the standard regimens for the 
therapy of stage IV NSCLC based on the four-arm ECOG trial [32]. One randomized trial 
investigated the role of single agent docetaxel in stage III NSCLC, either as induction therapy 
before radiotherapy or as neoadjuvant treatment [33]. The control arm was local therapy alone. 
There was a trend towards a favorable survival in the docetaxel arm. 
Previous SAKK trials for stage IIIA(N2) NSCLC 
The SAKK substantially contributed to establish a standard of care for patients with locally 
advanced stage III NSCLC. In the single-arm phase II trial SAKK 16/96, 90 patients with stage 
IIIA(N2) NSCLC were treated with three cycles of neoadjuvant chemotherapy using cisplatin and 
docetaxel followed by surgery [18]. Postoperative radiotherapy was offered to patients with 
involvement of the first mediastinal lymph nodes or with positive resection margins. The overall 
response rate was 66%. With surgery alone the 5-year overall survival in this group of patients is 
9% for T3N1 disease, respectively 13% for T1-3N2 disease [34]. This rate was improved by the 
addition of neoadjuvant chemotherapy with a median overall survival of 35 months and a cure rate 

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(survival without evidence of disease) after 3 years of 36% [23]. Eighty-seven percent of patients 
underwent surgery. Radical resection of the residual tumor was possible in 84%, complete 
resection was possible in 57% of the operated patients. The median duration of remission was 15 
months. Several clinical and pathological assessments (clinical response, pathological response, 
mediastinal down-staging) as well as complete resection were significantly associated with 
improved prognosis.  
The addition of radiotherapy as a third treatment modality to neoadjuvant chemotherapy and 
surgery was investigated in the trial SAKK 16/00 [35]. Patients randomized into the chemotherapy-
alone arm received three cycles of cisplatin/docetaxel whereas patients allocated to the combined 
therapy arm received the same chemotherapy regimen, followed by accelerated concomitant boost 
of 44 Gy in 22 fractions within 3 weeks. There was no difference in local failure, event-free survival 
or OS between the two arms. 
In total, more than 400 patients with stage IIIA NSCLC were treated within the previous SAKK 
trials. Based on the results of these trials, induction chemotherapy with cisplatin and docetaxel for 
three cycles followed by tumor resection is now an accepted standard of care. However, with a 12-
month EFS of 48% only, based on the SAKK experience, the addition of new therapeutic 
approaches is necessary to improve outcomes for patients with advanced, resectable NSCLC. 
2.3 
Cancer immunotherapy 
Cancer immunotherapy is attracting increasing attention following recent outstanding results of 
immunotherapeutic approaches in various metastatic solid tumors [36-38]. Based on these 
promising results and the development of new molecules unleashing the immune system, 
immunotherapy has again raised interest in the treatment of lung cancer after controversial results 
from early clinical immunotherapy trials. 
Immune checkpoint inhibitors have so far only been investigated in advanced/metastatic lung 
cancer and mainly in pre-treated patients. The activity of the antibody against cytotoxic T-
lymphocyte-associated protein (CTLA)-4 ipilimumab (10 mg/kg) in combination with paclitaxel and 
carboplatin was evaluated in a randomized phase II trial in patients with chemotherapy-naïve stage 
IIIB(IV) NSCLC [39]. The immune-related progression free survival (ir-PFS) as primary endpoint 
was significantly prolonged in patients receiving a phased schedule of ipilimumab versus 
chemotherapy alone (median ir-PFS 5.7 vs. 4.6 months, HR 0.72, p=0.05). Combining ipilimumab 
with paclitaxel and carboplatin did not increase overall treatment-related toxicities.  
In a phase I trial the anti-programmed cell death protein (PD)-1 antibody nivolumab was 
administered in monotherapy to patients with various solid tumors, including 129 patients with 
NSCLC [40, 41]. In NSCLC patients, objective responses were observed across doses of 1-10 
mg/kg and in all histological subtypes. With extended treatment, the median response duration for 
the 3 mg/kg dose had not been reached at the time of analysis (range, 16.1+ to 133.9+ weeks). 
The phase II trial CheckMate 063 investigated nivolumab in patients with metastatic squamous cell 
carcinoma of the lung previously treated with two or more lines of palliative chemotherapy [42]. The 
objective response rate was 14.5%, whereas 26% of patients showed disease stabilization. 77% of 
patients with an objective response showed ongoing response at the time of analysis. The median 
duration of response was not reached at the time of data analysis. Median OS in this heavily 
pretreated population was 8.2 months with 40.8% of patients living longer than 12 months. 
CheckMate 017 randomized patients to either second-line chemotherapy with docetaxel or 
nivolumab. Median OS was significantly improved with nivolumab (9.2 vs. 6.0 months, HR 0.59, 
95%CI 0.44-0.79, p=0.00025) [43]. The CheckMate 057 trial asked the same question in patients 
with metastatic lung adenocarcinoma. The trial was recently unblinded based on a planned interim 
analysis showing superiority for the primary endpoint overall survival [44].  
In the KEYNOTE-001 trial 495 stage IV NSCLC patients with programmed cell death ligand (PD-
L)1 expression were randomized between two schedules of the anti-PD-1 antibody pembrolizumab 
(10 mg/kg every two or every three weeks) [45]. The ORR was 19.4%. The median duration of 
response was 12.5 months with a median progression-free survival of 3.7 months and a median 
OS of 12.0 months.  
The first results from the OAK trial, a randomized phase III trial with the anti-PD-L1 inhibitor 
atezolizumab in second-line therapy for NSCLC, have been reported very recently. In this trial, 

 
 
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1225 patients after failure of at least one platinum-based therapy were randomized between 
docetaxel and atezolizumab. OS was improved by 4.2 months with atezolizumab (9.6 vs. 13.8 
months, HR 0.73, p=0.0003) [46].  
2.4 
Novel investigational product  
MEDI4736 is a human monoclonal antibody (mAb) of the immunoglobulin (Ig)G1 kappa subclass 
that inhibits binding of PD-L1 [B7 homolog 1 (B7-H1), cluster of differentiation (CD)274] to PD-1 
[CD279] and B7-1 [CD80] [47]. MEDI4736 is composed of two identical heavy chains and two 
identical light chains, with an overall molecular weight of approximately 149 kDa. MEDI4736 
contains a triple mutation in the constant domain of the IgG1 heavy chain that reduces binding to 
complement protein C1q and the Fcγ receptors involved in triggering effector function [48]. 
PD-1 is an extracellular protein that down-regulates immune responses primarily in peripheral 
tissues through binding to its two ligands PD-L1 and PD-L2. As inhibitory receptor expressed on T 
cells following T-cell activation, PD-1 sustains, at least in part, a T cell dysfunctional state upon 
chronic stimulation such as chronic infection or cancer [49, 50]. Binding of PD-L1 with PD-1 inhibits 
T-cell proliferation, cytokine production, and cytolytic activity, leading to functional inactivation of T 
cells. The latter is commonly referred to as T cell exhaustion. B7.1 is a molecule expressed on 
antigen-presenting cells and activated T cells. In contrast to the interaction of CD28/B7.1, PD-L1 
binding to B7.1 on T cells mediates inhibition of T-cell activation and cytokine production [50, 51]. 
Overexpression of PD-L1 on tumor cells has been reported to impede antitumor immunity, 
resulting in immune evasion [52]. Therefore, interruption of the PD-L1/PD-1 pathway represents an 
attractive strategy to restore tumor-specific T-cell immunity. PD-L1 expression is prevalent in many 
human tumors. PD-L1 expression can be found in up to 50% of patients with NSCLC and is 
associated with a poor prognosis [53]. However, the role of PD-L1 expression has not been clearly 
defined as PD-L1 is not only expressed on tumor cells but also on infiltrating immune cells  
2.4.1 
Preclinical data  
The non-clinical experience is fully described in the current version of the Investigator’s Brochure 
(IB) [47]. 
MEDI4736 antagonizes the inhibitory effect of PD-L1 by blocking PD-L1 binding to PD-1 on human 
T cells. This results in the recovery of T cell effector functions such as cellular proliferation and 
release of interferon (IFN)-γ. In vivo studies showed that MEDI4736 inhibits tumor growth in a 
xenograft model via a T-cell dependent mechanism. Moreover, an anti-mouse PD-L1 antibody lead 
to improved survival in a syngeneic tumor model when given as monotherapy and resulted in 
complete tumor regression in >50% of treated mice when given in combination with chemotherapy. 
2.4.2 
Pharmacokinetics and pharmacodynamics  
Clinical data is fully described in the current version of the IB [47]. 
The pharmacokinetics (PK) and immunogenicity profiles of MEDI4736 as monotherapy are 
described below based on data from key studies. 
As of February 9th 2015, PK data were available for 378 patients in the dose-escalation and dose-
expansion phases of Study CD-ON-MEDI4736-1108 following treatment with MEDI4736 0.1 to 10 
mg/kg every 2 weeks (q2w) or 15 mg/kg every 3 weeks (q3w). The maximum observed 
concentration (Cmax) increased in an approximately dose-proportional manner over the dose range 
of 0.1 to 15 mg/kg. The area under the concentration-time curve from 0 to 14 days (AUC0-14) 
increased in a greater than dose-proportional manner over the dose range of 0.1 to 3 mg/kg and 
increased dose-proportionally at ≥ 3 mg/kg. These results suggest that MEDI4736 exhibits 
nonlinear PK likely due to saturable target-mediated clearance at doses < 3 mg/kg and approaches 
linearity at doses ≥ 3 mg/kg. Near complete target saturation (soluble PD-L1 and membrane 
bound) is expected with MEDI4736 ≥ 3 mg/kg q2w. Exposures after multiple doses showed 
accumulation consistent with the PK parameters estimated from the first dose. In addition, 
simulations indicated that following MEDI4736 10 mg/kg q2w dosing, >90% of patients are 
expected to maintain PK exposure ≥ 40 µg/ml throughout the dosing interval. 

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As of February 9th 2015, a total of 388 patients provided samples for anti-drug antibodies (ADA) 
analysis. Only 8 of 388 patients (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. 
2.4.3 
Safety  
The safety profile of MEDI4736 as monotherapy and combined with other anticancer agents is 
consistent with the pharmacology of the target and other agents in the immune checkpoint inhibitor 
class. No tumor types appeared to be associated with unique AEs. Immune-related AEs, which are 
important risks of immune checkpoint inhibitors, have been observed with MEDI4736 and include 
colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, endocrinopathy, 
dermatitis, and nephritis [47]. These events are manageable by available/established treatment 
guidelines as described in the present protocol.  
Adverse event profile of MEDI4736 monotherapy 
The safety profile of MEDI4736 monotherapy in the 694 patients with advanced solid tumors 
treated at 10 mg/kg q2w in Study CD-ON-MEDI4736-1108 has been broadly consistent with that of 
the overall 1,279 patients who have received MEDI4736 monotherapy (not including patients 
treated with blinded investigational product) across the clinical development program. The majority 
of treatment-related AEs was 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 May 7th 2015, among the 694 patients treated with MEDI4736 10 
mg/kg q2w in this study, a total of 378 patients (54.5%) experienced a treatment-related AE, with 
the most frequent (occurring in ≥ 5% of patients) 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 patients (9.4%). Treatment-related ≥ Grade 3 events reported in 3 or more patients (≥ 0.4%) 
were fatigue (12 patients, 1.7%); increased aspartate aminotransferase (AST; 7 patients, 1.0%); 
increased 
gamma-glutamyltransferase 
(GGT; 
6 
patients, 
0.9%); 
increased 
alanine 
aminotransferase (ALT; 5 patients, 0.7%); and colitis, vomiting, decreased appetite, and 
hyponatremia (3 patients, 0.4% each). Six patients 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 patients were colitis and pneumonitis (3 
patients each). A majority of the treatment-related SAEs were ≥ Grade 3 in severity and resolved 
with or without sequelae. AEs that resulted in permanent discontinuation of MEDI4736 were 
considered as treatment related in 18 patients (2.6%), with colitis being the most frequent 
treatment-related AE resulting in discontinuation (3 patients). A majority of the treatment-related 
AEs resulting in discontinuation of MEDI4736 were ≥ Grade 3 in severity and resolved with or 
without sequelae. 
The safety profile of MEDI4736 monotherapy in Study CD-ON-MEDI4736-1108 is generally 
consistent with that of Study D4191C00003/ATLANTIC in patients with locally advanced or 
metastatic NSCLC treated with MEDI4736 10 mg/kg q2w. As of May 5th 2015, 264 of 303 patients 
(87.1%) reported any AE in this study. Overall, events reported in ≥ 10% of patients 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 patients experienced AEs that were Grade 1 
or 2 in severity and manageable by general treatment guidelines as described in the current 
protocol. Grade 3 or higher AEs were reported in 107 of 303 patients (35.3%). A total of 128 
patients (42.2%) reported AEs that were considered by the investigator as related to MEDI4736. 
Treatment-related AEs (all grades) reported in ≥ 2% of patients 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 patients were pneumonitis (3 patients) and 
increased GGT (2 patients). There was no treatment-related Grade 4 or 5 AEs. Ninety-four of 303 
patients (31.0%) reported any SAE. SAEs that occurred in ≥ 1.0% of patients 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 

 
 
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progression (1.0% each). Nine patients had an SAE considered by the investigator as related to 
MEDI4736. Each treatment-related SAE occurred in 1 subject each with the exception of 
pneumonitis, which occurred in 3 patients. Fifteen of 303 patients (5.0%) have died due to an AE 
(pneumonia (3 patients); general physical health deterioration, disease progression, hemoptysis, 
dyspnea (2 patients each); pulmonary sepsis, respiratory distress, cardiopulmonary arrest 
[verbatim term (VT)], hepatic failure, and sepsis (1 subject each). None of these events was 
considered related to MEDI4736. Twenty-three of 303 patients (7.6%) permanently discontinued 
MEDI4736 treatment due to AEs. Events that led to discontinuation of MEDI4736 in ≥ 2 patients 
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. 
2.4.4 
Clinical data  
As of the data cut-off dates (15 April 2015 to 12 July 2015), a total of 1’883 patients have been 
enrolled and treated in 30 ongoing clinical studies with MEDI4736, including 20 sponsored (Table 
2) and 10 collaborative studies. Of the 1’883 patients, 1’279 received MEDI4736 monotherapy, 440 
received MEDI4736 in combination with tremelimumab or other anticancer drugs. Fourteen 
received other agents (gefitinib, MEDI6383), and 150 have been treated with blinded 
investigational product. No studies have been completed so far nor has one of the trials been 
terminated prematurely due to toxicity.  
Table 2. Overview of ongoing sponsored clinical trials with MEDI4736, as of July 2015. A comprehensive list 
on ongoing sponsored and collaborative MEDI4736 studies can be found in the current version of the IB. 
Study Number  
Phase 
Study Population 
Treatment Regimen 
Patients 
Treated 
Sponsored MEDI4736 Monotherapy Studies (N=1’149) 
CD-ON-MEDI4736-1108 
(NCT01693562) 
I/II 
Advanced solid tumors 
MEDI4736 q2w or q3w 
736 
D4190C00002 
(NCT01938612) 
I 
Advanced solid tumors 
(Japan) 
MEDI4736 q2w or q3w 
70 
D4190C00007 
(NCT02117219) 
I 
MDS 
MEDI4736 q2w 
32 
D4193C00001 (HAWK) 
(NCT02207530) 
II 
Recurrent/metastatic PD-
L1+ SCCHN 
MEDI4736 q2w 
8 
D4190C00003 (ATLANTIC) 
(NCT02087423) 
II 
Locally 
advanced/metastatic PD-
L1+ NSCLC (stage IIIB/IV) 
MEDI4736 q2w 
303 
D4190C00001 (PACIFIC) 
(NCT02125461) 
III 
Locally advanced, 
unresectable NSCLC 
(stage III) 
MEDI4736 q2w or 
placebo 
115 1 
 
Sponsored MEDI4736 Combination or Sequential Therapy Studies (N=350) 
D-ON-MEDI4736-1161 
(NCT02027961) 
I 
Metastatic or unresectable 
melanoma 
MEDI4736 q2w + 
trametinib ± dabrafenib 
65 
D791PC00001 
(NCT02088112) 
I 
Locally 
advanced/metastatic 
NSCLC 
MEDI4736 q2w + 
gefitinib 
33 2 
D6020C00001 
(NCT02118337) 
I 
Advanced malignancies 
MEDI4736 q2w + 
MEDI0680 (AMP-514) 
q2w or q4w 
21 
D4880C00010 
(NCT02141347) 
I 
Advanced solid 
malignancies (Japan) 
MEDI4736 q2w + 
Tremelimumab 
10 
D4190C00010 
(NCT02261220) 
I 
Advanced solid tumors 
MEDI4736 q2w + 
Tremelimumab 
51 
D4190C00011 
(NCT02262741) 
I 
Recurrent/metastatic 
SCCHN 
MEDI4736 q2w + 
Tremelimumab 
13 
D6050C00001 
(NCT02221960) 
I 
Advanced solid tumors 
MEDI6383 alone and in 
combination With 
MEDI4736 
13 3 

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D4190C00006 
(NCT02000947) 
IB 
Advanced NSCLC 
MEDI4736 q2w + 
Tremelimumab 
102 
D5160C00006 (TATTON) 
(NCT02143466) 
IB 
EGFRm+ advanced 
NSCLC 
AZD9291 in combination 
with MEDI4736 
23 
D4190C00021 
(NCT02340975) 
IB/II 
Metastatic/recurrent gastric 
or GEJ adenocarcinoma 
MEDI4736 with 
Tremelimumab, 
MEDI4736 or 
Tremelimumab 
monotherapy 
1 
D4981C00001 
(NCT02205333) 
IB/II 
Advanced solid tumors or 
aggressive B-cell 
lymphomas 
MEDI6469 in 
combination with 
MEDI4736 
13 
D4193C00003 (CONDOR) 
(NCT02319044) 
II 
Recurrent/metastatic PD-
L1- SCCHN 
MEDI4736 monotherapy, 
tremelimumab 
monotherapy, and 
MEDI4736 + 
tremelimumab 
combination therapy 
8 1 
D4191C00011 
(NCT02179671) 
IIA 
Locally 
advanced/metastatic 
NSCLC 
Selected small molecules 
(Gefitinib, AZD9291, or 
Selumetinib + Docetaxel) 
or a 1st immune-
mediated therapy 
(Tremelimumab) with a 
sequential switch to a 
2nd immune-mediate 
therapy (MEDI4736) 
19 
D4191C00004 (ARCTIC) 
(NCT02352948) 
III 
Locally 
advanced/metastatic 
NSCLC (stage IIIB-IV) 
MEDI4736, given as 
monotherapy or in 
combination with 
Tremelimumab 
determined by PD-L1 
expression versus 
standard of care 
27 1 
MDS: myelodysplastic syndrome; q2w: every 2 weeks; q3w: every 3 weeks; q4w: every 4 weeks; CRT: chemo-
radiotherapy. 
1 patients received blinded investigational product 
2 one of the 33 patients received gefitinib only 
3 all 13 patients received MEDI6383 monotherapy 
Partial efficacy data are available for two monotherapy trials (CD-ON-MEDI4736-1108 and 
D4190C00007) and two combination therapy studies (CD-ONMEDI47361161 and D4190C00006). 
Clinical activity has been observed in all four studies.  
Study CD-ON-MEDI4736-1108 
Overall, 456 of 694 patients treated with MEDI4736 10 mg/kg q2w were evaluable for response 
(defined as having ≥ 24 weeks follow-up, measurable disease at baseline, and ≥ 1 follow-up scan, 
or discontinued due to disease progression or death without any follow-up scan) In PD-L1 
unselected patients, the objective response rate (ORR), based on investigator assessment per 
RECIST v1.1, ranged from 0% in uveal melanoma (n=23) to 20% in bladder cancer (n=15), and 
disease control rate at 24 weeks 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 patients. 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, disease control rate at 24 weeks was highest in advanced 
cutaneous melanoma (n=3; 66.7%), NSCLC (n=86; 36%), HCC and bladder cancer (n=3 each; 
33.3% each), and SCCHN (n=22; 18.2%). 
Study D4190C00007 
Of the 32 patients with myelodysplastic syndrome (MDS) treated in this trial, 21 patients had at 
least 1 post-baseline disease assessment. Among these patients, the best overall responses were 

 
 
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marrow complete remission in 4 patients (19%); stable disease in 4 patients (19%); and 
progressive disease in 5 patients (23.8%). The remaining 8 patients (38.1%) did not meet the 
criteria for complete remission, marrow complete remission, partial remission, stable disease, or 
progressive disease at the date of assessment. 
Study CD-ON-MEDI4736-1161 
Of the 65 patients with metastatic or unresectable melanoma treated with the combination of 
MEDI4736 and BRAF inhibitor (BRAFi; dabrafenib)/MEK inhibitor (MEKi; trametinib), 63 patients 
were evaluable for response. A total of 35 patients (55.6%) had a best overall response of 
confirmed or unconfirmed PR The disease control rate (CR + PR + SD ≥ 12 weeks) was 79.4%. 
Study D4190C00006 
This study is a multicenter, non-randomized, open-label, phase Ib study enrolling immunotherapy-
naïve patients with metastatic NSCLC [54]. Patients were treated with MEDI4736 in doses of 3 
mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg every 4 weeks, or 10 mg/kg every 2 weeks, and 
tremelimumab in doses of 1 mg/kg, 3 mg/kg, or 10 mg/kg every 4 weeks for six doses then every 
12 weeks for three doses. Between Oct 28, 2013, and Apr 1, 2015, 102 patients were enrolled into 
the dose-escalation phase and received treatment. The maximum tolerated dose was exceeded in 
the cohort receiving MEDI4736 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg, with two 
(30%) of six patients having a dose-limiting toxicity (one G3 increased aspartate aminotransferase 
and alanine aminotransferase and one G4 increased lipase). The most frequent treatment-related 
G3 and G4 AEs were diarrhea (eleven [11%]), colitis (nine [9%]), and increased lipase (eight [8%]). 
Discontinuations attributable to treatment-related AEs occurred in 29 (28%) of 102 patients. 
Treatment-related serious AEs occurred in 37 (36%) of 102 patients. 22 patients died during the 
study, and three deaths were related to treatment. The treatment-related deaths were due to 
complications arising from myasthenia gravis (MEDI4736 10 mg/kg every 4 weeks plus 
tremelimumab 1 mg/kg), pericardial effusion (MEDI4736 20 mg/kg every 4 weeks plus 
tremelimumab 1 mg/kg), and neuromuscular disorder (MEDI4736 20 mg/kg every 4 weeks plus 
tremelimumab 3 mg/kg). Evidence of clinical activity was noted both in patients with PD-L1-positive 
tumors and in those with PD-L1-negative tumors. Investigator-reported confirmed objective 
responses were achieved by six (23%, 95% CI 9-44) of 26 patients in the combined tremelimumab 
1 mg/kg cohort, comprising two (22%, 95% CI 3-60) of nine patients with PD-L1-positive tumors 
and four (29%, 95% CI 8-58) of 14 patients with PD-L1-negative tumors, including those with no 
PD-L1 staining (four [40%, 95% CI 12-74] of ten patients).  
Study D5160C00006 (TATTON) 
TATTON is a trial investigating the combination of MEDI4736 with the third generation EGFR 
tyrosine kinase inhibitor osimertinib in EGFR mutation-positive NSCLC [55]. In this phase I trial, 
patients received osimertinib 80 mg QD plus MEDI4732 3 mg/kg bi-weekly or osimertinib 80 mg 
QD plus MEDI4736 10 mg/kg bi-weekly. The latter dose was chosen for the dose expansion 
cohort. The trial was halted after an increase in interstitial lung disease (ILD) has been reported 
with the combinatioin of osimertinib and MEDI4736 compared to what would be expected with 
either drug alone. ILD was reported in 13 out of 34 patients (38%). Five events were G3/4. In 
patients with prior EGFR-tyrosine kinase inhibitor therapy, investigator-assessed ORR was 67% 
(6/9) and 21% (3/14) in those with T790M positive and T790M negative NSCLC, respectively, and 
70% (7/10) in EGFRm treatment-naïve patients. 
2.4.5 
Potential biomarkers 
This trial provides the unique opportunity for a comprehensive translational research program 
through the collection of tumor tissue from treatment-naïve patients, tumor resection specimens 
after neoadjuvant therapy and re-biopsies at the time of tumor progression during immunotherapy. 
There are conflicting results concerning the predictive value of PD-L1 expression for anti-PD-L1 
antibody therapy. Emerging data suggest that patients whose tumors show PD-L1 expression by 
immunohistochemistry derive more benefit from anti-PD-L1 directed treatment, but the presence of 
tumor responses in patients with low levels or even lack of expression of PD-L1 challenge the role 
of PD-L1 expression as an exclusionary predictive marker [56].  

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Another recently published study showed that the number of somatic mutations and candidate 
neoantigens generated from these mutations may predict response to immune checkpoint 
inhibition in malignant melanoma [57]. 
A recent study showed that higher non-synonymous mutation burden in tumors was associated 
with improved objective response, durable clinical benefit, and progression-free survival in two 
independent cohorts [58]. Furthermore, smoking history, higher neoantigen burden, and DNA 
repair pathway mutations also correlated with efficacy of immune checkpoint inhibition [58]. 
However, these factors were also associated with mutation burden. Smoking status has been 
shown to correlate with response rate to anti-PD-L1 therapy in a variety of clinical trials [59, 60].  
2.4.6 
Microbiome 
The gut microbiota plays an important role in shaping systemic immune resonses [61-63]. In the 
cancer context, a role for intestinal microbiota in mediating immune activation in response to 
chemotherapeutic agents has been demonstrated [64, 65]. Sivan et al. were among the first to 
show the impact of intestinal microbiota on response to immune checkpoint inhibitors [66]. They 
compared melanoma growth in mice harboring distinct commensal microbiota and observed 
differences in spontaneous antitumor immunity, which were eliminated upon cohousing or after 
fecal transfer. Sequencing of the 16S ribosomal RNA identified Bifidobacterium as associated with 
the antitumor effects. In their study, oral administration of Bifidobacterium alone improved tumor 
control to the same degree as PD-L1-specific antibody therapy, and combination treatment nearly 
abolished tumor outgrowth. Moreover, a study by Vétizou et al. confirmed the hypothesis that 
manipulating the microbiota might modulate cancer immunotherapy [67]. In their study they were 
able to show that antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In 
mice and patients, T cell responses specific for Bacteroides thetaiotaomicron or Bacteroides 
fragilis were associated with the efficacy of CTLA-4 blockade. 
2.5 
Rationale for performing the trial 
Despite multimodal therapy, the cure rate of patients with stage IIIA NSCLC is poor and therapy 
outcome failed to improve during the past years. The addition of immunotherapy with MEDI4736 as 
a novel treatment modality has the potential to improve the outcome without adding substantial 
toxicity to an otherwise intensive multimodality treatment, as MEDI4736 has been generally well 
tolerated. Based on the above mentioned evidence on immune checkpoint inhibition, there is a 
strong rationale to test this novel treatment modality also in the curative setting in order to improve 
local tumor control and prevent distant metastasis to improve the cure rate in this patient 
population. 
A few other trials explore the role of immune checkpoint control in a curative setting. The PEARLS 
trial is a randomized phase III trial investigating adjuvant pembrolizumab in completely resected 
NSCLC patients with stage I-IIIA disease. The PACIFIC trial (NCT02125461) is a randomized 
phase III trial comparing consolidation therapy with MEDI4736 to placebo after definitive combined 
radio-chemotherapy. In contrast to these ongoing trials evaluating immunotherapy protocols in 
adjuvant settings, our trial will explore the addition of immune checkpoint inhibition already in the 
neoadjuvant setting. 
To the best of our knowledge, our current trial is among one of the first trials worldwide 
investigating the therapeutic efficacy of PD1/PD-L1 inhibition before tumor resection and thus is at 
the forefront of the development of innovative approaches for the treatment of locally advanced 
NSCLC. 
Rationale for neoadjuvant immune checkpoint inhibition 
As immune checkpoint inhibition with the anti-PD-L1 antibody MEDI4736 induces an antitumor 
immune response in metastatic patients, the use of this approach prior surgical resection of the 
tumor is justified. The tumor is probably inducing and maintaining the host immune response by its 
immunogenicity. Furthermore, it is expected that neoadjuvant chemotherapy will increase tumor 
immunogenicity through increased antigen release due to tumor cell destruction.  
We opted to administer two cycles of neoadjuvant MEDI4736. On one hand, this allows for surgical 
resection, which is an established standard procedure after induction chemotherapy, at an early 

 
 
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time point. On the other hand, it is known from trials in palliative setting that more than half of the 
patients showing an objective response to immune checkpoint inhibition have already a reduction 
in tumor size at the first radiographic re-evaluation. Moreover, neoadjuvant administration of 
MEDI4736 gives a unique opportunity to evaluate the mechanisms of immune response and 
induction of antitumor immunity in the resected tumor tissue. Hence, the trial also includes a vast 
array of translational research questions.  
The addition of 2 cycles of neoadjuvant immunotherapy after neoadjuvant chemotherapy delays 
surgical resection. However, it is well known that patients showing progressive disease very shortly 
after the end of chemotherapy have a dismal prognosis that cannot be improved by surgery. 
Rationale for adjuvant immune checkpoint inhibition 
It is hypothesized from preclinical data that immunotherapy may work best in the situation of 
minimal residual disease. The adjuvant setting is therefore the ideal clinical scenario to test the 
exact place of immunotherapy with immune checkpoint inhibitors to improve the cure rate of lung 
cancer patients after surgery. A role for immune checkpoint inhibition in adjuvant setting was 
recently demonstrated for melanoma. In the EORTC 18071 trial, adjuvant therapy with the CTLA-4 
antibody ipilimumab significantly improved recurrence-free survival in stage III malignant 
melanoma [68]. The randomized US intergroup phase III trial (E1609) is currently investigating 
standard high-dose interferon alfa-2b vs. ipilimumab in stage III-IV melanoma after surgical 
resection. In the palliative setting these agents are usually given for up to one or two years and 
have demonstrated long lasting disease control. We therefore decided for treatment duration of 
one year after tumor resection. 
Rationale for fixed dose of MEDI4736 
A population PK model was developed for MEDI4736 using monotherapy data from a Phase I 
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 on PK of MEDI4736 (coefficient of ≤ 0.5). 
The impact of body weight-based (10 mg/kg q2w) and fixed dosing (750 mg q2w) of MEDI4736 
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 weight of ~75 kg). A total of 1000 patients were simulated using 
body weight distribution of 40–120 kg. Simulation results demonstrate that body weight-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 I 
through Phase III (N=654; doses= 0.01 to 15 mg/kg q4w or q90d; metastatic melanoma) [69]. 
Population PK model indicated minor impact of body weight on PK of tremelimumab (coefficient of 
≤ 0.5). The weight-based (1 mg/kg Q4W) and fixed dosing (75 mg/kg q4w; based on median body 
weight 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 MEDI4736, simulations indicated that both body 
weight-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 [70-73]. 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 [71]. 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 [72].  
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 use fixed dosing regimens. Based on average body weight of 75 kg, a 
fixed dose of 750 mg q2w MEDI4736 (equivalent to 10 mg/kg q2w) is included in the current study. 
 
 

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2.6 
Choice of design 
Rationale for single arm phase II design 
Immune checkpoint inhibition with anti-PD-L1 antibodies is a novel treatment approach. So far, the 
only published data were generated from phase I and single-arm phase II trials in other indications 
than lung cancer. Our trial is to our knowledge the first study investigating the neoadjuvant use of 
an immune checkpoint inhibitor in locally advanced NSCLC. As the Lung Cancer Project Group of 
the SAKK has a long standing interest in stage IIIA(N2) disease, robust historical data from 
previous trial exist and will serve as comparator for the current trial. Furthermore, the trial selects 
the same patient population (same inclusion and exclusion criteria) and the same chemotherapy 
backbone. That will give us the opportunity to put the results of the present trial into clinical 
perspective. 
2.7 
Choice of trial population 
We will include patients with stage IIIA(N2) disease as most of these patients are amenable for 
curative resection and still in need of more efficacious therapeutic options. 
Patients will not be selected based on histological subtype or genomic aberrations as these 
parameters do currently not influence treatment choice in the advanced disease setting. 
Patients will also not be pre-screened for PD-L1 expression since the predictive role of PD-L1 
expression in the tumor tissue is still unclear and should not guide treatment decisions for immune 
checkpoint inhibition. Furthermore, the use of PD-L1 expression status by immunohistochemistry 
as a predictive biomarker is currently still cofounded by multiple unresolved issues: variable 
detection antibodies, differing cut-off values in immunohistochemistry, tissue preparation, 
processing variability, primary versus metastatic biopsies, oncogenic versus induced PD-L1 
expression, and staining of tumor versus tumor-infiltrating immune cells. 
 

 
 
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3 
OBJECTIVES AND ENDPOINTS 
3.1 
Objective 
The objective of the trial is to demonstrate that the addition of neoadjuvant and adjuvant 
immunotherapy (with the anti-PD-L1 antibody MEDI4736) to standard neoadjuvant chemotherapy 
(with cisplatin/docetaxel) in primary resectable stage IIIA(N2) NSCLC is efficacious and feasible. 
3.2 
Endpoints 
For definition of endpoints see section 13. 
3.2.1 
Primary endpoint  
The primary endpoint of the trial is: 
• 
Event-free survival (EFS) at 12 months 
3.2.2 
Secondary endpoints  
Secondary endpoints of the trial are: 
• 
EFS 
• 
Overall survival (OS) 
• 
Objective response (OR) after neoadjuvant chemotherapy 
• 
OR after neoadjuvant immunotherapy 
• 
Pathological complete response (pCR) 
• 
Major pathological response (10% or less residual viable tumor) 
• 
Rate of nodal down-staging to < ypN2 
• 
Complete resection  
• 
Pattern of recurrence (local, loco-regional, distant) 
• 
Adverse events (AEs)  
• 
Postoperative 30-day mortality 
3.3 
Additional research questions 
• 
Comparison of the tumor immunome before (treatment-naïve) and after neoadjuvant chemo- 
and immunotherapy.  
• 
Investigation of efficacy outcome parameters (EFS, OR, OS) in relation to tissue expression of 
PD-L1 (tumor and immune cells). 
• 
Investigation of biomarkers for anti-PD-L1 treatment and their relation to efficacy endpoints of 
interest (EFS, OS and OR after neoadjuvant immunotherapy) in NSCLC. Historical control 
samples from previous SAKK trials will be used. 
• 
Investigation of the effect of the gut microbiota on the response to immunotherapy (optional). 
 
 

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4 
TRIAL DESIGN 
Multicenter, single-arm, phase II trial  
 
 
Please refer to sections 9 and 10 of this protocol for details on the treatment schedule and for 
instructions on treatment delays or premature discontinuation. 
5 
TRIAL DURATION AND TERMINATION 
The inclusion of patients is planned to start in Q1 2016 and will stop after the inclusion of 68 
patients, which is expected in Q1 2019. End of trial treatment is expected for Q3 2020. 
All patients will have a lifelong follow-up. The trial team reserves the right to evaluate if the follow-
up period can be stopped earlier.  
The trial may be stopped prematurely based on the results of an interim safety analysis (see 
section 15). In addition, accrual may be interrupted and/or the trial may be stopped early if new 
scientific data become available which substantially change the benefit/risk ratio. Decision on 
premature termination will be made by the SAKK Board. 
 
 
 

 
 
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6 
SELECTION OF PATIENTS 
For timelines see section 12. 
6.1 
Inclusion criteria 
To be eligible to enter this trial, patients must fulfill the following criteria. 
6.1.1 
Written informed consent according to ICH-GCP regulations before patient registration 
and any protocol-related procedures. 
6.1.2 
Pathologically proven NSCLC (adeno-, squamous-, large cell carcinoma or NSCLC not 
otherwise specified) irrespective of genomic aberrations or PD-L1 expression status. 
6.1.3 
Tumor tissue is available for the mandatory translational research (preferably histology, 
cytology allowed). 
6.1.4 
Tumor stage T1-3N2M0 (stage IIIA(N2) according to the TNM classification, 7th edition, 
October 2009 (see Appendix 2). Mediastinal lymph node staging has to follow the process 
chart depicted in Appendix 6. 
6.1.5 
Tumor is considered resectable based on a multidisciplinary tumor board decision made 
before neoadjuvant treatment. Resectable is when a complete resection can be achieved 
according to Rami-Porta [74]. 
6.1.6 
Measurable disease according to RECIST 1.1 criteria (non-nodal lesions ≥10 mm in 
longest diameter, lymph nodes ≥15 mm in short axis) by PET/CT with contrast enhanced 
CT-scan. 
6.1.7 
WHO performance status 0-1 (see Appendix 4). 
6.1.8 
Age 18-75 years at time of registration. 
6.1.9 
Appropriate lung function based on the ESTS guidelines (see Appendix 7) [75]: 
o For pneumonectomy: FEV1 and DLCO ≥80%. If one of both <80%, an exercise test 
peak VO2 >75% or 20ml/kg/min is needed, 
o For resection less than pneumonectomy (resection up to the calculated extent): 
exercise test peak VO2 ≥35% or ≥10ml/kg/min, with predicted postoperative FEV1 
and DLCO ≥ 30%. 
6.1.10 
Adequate hematological values: hemoglobin ≥ 90 g/L, absolute neutrophils count 
≥ 1.5 x 109/L, platelets count ≥ 100 x 109/L. 
6.1.11 
Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT ≤ 1.5 x ULN, AP ≤ 2.5 x ULN. 
6.1.12 
Adequate renal function: calculated creatinine clearance ≥ 60 mL/min, according to the 
formula of Cockcroft-Gault (see Appendix 3). 
6.1.13 
Women with child-bearing potential are using effective contraception (double method, see 
9.8) are not pregnant or lactating and agree not to become pregnant during participation in 
the trial and during 90 days after the last treatment. A negative serum pregnancy test 
performed within 7 days before registration into the trial is required for all women with 
child-bearing potential. Men agree not to father a child during participation in the trial and 
during 90 days after the last treatment.  
6.1.14 
Patient 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. 
6.2 
Exclusion  criteria 
Any potential patient who meets any of the following criteria has to be excluded from entering the 
trial. 
6.2.1 
Presence of any distant metastasis or N3 disease. Brain metastases have to be excluded 
by CT or MRI. 
6.2.2 
Sulcus superior tumors (Pancoast tumors). 

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6.2.3 
Previous or concomitant malignancy within 5 years prior registration with the exception of 
adequately treated localized non-melanoma skin cancer or cervical carcinoma in situ. 
6.2.4 
Any previous treatment for NSCLC. 
6.2.5 
Any previous treatment with a PD-1 or PD-L1 inhibitor, including MEDI4736. 
6.2.6 
Previous radiotherapy to the chest. 
6.2.7 
Absolute contraindications for the use of corticosteroids as premedication.  
6.2.8 
Concurrent treatment with other experimental drugs or other anticancer therapy, treatment 
in a clinical trial within 30 days prior to registration. 
6.2.9 
Current or prior use of immunosuppressive medication within 28 days before the first dose 
of MEDI4736, with the exceptions of intranasal and inhaled corticosteroids or systemic 
corticosteroids at physiological doses (i.e. which must not exceed 10 mg/day of 
prednisone or an equivalent corticosteroid) and the premedication for chemotherapy.  
6.2.10 
Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure NYHA 
III or IV (see Appendix 5), unstable angina pectoris even if medically controlled, history of 
myocardial infarction during the last 3 months, serious arrhythmias requiring medication 
(with exception of atrial fibrillation or paroxysmal supraventricular tachycardia). 
6.2.11 
Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 ECGs using 
Bazett’s Correction. 
6.2.12 
Preexisting peripheral neuropathy (> Grade 1). 
6.2.13 
Body weight less than 30 kg.  
6.2.14 
Active autoimmune disease requiring systemic treatment within the past 3 months or a 
documented history of clinically severe autoimmune disease or a syndrome that requires 
systemic steroids or immunosuppressive agents.  
Exceptions:  Vitiligo or resolved childhood asthma/atopy  
 
Hypothyroidism stable on hormone replacement or Sjorgen’s syndrome  
6.2.15 
Active or prior documented inflammatory bowel disease (e.g. Crohn’s disease, ulcerative 
colitis). 
6.2.16 
Known evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency 
virus (HIV) infection.  
6.2.17 
History of primary immunodeficiency. 
6.2.18 
History of allogeneic organ transplant. 
6.2.19 
Known history of previous clinical diagnosis of tuberculosis. 
6.2.20 
Receipt of live attenuated vaccination any time during trial therapy with MEDI4736 and 
within 30 days of receiving the last dose of MEDI4736. 
6.2.21 
Any concomitant drugs contraindicated for use with MEDI4736: this includes systemic 
corticosteroids (exceptions see 6.2.9), methotrexate, azathioprine, and tumor necrosis 
factor (TNF)-α blockers. Any concomitant drugs contraindicated for use with the other trial 
drugs according to the locally approved product information. 
6.2.22 
Known hypersensitivity to trial drugs (cisplatin and docetaxel), to the IMP or to any 
excipient. 
6.2.23 
Any other serious underlying medical (e.g. uncontrolled diabetes mellitus, active 
uncontrolled infection, active gastric ulcer, uncontrolled seizures, severe hearing 
impairment), psychiatric, psychological, familial or geographical condition  that, in the 
judgment of the investigator, may interfere with the planned staging, treatment and follow-
up, affect patient compliance or place the patient at high risk from treatment-related 
complications. 
  

 
 
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7 
REGISTRATION 
7.1 
Pre-registration procedure 
Prior to registration, the following steps have to be performed: 
• 
Fill in the patient screening and enrollment list, 
• 
Check the eligibility criteria, 
• 
Check the availability of tumor tissue (preferably histology, cytology allowed) for the 
retrospective central pathology review (refer to section 17 for further information), 
• 
Check resectability based on a multidisciplinary tumor board decision, 
• 
Obtain written informed consent from the patient prior to any protocol-specific procedure  
- 
Main PIS/IC, mandatory for trial participation  
(consent for the mandatory translational research and for the optional research 
question with stool is incorporated in the main PIS/IC) 
- 
PIS/IC biobank, optional for trial participation, 
• 
Baseline blood for the mandatory translational research can be collected from 14 days prior 
to registration until the first day of trial treatment (prior to the administration of the first 
treatment dose), at the latest; samples have to be shipped immediately upon collection 
(refer to section 18 for details). 
• 
Baseline stool for the optional translational research can be collected from 14 days prior to 
registration until the first day of trial treatment (prior to the administration of the first 
treatment dose), at the latest.  
If applicable, instruct the patient and dispense the stool collection kit (refer to section 18 for 
details).  
7.2 
Registration procedure 
Registration is done via Internet (www.sakk.ch/edc). 
Only if this is not possible due to technical problems, e.g. unavailability of the web-based electronic 
data capture (EDC) system: by faxing the completed, dated and signed paper version of the 
eligibility (“form E”) case report form (CRF) to the SAKK CC. 
Fax +41 31 508 41 42 
(Opening hours: Monday to Friday 8:00 a.m. to 5:00 p.m.) 
In order to receive authorization for online registration and data entry, sites must send a copy of 
the completed staff list (available on the SAKK website) to the SAKK CC. Login details for the EDC 
system will be sent to authorized persons within 2 working days.  
The SAKK CC will be closed on the following days: 
 
1st January 
1st August (National holiday)* 
 
2nd January 
4th Monday of November, from 3:00 pm 
 
Good Friday (Friday before Easter)* 
24th December (from 12:00 noon) 
 
Easter Monday 
25th December  
 
Ascension Thursday* 
26th December  
 
Whit Monday (Pentecost) 
31st December (from 12:00 noon) 
 
* The SAKK CC will close at 4:00 pm on weekdays before these holidays. 
 
 

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7.3 
After registration 
• 
Report the medical history, baseline clinical and laboratory information, tumor location and 
baseline symptoms in the electronic (e)CRFs,  
• 
Update the screening and enrollment list, 
• 
Fill in the patient identification list, 
• 
Tumor samples must be sent to Central Pathology for review at the latest 30 days after 
registration (refer to section 17 for further details). 
• 
Ensure that blood (and stool from consenting patients) has been or will be shipped to the 
research laboratory (refer to section 18). 
The printout of the eCRF form (“form ER”), dated and signed by the treating investigator 
(authorized physician according to the staff list), has to be sent to the SAKK CC by email or fax 
within one month after registration. 
Trial therapy should be started within 7 days from registration. 
 
 
 

 
 
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8 
DRUG SUPPLY AND HANDLING  
8.1 
Drugs in protocol 
8.1.1 
Investigational medicinal product (IMP) 
For this trial MEDI4736 (durvalumab) is the IMP.  
MEDI4736 is a human mAb of the IgG1 kappa subclass directed against PD-L1. It contains a triple 
mutation in the constant domain of the IgG1 heavy chain that reduces binding to C1q and Fcγ 
receptor. 
MEDI4736 is an investigational product which is not approved for any indication in any country. 
8.1.2 
Other drugs for anticancer treatment 
Cisplatin and docetaxel are approved in Switzerland, in Europe and in the USA for the treatment of 
NSCLC and are not investigational drugs in the context of this trial. Cisplatin and docetaxel will be 
given pre-operatively and prior to MEDI4736 as standard backbone treatment according to their 
Swissmedic-approved indication, the applicable safety precautions and the Swiss law. 
For both drugs, generic products do exist and may be used.  
8.2 
Drug supply and handling of MEDI4736 
8.2.1 
Drug supply 
MEDI4736 
will 
be 
supplied 
by 
the 
Investigational 
Products 
Supply 
section 
of 
AstraZeneca/MedImmune as a concentrate solution for infusion and provided free of charge by 
SAKK to all study sites. The distribution will be managed by an authorized pre-wholesaler located 
in Switzerland. 
Instructions on ordering and shipment, and a drug order form are provided in separate documents 
which can be downloaded from the SAKK website (www.sakk.ch  Members  Trials  Lung 
Cancer  SAKK 16/14  Useful tools  IMP). 
8.2.2 
Handling and safety of MEDI4736 
Refer to the current version of the IB for the handling and safety of the IMP [47]. 
MEDI4736 is formulated at a concentration of 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM 
trehalose dihydrate, 0.02% [weight/volume] polysorbate 80, pH 6.0. The investigational product is 
supplied as a vialed liquid solution in clear 10R glass vials closed with an elastomeric stopper and 
a flip-off cap overseal.  
Each vial contains 500 mg (nominal) of active investigational product at a concentration of 50 
mg/mL (500 mg/vial).  
Unopened vials of liquid MEDI4736 must be stored at 2°C to 8°C.  MEDI4736 must be used within 
the individually assigned expiry date noted on the label. Vials must be used for specific subjects 
and must not be shared between patients.  
The handling of open vials and the in-use storage and stability are described in section 9.3.2. 
8.2.3 
Labeling of MEDI4736 
The IMP will be labeled in English. The following information will be indicated on the label: 
SAKK 16/14 
MEDI4736 500 mg in 10 mL (50 mg/mL); for infusion; Store at 2°C to 8°C  
For use in clinical trial only / Free of charge  
Batch Number 
Expiry date 
Name of site: _____________________ 
Name of principal investigator: _______________________ 
UPN: 16/14_ ____________________ 

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Dispensing date: _____________________ 
SAKK - Swiss Group for Clinical Cancer Research, Effingerstrasse 33, CH - 3008 Bern, 
Phone: +41 31 3899191 
8.2.4 
Dispensing and accountability of MEDI4736 
The unique patient number (UPN), as well as the names of the site and principal investigator, must 
be written on the label of the bottle as soon as MEDI4736 is dispensed. 
Trained personnel should prepare infusion bags under aseptic conditions. The solution will be 
diluted with 0.9% [weight/volume] saline for i.v. infusion, according to the instructions provided in 
section 9.3.2. 
Please ensure the use of the drug inventory log (available on www.sakk.ch  Members  Trials 
 Lung Cancer  SAKK 16/14  Useful tools  IMP), which must be kept up-to-date and identify 
the receipt and dispensing of the drug (including date, amount, batch number, UPN).  
8.2.5 
Unused MEDI4736 
Unused, partly unused or expired trial medication will be destroyed at the site according to local 
guidelines.  
The destruction of unused or expired medication should take place at the conclusion of the trial, 
upon approval by the Clinical Research Associate (CRA) and is to be documented on the drug 
inventory log and additionally, in the trial-specific IMP destruction certificate (provided by SAKK 
and available on the SAKK website). 
8.3 
Drug supply and handling of cisplatin and docetaxel  
8.3.1 
Drug supply 
Cisplatin and docetaxel are applied within their approved indication and will thus be prescribed and 
purchased according to the routine procedures of the participating sites. 
8.3.2 
Handling and safety of cisplatin and docetaxel 
Both drugs will be administered as a background medication, according to the approved dose and 
schedule for NSCLC, following the locally established clinical routine and national as well as 
international treatment guidelines [18, 35, 76]. 
For handling and safety of cisplatin and docetaxel, please refer to the respective product 
information (which can be downloaded from www.swissmedicinfo.ch). National guidelines on 
handling of cytostatic drugs have to be considered (e.g. in Switzerland: [77]).  
8.4 
Product quality complaint handling 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, packaging, shipment and storage (e.g. wrong storage condition during 
transport). A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, 
and complete reporting and analysis of PQC information from clinical trials are crucial for the 
protection of patients, investigators and the sponsor, and are mandated by regulatory agencies 
worldwide. 
8.4.1 
Procedures 
In case site staff identifies a potential product complaint situation, the product is placed in 
quarantine and SAKK CC must be contacted immediately.  
PQCs must be forwarded within 24 hours to the SAKK CC (form available on www.sakk.ch  
Members  Trials  Lung Cancer  SAKK 16/14). If the defect is combined with a SAE/SAR, the 
site staff must additionally report the event to SAKK CC according to the reporting timelines for 
SAEs (see section 11). SAKK CC will inform the site how to proceed with the suspected product.  

 
 
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9 
TRIAL TREATMENT 
9.1 
Treatment overview 
• 
Neoadjuvant chemotherapy with cisplatin and docetaxel: 3 cycles of 21 days 
o Cisplatin 
100 mg/m2  
d1 
(corresponds to day 1, 22, 43 / week 1, 4, 7) 
o Docetaxel 
85 mg/m2 
d1  
(corresponds to day 1, 22, 43 / week 1, 4, 7) 
• 
Neoadjuvant immunotherapy with MEDI4736: 2 cycles of 14 days 
o MEDI4736 
750 mg 
d1  
(corresponds to day 64, 78 / week 10, 12) 
• 
Surgery 
o Between 2 and 4 weeks after the last application of MEDI4736  
  
 
(corresponds to days 92-106 / week 14-16) 
• 
Radiotherapy  
recommended for R1/R2 resection (incl. extracapsular spread of mediastinal LN metastases) 
o Between 2 and 4 weeks after surgery  
 
• 
Adjuvant immunotherapy with MEDI4736  
Should start within 4-6 weeks after surgery or within 2 weeks after completion of radiotherapy 
o MEDI4736 
750 mg 
d1  
every 2 weeks for a max. of 1 year (26 cycles)  
 
Week 
1 
4 
7 
10 
12 
14-16 
a) 
18-22   
b) c) 
20-24 
F 
70-74 
d) 
Day 
1 
22 
43 
64 
78 
92-106 
120-
148 
134-
162 
 
 
Cisplatin 
100 mg/m2 
x 
x 
x 
 
 
Surgery 
 
 
 
 
Docetaxel 
85 mg/m2 
x 
x 
x 
 
 
 
 
 
 
MEDI4736 
750 mg 
 
 
 
x 
x 
x 
x 
F 
x 
a) Surgery must be performed between 2 and 4 weeks after the last application of 
immunotherapy. 
b) Adjuvant MEDI4736 treatment should start between 4-6 weeks after surgery (for R0 patients 
or when no RT is applied). 
c) For patients with R1/R2 resection, incl. extracapsular spread of mediastinal lymph node 
metastases, who will receive post-surgery radiation therapy: radiotherapy should start 4-6 
weeks after surgery; the first infusion of adjuvant MEDI4736 should take place within 2 weeks 
after completion of radiotherapy. 
d) Adjuvant immunotherapy is administered for a maximum of 1 year (26 cycles). 
9.2 
Chemotherapy with cisplatin/docetaxel 
Please refer to the respective locally approved product information sheets for detailed information 
on handling and safety of cisplatin and docetaxel (also available online at www.swissmedicinfo.ch). 
9.2.1 
Schedule 
Neoadjuvant chemotherapy with cisplatin and docetaxel is administered as backbone treatment 
and according to the current standard of care in Switzerland (based on trials SAKK 16/96 and 
SAKK 16/00). The treatment is given for a total of 3 cycles (21 days each).  

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The second and third cycles start on day 22 and day 43 respectively, provided neutrophils are ≥ 
1.0 x 109/L and thrombocytes are ≥ 100 x 109/L. Otherwise, treatment is temporarily interrupted 
until recovery for a maximum of two weeks. 
If treatment cannot be resumed after a maximum delay of two weeks, chemotherapy will be 
discontinued permanently and the patient may proceed to anti-PD-L1 therapy (the possibility to go 
to the next treatment step should be evaluated with the coordinating investigators).  
9.2.2 
Dose and administration 
Docetaxel should be given before cisplatin, as follows: 
- docetaxel 85 mg/m2 1 hour i.v. infusion d1 then 
- cisplatin 100 mg/m2 1 hour i.v. infusion d1  
A split dose of cisplatin (50 mg/m2 day 1 and day 2) is allowed at the discretion of the local 
investigator.  
The use of cisplatin is mandatory in the 1st cycle. However, cisplatin can be replaced by carboplatin 
for the 2nd and 3rd cycle of neoadjuvant chemotherapy in case of cisplatin-induced toxicity. 
Carboplatin should be dosed as follows: carboplatin AUC6 (Calvert formula: carboplatin in mg = 
AUC x (CrCl + 25)).  
The use of generic drugs for cisplatin and docetaxel is allowed.  
Refer to section 10.7 for details on the measures to be taken in the occurrence of AEs during 
chemotherapy. 
9.2.3 
Premedication 
Premedication with dexamethasone is mandatory. Recommendation: 8 mg x 2 p.o. one day before 
chemotherapy (d-1) and for an additional 2 days (i.e. d1 & d2) at each chemotherapy cycle. 
Application scheme as per local practice is also accepted. 
9.2.4 
Supportive medication 
Hydration and anti-emetic therapy are to be performed according to the ESMO/MASCC guidelines 
for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting [78] and at the 
discretion of the treating investigator.  
Granulocyte-Colony Stimulating Factor (G-CSF)  
G-CSF must be administered during all three chemotherapy cycles.  
Recommended doses: G-CSF 30 millions of units for patients up to 75 kg and 48 millions of units 
above 75 kg on day 3 to 8 (5 days minimum) or pegfilgrastim as a single dose of 6 mg on day 5 of 
each cycle. 
9.2.5 
Warnings and precautions 
Surveillance during treatment with docetaxel  
In case a docetaxel hypersensitivity reaction occurs despite premedication, it is very likely to occur 
within a few minutes from the start of the first or of the second infusion of docetaxel. Therefore, 
during the 1st and the 2nd infusion, a careful evaluation of general sense of well-being should be 
performed. Whenever possible monitoring of blood pressure and heart rate has to be performed by 
a physician or nurse for at least the first 10 minutes, so that immediate intervention could occur in 
response to symptoms of an untoward reaction.  
Facilities and equipment for resuscitation should be immediately available: antihistamine, 
corticosteroids, aminophylline and epinephrine. 
9.3 
Immunotherapy with MEDI4736 
Detailed information on handling and safety of the IMP is provided in the IB [47] and in the toxicity 
management guidelines (see protocol section 10.8).  
Investigators should be familiar with the current version of the IB. 
 

 
 
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9.3.1 
Schedule 
In neoadjuvant setting:  
MEDI4736 will be administered on day 1 of each cycle, for 2 cycles of 14 days each, after 
treatment with cisplatin/docetaxel.  
MEDI4736 therapy should start on day 1 of week 10 after completion of chemotherapy. In case of 
interruptions or premature discontinuation of chemotherapy, MEDI4736 treatment should start 3 
weeks after the last dose of chemotherapy (provided AEs are resolved as described in section 
10.7) but no later than 5 weeks after the last dose of chemotherapy.  
Of note: all patients have to undergo a radiological re-assessment within one week before starting 
MEDI4736 (see section 12.2). 
In adjuvant setting:  
MEDI4736 will be administered every 14 days for 1 year (on day 1 of each cycle, maximum 26 
cycles). 
• For patients with R0 resection or when no radiotherapy is applied, the first infusion should start 
within 4-6 weeks after surgery (e.g. week 18-22 from the start of chemotherapy when no 
treatment delays occurred).  
• For patients with R1/R2 resection who will undergo post-surgery radiotherapy, the first infusion 
of adjuvant MEDI4736 should take place within 2 weeks after completion of radiotherapy.  
9.3.2 
Dose and administration 
A fixed dose of 750 mg MEDI4736 will be administered at room temperature (approximately 25°C) 
by controlled infusion via an infusion pump into a peripheral or central vein.  
The preparation of infusion bags should be done under aseptic conditions by trained personnel. 
The calculated volume of MEDI4736 is added to the i.v. bag, and the bag is mixed by gentle 
inversion to ensure homogeneity of the dose in the bag. The final concentration of MEDI4736 must 
be between 1-20 mg/ml. 
In-use storage and stability 
Total in-use storage time from needle puncture of MEDI4736 vial to start of administration should 
not exceed 4 hours at room temperature or 24 hours at 2-8°C. If in-use storage time exceeds these 
limits, a new dose must be prepared from new vials. Infusion solutions must be allowed to 
equilibrate to room temperature prior to commencement of administration. MEDI4736 does not 
contain preservatives and any unused portion must be discarded. 
Prior to the start of the infusion, ensure that the bag contents are at room temperature to avoid an 
infusion reaction due to the administration of the solution at low temperatures. Vials must be used 
for specific subjects and must not be shared between patients. 
Following preparation of MEDI4736, the entire contents of the i.v. bag should be administered as 
an i.v. infusion over approximately 60 minutes (±5 minutes), using a 0.2-µm in-line filter.  
The i.v. line will be flushed with a volume of normal saline equal to the priming volume of the 
infusion set used after the contents of the i.v. bag are fully administered, or complete the infusion 
according to institutional policy to ensure the full dose is administered. 
Of note: Alternatively to saline 0.9%, MEDI4736 could also be diluted in 5% (w/v) dextrose. Since 
the compatibility of MEDI4736 with other i.v. medications and solutions, other than normal saline 
0.9% and dextrose 5% is not known, the MEDI4736 solution should not be infused through an i.v. 
line in which other solutions or medications are being administered. 
9.3.3 
Premedication  
In the event of an infusion-related reaction, premedication may be used before the next infusion 
(see 
section 
10.8.2 
for 
management 
guidelines). 
Prescription 
of 
acetaminophen 
or 
diphenhydramine is allowed. 
9.3.4 
Supportive medication 
None. 

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9.3.5 
Warnings and precautions 
As with the administration of any immunoglobulin (Ig), infusion reactions and acute IgE-mediated 
allergic reactions may occur, may be severe and may result in death. Patients must be monitored 
during and after infusion with assessment of vital signs at the times specified in section 12. 
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.  
Although MEDI4736 is a human mAb, it is possible for humans to develop antidrug antibodies. The 
occurrence of such antidrug antibodies could result in immune complex disease (with 
manifestations such as arthralgia, serum-sickness, abdominal pain, back pain, and vasculitis) or 
altered MEDI4736 levels or activity. 
Owing to the drug’s mechanism of action and nonclinical findings, patients should be monitored for 
the 
development 
of 
immune-mediated 
reactions 
such 
as 
enterocolitis, 
dermatitis, 
hepatitis/hepatotoxicity, endocrinopathy, pneumonitis, neuropathy, serious infection, infusion-
related reactions, anaphylaxis or serious allergic reaction and immune complex disease.  
Refer to section 10.8 for toxicity management guidelines during MEDI4736 treatment.  
9.4 
Surgery 
Surgery is to be performed within 2-4 weeks after the last application of MEDI4736. 
Tumor resection includes an anatomical resection with a mediastinal lymph node dissection as 
previously described by Lardinois et al. [79]. Anatomical resection can be pneumonectomy, 
lobectomy, bilobectomy or sleeve procedures. Tumor resection can be performed using an open 
approach or the video-assisted thoracoscopy (VATS) technique. Due to the fact that no 
prospective randomized studies have demonstrated an oncological equivalence of limited resection 
compared to lobectomy in early stage NSCLC, limited resection procedures (e.g. segmentectomy) 
are not allowed in this trial and patients functionally not eligible for at least a lobectomy have to be 
excluded. 
In the case of T3 tumors with infiltration of the chest wall, an en bloc resection of the lobe with a 
part of the chest wall with a sufficient resection margin will be performed. In the case of infiltration 
of the mediastinum (T3 with infiltration of the phrenic nerve, of the mediastinal pleura, of the 
peridardium, or of the diaphragm), an en bloc resection should be possible. 
N2 disease is considered as unresectable when mediastinal nodes are bulky fixed with no visible 
tissue plane between nodes and trachea or invasion of the great vessels (aorta, pulmonary trunk or 
superior vena cava) or heart on radiological exams. In case of doubt, mediastinoscopy should be 
performed to rule out tracheal or carinal invasion. 
The treating investigator should contact the supporting surgeons in case of uncertainties or 
questions. 
9.5 
Postoperative radiotherapy 
Postoperative radiotherapy is highly recommended for patients with R1/R2 resection, including 
patients with extracapsular spread of mediastinal lymph node metastases.  
For all other patients the use of postoperative radiotherapy is not permitted. 
Radiotherapy should start 4-6 weeks after surgery and is to be performed in accordance with the 
standard of care for this patient group and will follow the institutional guidelines. 
The treating investigator should contact the coordinating investigators in case of questions. 
 
 

 
 
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9.6 
General remarks on dose modifications and delays 
Cisplatin and docetaxel must not be delayed for longer than 2 weeks (also for vacations). Doses 
omitted for AEs are not replaced. Once the dose of the chemotherapeutic drug has been reduced 
for any type of AE, it must not be increased at a later date.  
If a patient has to permanently discontinue chemotherapy early due to high-grade or persistent AE 
(> 2 weeks) and there is no evidence of progressive disease, he/she will proceed to MEDI4736 
therapy if possible. 
Neoadjuvant MEDI4736 must not be delayed for longer than 2 weeks (also for vacations).  
If a patient has to permanently discontinue MEDI4736 treatment in the neoadjuvant setting due to 
high-grade or persistent AE (> 2 weeks) and there is no evidence of progressive disease, he/she 
may proceed to surgery if possible. 
Adjuvant MEDI4736 must not be delayed for longer than 6 weeks in case of AEs (also for 
vacations).  
If a patient has to permanently discontinue MEDI4736 treatment in the adjuvant setting due to 
high-grade AEs or AEs persisting for longer than 4 weeks, he/she will enter the follow-up phase.  
AE-specific dose modifications are described in sections 10.7 and 10.8. For all AEs that are not 
mentioned in these sections, refer to the corresponding locally approved product information for 
cisplatin and docetaxel or the IB for MEDI4736, respectively. In case of conflicting 
recommendations, use the most restrictive treatment adjustment. 
The coordinating investigators should be contacted in case the investigator has any doubts about 
treatment delays and/or dose modifications. 
9.7 
Treatment duration 
Patients will be transferred to the follow-up phase as soon as one of the following events occurs: 
• 
Treatment was completed as per protocol, 
• 
Occurrence of an event  (i.e. relapse/progression or second tumor; see section 13.2.1),  
• 
Unacceptable toxicity,  
 
The possibility to go to the next treatment step should be evaluated with the coordinating 
investigators (refer to section 9.6 above), 
• 
Patient refusal  (see section 20.4 on premature withdrawal), 
• 
Withdrawal by the physician  (see section 20.4 on premature withdrawal), 
• 
Resection according to protocol cannot be performed, 
• 
Treatment with cisplatin/docetaxel or neoadjuvant MEDI4736 has to be delayed for more 
than 2 weeks (also for vacations),  
The possibility to go to the next treatment step should be evaluated with the coordinating 
investigators (refer to section 9.6 above), 
• 
Treatment with adjuvant MEDI4736 has to be delayed for more than 6 weeks (also for 
vacations), 
• 
Initiation of alternative anticancer treatment including another investigational agent (see 
section 9.8 below), 
• 
Patient becomes pregnant. 
If incorrectly enrolled, patients should discontinue treatment. The patient may resume treatment 
after an evaluation of any potential safety concerns with the coordinating investigators. 
All patients will be followed up lifelong (unless the SAKK Board decides on premature trial 
termination).  
See section 12.8 for evaluations after treatment termination. 
No trial-specific assessments will be performed after recurrence. 

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9.8 
Treatments not permitted during trial treatment phase 
The following treatments are not permitted during the trial treatment phase:  
• 
Other anticancer treatments, 
• 
Investigational treatments, 
• 
Immunosuppressive medications (such as but not limited to: methotrexate, azathioprine, and 
TNF-α blockers) within 28 days of the first dose of MEDI4736  
Exception:  
-  systemic corticosteroids at doses not exceeding 10 mg/day of prednisone or equivalent 
-  premedication for neoadjuvant chemotherapy  
-  immunosuppressive medications for the management of MEDI4736-related AEs or in 
patients with contrast allergies  
-   inhaled and intranasal corticosteroids,  
• 
Live attenuated vaccination within 30 days of MEDI4736 dosing (i.e. 30 days prior to the first 
dose, during treatment with MEDI4736 and for 30 days after discontinuation of MEDI4736).  
Inactivated viruses, such as those in the influenza vaccine, are permitted. 
9.9 
Precaution 
9.9.1 
Contraception 
The following precaution is valid for women taking part in the clinical trial: 
Women of childbearing potential who are sexually active with a non-sterilized male partner must 
use two methods of effective contraception from inclusion, and must agree to continue using such 
precautions for at least 90 days after the final dose of trial drugs or following the last infusion of 
MEDI4736. Cessation of birth control after this point should be discussed with a responsible 
physician. Periodic abstinence, the rhythm method or the withdrawal method are not acceptable 
methods of birth control. 
o Women of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal 
(defined as 12 months with no menses without an alternative medical cause). 
o Women must use two acceptable methods of effective contraception as described in the table 
below. Effective contraceptives can be hormonal (e.g. contraceptive pill, injections, or 
implants) or mechanical (e.g. condom, intrauterine pessar, diaphragm, cervical cap or another 
device). Women using mechanical contraceptives have to combine two methods of 
mechanical contraception (like condom, coil, diaphragm or another device). Women using 
hormonal contraceptives must use one additional method of mechanical contraception. 
The following precaution is valid for men taking part in the clinical trial: 
o Non-sterilized males who are sexually active with a female partner of childbearing potential 
must use two acceptable methods of effective contraception (see table below) from 
registration and for 90 days after receipt of the final dose of trial drugs or MEDI4736. 
o Males should refrain from fathering a child or donating sperm during the study and for 90 days 
following the last dose of MEDI4736. 
Effective methods of contraception (two methods must be used) are: 
Barrier Methods 
Intrauterine Device Methods 
Hormonal Methods 
Male condom plus spermicide 
Copper T 
Implants 
Cap plus spermicide 
Progesterone T1 
Hormone shot or injection 
Diaphragm plus spermicide 
Levonorgestrel-releasing 
intrauterine system (e.g. Mirena®)1 
Combined pill  /  Minipill 
Patch 
1This is also considered a hormonal method 
9.9.2 
Blood donation 
Patients should not donate blood during trial treatment and for at least 90 days following the last 
infusion of MEDI4736. 

 
 
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10 
ADVERSE EVENT REPORTING, DOSE 
MODIFICATIONS AND SUPPORTIVE TREATMENT 
The principal investigator is responsible for ensuring that all local staff involved in the trial is 
familiar with the content of this section. 
10.1 
Definition of AE 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom 
or disease temporally associated with the use of a medical treatment or procedure that may or may 
not be considered related to the medical treatment or procedure (as defined in ICH-GCP). 
10.2 
Reporting of AEs 
Patients will be instructed by the investigator to report the occurrence of any AE.  
The investigator assesses and records all AEs observed during the AE reporting period from 
registration until 30 days after administration of last dose. This includes but is not limited to any 
clinically significant worsening of a patient’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. The investigator assesses the event for severity, relation 
to trial treatment and possible etiologies, and whether the event meets the criteria of an SAE (see 
section 11). 
AEs ongoing beyond the end of the reporting period need to be followed up until resolution, 
stabilization (with the expectation that it will remain chronic) or start of alternative anticancer 
therapy. 
AEs are coded with the NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03, 
and assigned a Grade (from 1 = mild to 5 = death related to AE) as well as a relationship to trial 
treatment. The NCI CTCAE v4.03 (as pdf) as well as instructions on how to use the criteria can be 
found on http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Note:  
• 
Report the start and end date of the event and any changes in grading observed within the 
reporting period.  
• 
Baseline symptoms will be recorded on the CRF and will continue to be followed up during 
treatment.  
• 
AEs are documented by the codes according to CTCAE v4.03. If none of the codes are 
applicable, it exists for each of the 26 system organ classes (SOCs) the term ‘others’ to 
describe the AE. If the term ‘others’ is applicable, briefly describe the AE in a comprehensive 
and understandable manner. 
• 
Laboratory values will be documented as absolute values on the CRFs and should not be 
recorded as AE in addition. Out of range laboratory values occurring outside of predefined 
assessment times or any laboratory values not specifically asked to be assessed by the 
protocol should only be documented as AE if they are Grade 3 or higher.  
• 
Weight and blood pressure measurements will be documented as absolute values on the CRFs 
and should not be recorded as AE in addition. Exception: AE hypertension to be documented if 
a therapy is indicated. 
• 
Relationship of AEs to treatment is assessed using the following scale: 
1 Unrelated  The adverse event is clearly not related to the trial treatment. The AE is 
completely independent of trial treatment and/or evidence exists that the event 
is definitely related to another etiology. 
2 Unlikely  
The adverse event is doubtfully related to the trial treatment. Temporal 
association between the AE and the trial treatment and the nature of the event 
is such that the trial treatment is not likely to have had any reasonable 

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association with the observed illness/event (cause and effect relationship 
improbable but not impossible). 
3 Possibly  
The adverse event may be related to the trial treatment. Less clear temporal 
association; other etiologies also possible. 
4 Probably  The adverse event is likely related to the trial treatment. Clear-cut temporal 
association and a potential alternative etiology are not apparent. 
5 Definitely  The adverse event is clearly related to the trial treatment. Clear-cut temporal 
association and no other possible cause. 
10.3 
Definition of AE of special interest (AESI) 
AESIs are events of scientific and medical interest specific to the further understanding of the 
MEDI4736 safety profile and require close monitoring and rapid communication by the investigator 
to the sponsor. The rapid reporting of these AESIs allows ongoing analysis of these events in order 
to characterize and understand them in association with the use of this investigational product. 
AESIs may be serious (see section 11 for the definition of seriousness), or non-serious.  
MEDI4736 belongs to a new class of anticancer therapies, called “checkpoint-inhibitors” that 
amplify antitumor immune responses by blocking inhibitory signaling pathway modulated by the co-
inhibitory or co-stimulatory receptors, CTLA-4 and PD-1, expressed on T cells [80]. This class of 
IMP can have a wide spectrum of immune-mediated reactions that have been considered 
inflammatory in nature and can affect any organs of the body. Refer to the current version of the IB 
for further information. 
10.3.1 Pneumonitis 
Immune-mediated pneumonitis is characterized by inflammation focally or diffusely affecting the 
lung parenchyma that may be result of effects of checkpoint inhibitors against the normal lung 
parenchyma. Presentations of pneumonitis range from asymptomatic lung infiltrates to those that 
mimic severe bacterial pneumonia. For symptomatic patients, complaints and findings may include 
dyspnea, cough, tachypnea, pleuritic chest pain, and hypoxia.  
In clinical studies with MEDI4736 monotherapy, 23 of 1’149 patients (2.0%) reported 24 serious 
and non-serious events (10 serious; 14 non-serious) of pneumonitis/interstitial lung disease across 
all doses and indications in 4 of the 5 open-label monotherapy studies [47]. 
Initial work-up should include high-resolution CT scan, ruling out infection, and pulse oximetry. 
Pulmonary consultation is highly recommended.  
10.3.2 Hypersensitivity reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-PD-L1 
and anti-PD-1 therapy [81]. 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 mAb, 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. 
In clinical studies with MEDI4736 as a monotherapy, the incidence of reported potential infusion-
related reaction was low. Ten of 1,265 patients treated with MEDI4736 in 5 sponsored 
monotherapy studies reported 14 serious cases of infusion-related reactions, giving an overall 
frequency of 0.8%. 
The potential risk of immune complex disease for MEDI4736 is theoretical based on the known risk 
associated with mAbs and other proteins. The incidence of MEDI4736 ADA-positive subjects in 
clinical studies is low, and hence the risk of immune complex disease is likely to be low. 
10.3.3 Hepatic function abnormalities (hepatotoxicity) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 
antibodies [81]. Inflammatory hepatitis has been reported in 3% to 9% of subjects treated with anti-

 
 
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CTLA-4 monoclonal antibodies (e.g. ipilimumab).  The clinical manifestations of ipilimumab-treated 
patients included general weakness, fatigue, nausea and/or mild fever and increased liver function 
tests such as AST, ALT, AP and/or total bilirubin. Across approximate 1,200 patients who have 
received MEDI4736 monotherapy 10 mg/kg q2w, 0.3% of subjects experienced an event of 
‘hepatitis’. 
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 local investigator 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 investigational product.  
Cases where a patient shows an AST or ALT ≥ 3x ULN or total bilirubin ≥ 2x ULN may need to be 
reported as SAEs, These cases should be reported as SAEs if, after evaluation they meet the 
criteria for a Hy’s Law case or if any of the individual liver test parameters fulfill any of the SAE 
criteria. 
Criteria for Hy’s Law (FDA Guidance) 
• 
The drug causes hepatocellular injury, generally shown by a higher incidence of 3 fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug or 
placebo.  
• 
Among trial patients showing such aminotransferase elevations, often with aminotransferases 
much greater than 3 x ULN, one or more also show elevation of serum total bilirubin to >2 x 
ULN, without initial findings of cholestasis (elevated serum AP).  
• 
No other reason can be found to explain the combination of increased aminotransferases and 
total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another 
drug capable of causing the observed injury. 
Hepatic function abnormality in a patient receiving MEDI4736, with or without associated clinical 
manifestations, is required to be reported as “hepatic function abnormal” 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 MEDI4637, the decision to continue dosing of the patient will be based on the 
clinical judgment of the investigator. 
• If no definitive underlying diagnosis for the abnormality is established, dosing of the patient 
must be interrupted immediately. Follow-up investigations and inquiries must be initiated by 
the investigational site without delay. 
10.4 
Reporting of AESI 
AESIs in patients receiving MEDI4736 must be reported to SAKK CC as follows: 
• 
Non-serious AESI: online, through the EDC system (www.sakk.ch/edc), by creating a new AE 
for the corresponsing patient, within 1 working day after knowledge of the event; the tick-box 
whether the event is an AESI must be checked. 
• 
Serious AESI: by Fax, within 24 hours of knowledge of the event, using the SAE form in 
case the AESI complies with the definition for seriousness (see section 11).  
The SAKK CC will forward each individual report to the coordinating investigator and to 
AstraZeneca within 1 working day after receipt from the site.  
10.5 
Drug-related AEs 
Very common and common AEs related to cisplatin/docetaxel and MEDI4736 are presented in the 
tables below (see 10.5.1 and 10.5.2). 

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Please refer to the locally approved product information of cisplatin and docetaxel for exhaustive 
information concerning chemotherapy drug-related AEs (see e.g. http://www.swissmedicinfo.ch/) . 
Please note that the frequencies of AEs associated with MEDI4736 and summarized in the tables 
below may undergo changes as the number of patients being exposed to this investigational 
product is still small. Always refer the most current IB version for an exhaustive list of AEs 
related to MEDI4736. 
10.5.1 Very common (> 10%)  
SOC (CTCAE v4.03) 
Cisplatin 
Docetaxel 
MEDI4736 
Blood and lymphatic 
system disorders 
 Anemia 
Anemia  
 
Infections and 
infestations 
 
Pharyngitis, Other 
Infections, Rhinorrhea 
 
Immune system disorders 
 
Anaphylactoid type 
reactions, 
Hypersensitivity 
reactions 
 
Investigations 
White blood cell 
decreased, Platelet 
count decreased 
Neutrophil count 
decreased, Platelet 
count decreased 
 
Ear and labyrinth 
disorders 
Tinnitus, Hearing 
impaired 
 
 
Eye disorders 
 
Watering eyes 
 
Gastrointestinal disorders 
Nausea, Vomiting 
Diarrhea, Nausea, 
Vomiting, Stomatitis 
Diarrhea (G1/G2) 
General disorders and 
administration site 
conditions 
 
Fever, Flu like 
symptoms, Chills, 
Edema limbs  
Fatigue 
Metabolism and nutrition 
disorders 
 
Anorexia 
 
Musculoskeletal and 
connective tissue 
disorders 
 
Myalgia, Muscular 
weakness 
 
Nervous system 
disorders 
 
Peripheral sensory 
neuropathy 
 
Psychiatric disorders 
 
Insomnia 
 
Renal and urinary 
disorders 
Urinary retention, Acute 
kidney injury  
 
 
Respiratory, thoracic and 
mediastinal disorders 
 
Dyspnea 
 
Skin and subcutaneous 
tissue disorders 
 
Alopecia, Erythema, 
Pruritus, Nail loss 
Pruritus, Rash (G1/G2) 
 
10.5.2 Common (1-10%)  
SOC (CTCAE v4.03) 
Cisplatin 
Docetaxel 
MEDI4736 
Blood and lymphatic 
system disorders 
 
Febrile neutropenia 
Anemia 
Cardiac disorders 
 
Tachycardia 
 
Endocrine disorders 
 
 
Hypertyroidism, 
Hypothyroidism 
Eye disorders 
Blurred vision 
Conjunctivitis 
 
Gastrointestinal disorders 
 
Constipation, Abdominal 
pain, Esophagitis, 
Dysphagia, 
Nausea, Vomiting, 
Diarrhea  

 
 
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Gastrointestinal 
disorders - 
Other (odynophagia) 
General disorders and 
administration site 
conditions 
 
Injection site reaction 
Fever, Asthenia 
Infections and 
infestations 
 
Oral candidiasis  
 
Investigations 
 
Blood bilirubin 
increased, Alkaline 
phosphatase 
increased, Aspartate 
aminotransferase 
increased, Alanine 
aminotransferase 
increased 
Aspartate 
aminotransferase 
increased, Alanine 
aminotransferase 
increased, GGT 
increased, Weight loss, 
Creatinine increased 
Metabolism and nutrition 
disorders 
 
 
Decreased appetite/ 
Anorexia (G1)  
Musculoskeletal and 
connective tissue 
disorders 
 
Arthralgia 
Arthralgia, Myalgia 
Nervous system 
disorders 
Peripheral sensory  
neuropathy 
 
Dysgeusia 
Paresthesia  
Psychiatric disorders 
 
Depression 
 
Respiratory, thoracic and 
mediastinal disorders 
 
Epistaxis 
Pneumonitis, Dyspnea, 
Cough 
Skin and subcutaneous 
tissue disorders 
 
Dry skin 
 
Vascular disorders 
 
Hypotension, 
hypertension 
 
10.5.3 Immune-related AEs (irAEs)  
Based on the mechanism of action of MEDI4736 leading to T-cell activation and proliferation, there 
is the possibility of observing irAEs during the conduct of this trial. Potential irAEs include immune-
mediated pneumonitis, enterocolitis, dermatitis, hepatitis/hepatotoxicology, endocrinopathies, 
neuropathy /neuromuscular toxicity, nephritis, pancreatitis and myocarditis. Patients should be 
monitored for signs and symptoms of irAEs. In the absence of an alternate etiology (e.g. infection 
or PD/relapse) signs or symptoms of these events should be considered to be immune-related.  
10.5.4 Hypersensitivity and serious allergic reactions 
These events include infusion-related reactions, anaphylaxis/serious allergic reactions and immune 
complexe disease.  
10.6 
Safety parameters  
Renal function: 
Serum creatinine or calculated creatinine clearance (according to 
the formula of Cockcroft-Gault, see Appendix 3) 
Liver function: 
AST/ALT 
Hematological function: Hemoglobin, absolute neutrophils count, platelets count 
Metabolic function: 
Sodium (Na), potassium (K), magnesium (Mg)  
Cardiovascular function: Blood pressure, 12-lead ECG 
Vital signs: 
During MEDI4736 infusion - temperature, blood pressure, pulse rate, and 
respiratory rate  

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10.7 
Dose modifications and supportive treatment during treatment 
with cisplatin/docetaxel 
Refer also to the locally approved product information of cisplatin and docetaxel (see e.g. 
http://www.swissmedicinfo.ch/). 
10.7.1 Hematological adverse events  
Neutrophil count decreased 
Cisplatin 
Docetaxel 
G1 and G2 (≥ 1.0 x 109/L)  
No change. 
 
G3 or G4 (< 1.0 x 109/L) 
 
Delay for a maximum of 2 weeks until recovery to < G3; 
blood counts have to be measured twice weekly until 
recovery. 
Permanently discontinue chemotherapy if not recovered 
within 2 weeks. 
 
Platelet count decreased 
Cisplatin 
Docetaxel 
< 100 x 109/L prior each cycle 
Delay for a maximum of 2 weeks until recovery to > 100 x 
109/L. Blood counts have to be measured twice weekly until 
recovery. 
Permanently discontinue chemotherapy if not recovered 
within 2 weeks (proceed to MEDI4736 therapy if no PD and 
if clinically indicated). 
G3 (< 50 x 109/L)  
or  
G4 (< 25 x 109/L)  
during the cycle 
First 
occurrence 
No change. 
Reduce dose to 55 mg/m2. 
Second 
occurrence 
No change. 
Reduce dose to 30 mg/m2. 
10.7.2 Metabolic/laboratory adverse events 
In case of abnormal liver function or renal insufficiency prior each chemotherapy cycle, the 
following dose modifications must be applied.  
Of note: Every attempt should be made to document the etiology of the liver function impairment. 
Metastatic disease to the liver needs to be excluded. 
AST or ALT or AP or bilirubin 
Cisplatin 
Docetaxel 
G1 
No change. 
G2  
No change. 
Reduce dose to 55 mg/m2. 
G3 or G4  
Delay for a maximum 2 weeks until resolution to ≤ G2 and 
then restart with docetaxel dose reduced to 55 mg/m2. 
Permanently discontinue chemotherapy if not resolved 
within 2 weeks. 
 
Renal insufficiency 
Cisplatin 
Docetaxel 
Creatinine clearance < 60 ml/min 
prior each cycle 
Stop cisplatin and replace by 
carboplatin AUC6, acc. to 
Calvert formula (see 9.2). 
No change. 
10.7.3 Ear and labyrinth disorders 
Hearing impairment 
Cisplatin 
Docetaxel 
G1 (audiogram only) 
No change. 
≥ G2 
Stop cisplatin and replace by 
carboplatin AUC6, acc. to 
Calvert formula (see 9.2). 
No change. 

 
 
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10.7.4 Nervous system disorders 
Sensory / peripheral 
neuropathy 
Cisplatin 
Docetaxel 
G1 
No change. 
G2 
First occurrence 
Stop cisplatin and replace by 
carboplatin AUC6, acc. to 
Calvert formula (see 9.2). 
No change. 
In case of persistence at 
next administration 
Stop cisplatin and replace by 
carboplatin AUC6, acc. to 
Calvert formula (see 9.2). 
Reduce dose to 55 mg/m2. 
≥ G3 
Permanently discontinue chemotherapy. 
10.7.5 Gastrointestinal disorders 
Nausea and vomiting 
Cisplatin 
Docetaxel 
G1 or G2 
No change. 
G3 
First occurrence 
No change. 
No change. 
Second occurrence 
Stop cisplatin and replace by 
carboplatin AUC6, acc. to 
Calvert formula (see 9.2). 
Continue with the reduced 
dose of 55 mg/m2. 
 
Diarrhea 
Cisplatin 
Docetaxel 
G1 or G2 
No change. 
G3 
First occurrence 
No change. 
No change. 
Second occurrence 
No change. 
Continue with the reduced 
dose of 55 mg/m2. 
10.7.6 Docetaxel-induced hypersensitivity or anaphylactic type reactions  
Anaphylactic type 
reactions, 
hypersensitivity 
reactions 
Cisplatin 
Docetaxel 
Supportive treatment 
G1 
No change. Decrease infusion rate until 
recovery to Grade 0. Then 
complete infusion with initial 
infusion rate. 
 
G2 
No change. Interrupt infusion. 
 
Re-start infusion after recovery to 
Grade 0 at a slower rate and then 
increase incrementally to the 
initial rate. 
Give i.v. antihistamine1 and i.v. 
corticosteroids2. 
At subsequent cycles, 
antihistamines and steroids will be 
given i.v. 1 hour before infusion in 
addition to the premedication. 
G3 
First occurrence 
No change. Interrupt infusion. 
Once all signs and/or symptoms 
of hypersensitivity reaction 
disappear, infusion may be 
resumed within 24 hours from the 
interruption, if medically 
appropriate, and whenever 
possible. 
Reiteration of the premedication 
regimen is only recommended 
when docetaxel is re-infused more
than 3 hours after the interruption. 
Give i.v. antihistamine1 and 
corticosteroids2. 
Add epinephrine3 or broncho-
dilatators and/or i.v. fluids, macro-
molecules if indicated. 
At the subsequent cycles, 
dexamethasone will be given at 
20 mg orally 24, 18, 13, 7 and 1 
hour before docetaxel infusion. 
Additionally diphenhydramine (or 
equivalent) will be given at 50 mg 
i.v. 1 hr before docetaxel infusion. 

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Second occurrence 
Permanently discontinue chemotherapy. 
 
G4 
Permanently discontinue chemotherapy. 
 
1Antihistamines:  
Dexchlorphenidramine (Polaramine®) 5-10 mg i.v. or clemastine (Tavegyl®) 2 mg i.v. or 
diphenhydramine (Benadryl®) 25-50 mg i.v. or promethazine (Phenergan®) 50-100 mg i.v. 
2Corticosteroids: 
Dexamethason or equivalent of 5-10 mg i.v. 
3Epinephrine: 
Administered at 1:1’000 dilution (0.01 ml/kg with a maximum dose of 0.5 ml s.c. repeated every 20 
minutes as necessary). 
10.7.7 Fluid retention  
Peripheral edemas  
and/or  
pleural effusions 
Cisplatin 
Docetaxel 
Supportive measures 
G1 
No change 
 
G2 
The clinical tolerance of the therapy by the 
patient, the overall tumor response and the 
medical judgment of the investigator will 
determine if it is in the patient’s best interest to 
continue or to discontinue the treatment. 
Furosemid (20-40 mg once 
daily p.o.) should be started 
when signs and/or symptoms 
of fluid retention are observed, 
including weight gain G2 not 
otherwise explained. The 
addition of potassium and 
magnesium may be useful. 
≥ G3 
Permanently discontinue chemotherapy 
 
In case of a pleural effusion or ascites appearing or increasing during the treatment, the cytological 
examination and concomitant signs of disease progression or of peripheral fluid retention should 
allow deciding whether the effusion is related to the disease or the trial drugs. In case of difficulty to 
determine, the treatment should be continued until clear evidence of disease progression in other 
organs can be documented. 
10.7.8 Other adverse events 
Other AEs ≥ G3 (except alopecia) should be managed symptomatically when possible. 
Other AEs 
Cisplatin 
Docetaxel 
G3 
Delay for a maximum of 2 weeks until resolved 
to ≤ G1, then, if medically appropriate, reduce 
docetaxel to 55 mg/m2 (no further dose 
reduction is foreseen). 
G4 
Permanently discontinue chemotherapy. 
10.8 
Toxicity management guidelines during MEDI4736 therapy 
For AEs that are considered at least partly due to administration of MEDI4736 the following dose 
adjustment guidance may be applied: 
• 
Treat each of the AEs 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 MEDI4736 along with appropriate continuing supportive care,  
• 
All treatment interruptions should be documented with clear reasoning and documentation of 
the approach taken, 
• 
MEDI4736 must not be delayed for longer than 2 weeks during neoadjuvant treatment, and 6 
weeks during adjuvant treatment. 
Management guidelines for AEs associated with MEDI4736 (overall management and AE-specific 
management), are detailed in the tables below. Refer also to the most current version of the IB. 

 
 
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10.8.1 Immune-related reactions associated with MEDI4736 
Please also consider the most current version of the IB. 
IrAEs (Overall management for toxicities not noted below) 
Dose Modifications 
Toxicity Management 
Drug administration modifications of MEDI4736 will be made to manage 
potential irAEs based on severity of treatment-emergent toxicities 
graded per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation of MEDI4736 
based on severity/Grade (table below), permanently discontinue 
MEDI4736 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 
MEDI4736, 
• 
Recurrence of a previously experienced G3 treatment-related AE 
following resumption of dosing. 
 
 
G1 
No dose modification 
G2 
Hold MEDI4736 dose until G2 resolution to ≤ G1  
• If toxicity worsens then treat as G3 or G4 
• If toxicity improves to baseline then treat at next scheduled 
treatment date 
• Once event stabilizes to ≤ G1 and corticosteroid is reduced 
to a dose ≤10 mg of prednisone per day (or equivalent) then 
MEDI4736 treatment can be resumed at the next scheduled 
dose     
G3 
Depending on the individual toxicity, may permanently  
 
discontinue MEDI4736. Please refer to guidelines below 
G4 
Permanently discontinue MEDI4736 
 
Note: For G3 and above asymptomatic amylase or lipase levels hold 
MEDI4736 and if complete work up shows no evidence of pancreatitis, 
may continue or resume treatment. 
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 
and discussed 
with 
the 
coordinating 
investigators. 
- 
Symptomatic and topical therapy should be considered for low-grade (G1/G2, 
unless otherwise specified) irAEs.  
- 
For persistent (greater than 3 to 5 days) low-grade (G2) or severe (≥G3) irAEs, 
promptly start prednisone p.o. 1-2 mg/kg/day or i.v. equivalent.  
- 
If symptoms recur or worsen during corticosteroid tapering, increase the 
corticosteroid dose (prednisone dose, e.g. up to 2-4 mg/kg/day or i.v 
equivalent) until stabilization or improvement of symptoms, then resume 
corticosteroid tapering at a slower rate.  
 
- 
More potent immunosuppressives, such as TNF antagonist class (e.g. 
infliximab) or mycophenolate, etc. (refer to individual sections of the irAE 
management for specific type of immunosuppressive) should be considered 
for events not responding to systemic steroids after discussion with the 
coordinating investigators.   
- 
Discontinuation of MEDI4736 is not mandated for G3/G4 inflammatory 
reactions attributed to local tumour response (e.g. inflammatory reaction at 
sites of metastatic disease, lymph nodes, etc.). Continuation of MEDI4736 in 
this situation should be based upon a benefit/risk analysis for that patient.  
 

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Grade (CTCAE v4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis / Interstitial lung disease (ILD) 
Any Grade 
 
- Monitor patients for signs and symptoms of pneumonitis or ILD (new onset or 
worsening shortness of breath or cough). Patients should be evaluated with 
imaging and pulmonary function tests including other diagnostic procedures as 
described below 
- Initial work-up may include clinical evaluation, monitoring of oxygenation via 
pulse oximetry (resting and exertion), laboratory work-up and high-resolution CT 
scan  
G1  
(Asymptomatic, clinical 
or diagnostic 
observations only, 
intervention not 
indicated) 
No dose modification required. However, 
consider holding MEDI4736 dosing as 
clinically appropriate and during diagnostic 
work-up for other etiologies 
For G1 (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 
G2  
(Symptomatic, medical 
intervention indicated, 
limiting instrumental 
ADL)  
Hold MEDI4736 dose until resolution to ≤ G1 
• If toxicity worsens then treat as G3 or G4  
• If toxicity improves to baseline then the 
decision to reinitiate study drug/regimen at 
next scheduled treatment date will be 
based upon treating physician’s clinical 
judgment 
• Once event stabilizes to ≤ G1 and 
corticosteroid is reduced to a dose ≤10 mg 
of prednisone per day (or equivalent) then 
MEDI4736 treatment can be resumed at 
the next scheduled dose 
  
  
For G2 (mild to moderate new symptoms) 
- Monitor symptoms daily and consider hospitalization 
- Promptly start systemic steroids (e.g. prednisone 1-2 mg/kg/day or i.v. 
equivalent) 
- Re-imaging as clinically indicated 
- If no improvement within 3-5 days, additional workup should be considered and 
prompt treatment with i.v. methylprednisolone 2-4 mg/kg/day started  
- If still no improvement within 3-5 days despite i.v. methylprednisone at 2-4 
mg/kg/day, promptly start immunosuppressive therapy (e.g. infliximab at 5 
mg/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 and consider prophylactic antibiotics, 
antifungal or anti-PCP treatment (refer to current  NCCN guidelines for 
treatment of cancer-related infections (Category 2B recommendation)1 
- Consider pulmonary and infectious disease consult 
- Consider as necessary discussing with coordinating investigators 
                                            
1 ASCO Educational Book 2015; Michael Pestow MD; “Managing Immune Checkpoint Blocking Antibody Side Effects”, Section on Hepatotoxicity, pp 78 

 
 
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Grade (CTCAE v4.03) 
Dose Modifications 
Toxicity Management 
G3 or G4  
 
(G3: severe symptoms; 
limiting self-care ADL; 
oxygen indicated;  
G4: life threatening 
respiratory compromise, 
urgent intervention 
indicated, e.g. 
tracheostomy or 
intubation)  
Permanently discontinue MEDI4736 
 
For G3 or G4 (severe or new symptoms, new/worsening hypoxia, life threatening)  
- Promptly initiate empiric i.v. 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 (e.g. infliximab at 
5 mg/kg every 2 weeks dose) started. Caution: rule out sepsis and refer to 
infliximab label for general guidance before using infliximab  
- Once improving, gradually taper steroids 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) 
Diarrhea / Enterocolitis 
Any Grade  
 
 
- Monitor for symptoms that may be related to diarrhea/enterocolitis (abdominal 
pain, cramping, or changes in bowel habits such as increased frequency over 
baseline or blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs and ileus) 
- Patients should be thoroughly evaluated to rule out any alternative etiology (e.g. 
disease progression, other medications, 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 
G1  
(stool frequency of <4 
over baseline per day)  
No dose modification 
- 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 
G2  
(stool frequency of 4-6 
over baseline per day)  
Hold MEDI4736 until resolution to ≤G1 
• If toxicity worsens then treat as G3 or G4 
• If toxicity improves to baseline then treat at 
next scheduled treatment date 
• Once event stabilizes to ≤ G1 and 
corticosteroid is reduced to a dose ≤10 mg 
- 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 or i.v. equivalent  
- If event is not responsive within 3-5 days or worsens despite prednisone at 1-2 
mg/kg/day or i.v. equivalent, gastrointestinal consult should be obtained for 

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Grade (CTCAE v4.03) 
Dose Modifications 
Toxicity Management 
of prednisone per day (or equivalent) then 
MEDI4736 treatment can be resumed at 
the next scheduled dose 
consideration of further workup such as imaging and/or colonoscopy to confirm 
colitis 
and 
rule 
out 
perforation, 
and 
prompt 
treatment 
with 
i.v. 
methylprednisolone 2-4 mg/kg/day started  
- If 
still 
no 
improvement 
within 
3-5 
days 
despite 
2-4 
mg/kg 
i.v. 
methylprednisolone, promptly start immunosuppressives (e.g. infliximab at 5 
mg/kg once every 2 weeks2). Caution: Important to rule out bowel perforation 
and refer to infliximab label for general guidance before using infliximab  
- Consult coordinating investigators if no resolution to ≤ G1 in 3-4 days 
- Once improving, gradually taper steroids and consider prophylactic antibiotics, 
antifungals and anti-PCP treatment (please refer to current  NCCN guidelines 
for treatment of  cancer-related infections [Category 2B recommendation]) 
G3 or G4 
 
(G3: stool frequency of 
≥7 over baseline per 
day;  
G4: life threatening 
consequences) 
Permanently discontinue MEDI4736 
- Promptly initiate empiric i.v. methylprednisolone 2 to 4 mg/kg/day or equivalent  
- Monitor stool frequency and volume and maintain hydration   
- Urgent gastrointestinal consult and imaging and/or colonoscopy as appropriate 
- If still no improvement within 3-5 days of i.v. methylprednisolone 1 to 4 
mg/kg/day or equivalent, promptly start further immunosuppressives e.g. 
(infliximab at 5 mg/kg once every 2 weeks)   
- Caution: Ensure gastrointestinal consult to rule out bowel perforation and refer 
to infliximab label for general guidance before using infliximab  
- Once improving, gradually taper steroids and consider prophylactic antibiotics, 
antifungals and anti-PCP treatment (please refer to current  NCCN guidelines 
for treatment of  cancer-related infections [Category 2B recommendation]) 
Hepatitis (Elevated liver function tests (LFT)) 
Infliximab should not be used for management of immune-related hepatitis 
Any Grade 
  
- Monitor and evaluate liver function test: AST, ALT, AP and total bilirubin (TB)  
- Evaluate for alternative etiologies (e.g. viral hepatitis, disease progression, 
concomitant medications)  
G1  
(AST or ALT > ULN to 3 
x ULN and/or TB > ULN 
to 1.5 x ULN) 
No dose modification 
If it worsens, treat as G2 event 
- Continue LFT monitoring per protocol 
                                            
2 ASCO Educational Book 2015; Michael Pestow MD; “Managing Immune Checkpoint Blocking Antibody Side Effects”, Section on Diarrhea/Colitis, pp. 77 

 
 
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Grade (CTCAE v4.03) 
Dose Modifications 
Toxicity Management 
G2  
(AST or ALT > 3 to 5 x 
ULN and/or TB > 1.5-3 
x ULN) 
Hold MEDI4736 dose until resolution to ≤ G1 
• If toxicity worsens then treat as G3 or G4 
• If improves to baseline then treat at next 
scheduled treatment date 
• Once event stabilizes to ≤ G1 and 
corticosteroid is reduced to a dose ≤10 mg 
of prednisone per day (or equivalent) then 
MEDI4736 treatment can be resumed at 
the next scheduled dose 
- Regular and frequent checking of LFTs (e.g. every 1-2 days) until elevations of 
these are improving or resolved   
- If no resolution to ≤ G1 in 1-2 days, discuss with coordinating investigators. 
- If event is persistent (> 3-5 days) or worsens, promptly start prednisone 1-2 
mg/kg/day or i.v. equivalent  
- If still no improvement within 3-5 days despite 1-2 mg/kg/day of prednisone or 
i.v. equivalent, consider additional workup and prompt treatment with i.v. 
methylprednisolone 2-4 mg/kg/day started 
- If still no improvement within 3-5 days despite 2-4 mg/kg/day of i.v. 
methylprednisolone, promptly start immunosuppressives (mycophenolate 
mofetil at 500 mg every 12 hours)3 . Discuss with coordinating investigators if 
mycophenolate mofetil is not available.  Infliximab should NOT be used 
- Once improving, gradually taper steroids and consider prophylactic antibiotics, 
antifungals and anti-PCP treatment (please refer to current  NCCN guidelines 
for treatment of  cancer-related infections [Category 2B recommendation]) 
G3 
(AST or ALT > 5-20 x 
ULN and/or TB > 3-10 x 
ULN) 
For elevations in transaminases ≤ 8 × ULN, 
or elevations in bilirubin ≤ 5 × ULN:  
-Hold MEDI4736 dose until resolution to ≤ 
G1 or baseline   
-Resume MEDI4736 administration at the 
next scheduled dose if elevations down-
grade ≤ G1 or baseline within 14 days 
Permanently discontinue MEDI4736 if the 
elevations do not down-grade to ≤ G1 or 
baseline within 14 days  
For elevations in transaminases > 8 × ULN or 
elevations in bilirubin > 5 × ULN, 
discontinue MEDI4736  
Permanently discontinue MEDI4736 for any 
case meeting Hy’s law criteria (ALT > 3x 
ULN + bilirubin > 2x ULN without initial 
findings of cholestasis (i.e. elevated AP) 
and in the absence of any alternative 
cause4 
For G3 or G4 AST or ALT and/or TB elevation: 
- Promptly initiate empiric i.v. 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 
i.v. 
or 
equivalent, 
promptly 
start 
treatment 
with 
immunosuppressive therapy (mycophenolate mofetil at 500 mg every 12 hours)  
Discuss with coordinating investigators if mycophenolate is not available. 
Infliximab should NOT be used 
- Hepatology consult, abdominal workup, and imaging as appropriate 
- Once improving, gradually taper steroids and consider prophylactic antibiotics, 
antifungals and anti-PCP treatment (please refer to current  NCCN guidelines 
for treatment of  cancer-related infections [Category 2B recommendation]) 
                                            
3 ASCO Educational Book 2015; Michael Pestow MD; “Managing Immune Checkpoint Blocking Antibody Side Effects”, Section on Hepatotoxicity, pp. 78  
4 FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation 

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G4  
(AST or ALT > 20 x 
ULN and/or TB > 10 x 
ULN)  
Permanently discontinue MEDI4736  
Nephritis or Renal dysfunction (Elevated serum creatinine) 
Any Grade 
 
- Consult with nephrologist 
- Monitor for signs and symptoms that may be related to changes in renal function 
(e.g. routine urinalysis, elevated serum blood urea nitrogen (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 (G2), in order to prevent potential progression to higher 
grade event 
G1  
(Serum creatinine > 1-
1.5 x baseline; > ULN to 
1.5 x ULN)  
No dose modification 
- 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 G2 or G3 or G4  
- Consider symptomatic treatment including hydration, electrolyte replacement, 
diuretics, etc. 
G2  
(Serum creatinine > 1.5-
3.0 x baseline; > 1.5-3 x 
ULN) 
 
Hold MEDI4736 until resolution to ≤ G1 
• If toxicity worsens then treat as G3 or G4 
• If toxicity improves to baseline then treat at 
next scheduled treatment date 
• Once event stabilizes to ≤ G1 and 
corticosteroid is reduced to a dose ≤10 mg 
of prednisone per day (or equivalent) then 
MEDI4736 treatment can be resumed at 
the next scheduled dose 
- 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 or i.v. equivalent  
- If event is not responsive within 3-5 days or worsens despite prednisone at 1-2 
mg/kg/day or i.v. equivalent, additional workup should be considered and 
prompt treatment with i.v. methylprednisolone at 2-4 mg/kg/day started  
- Once improving gradually taper steroids and consider prophylactic antibiotics, 
antifungals and anti-PCP treatment (please refer to current  NCCN guidelines 
for treatment of  cancer-related infections [Category 2B recommendation])  
- When event returns to baseline, resume MEDI4736 and routine serum 
creatinine monitoring per study protocol 

 
 
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G3 or G4  
(G3:  Serum creatinine 
> 3 x baseline; > 3-6 x 
ULN 
G4: Serum creatinine > 
6 x ULN)  
Permanently discontinue MEDI4736 
- 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 or i.v. equivalent  
- If event is not responsive within 3-5 days or worsens despite prednisone at 1-2 
mg/kg/day or i.v. equivalent, additional workup should be considered and 
prompt treatment with i.v. methylprednisolone 2-4 mg/kg/day started  
- Once improving, gradually taper steroids and consider prophylactic antibiotics, 
antifungals and anti-PCP treatment (please refer to current  NCCN guidelines 
for treatment of  cancer-related infections [Category 2B recommendation]  
Rash (excluding Bullous skin formations) 
(Please refer to CTCAE version 4.03 for definition of severity/Grade depending on  type of skin rash) 
Any Grade  
 
Monitor for signs and symptoms of dermatitis (rash and pruritus)  
**IF 
THERE 
IS 
ANY 
BULLOUS 
FORMATION, 
THE 
COORDINATING 
INVESTIGATORS 
SHOULD 
BE 
CONTACTED 
AND 
MEDI4736 
DISCONTINUED** 
G1  
No dose modification 
- Consider 
symptomatic 
treatment 
including 
oral 
antipruritics 
(e.g. 
diphenhydramine or hydroxyzine) and topical therapy (e.g. urea cream) 
G2 
For persistent (> 1-2 weeks) G2 events, hold 
scheduled MEDI4736 until resolution to ≤ 
G1 or baseline  
•  If  toxicity worsens then treat as G3  
• If toxicity improves then  resume admini-
stration at next scheduled dose 
• Once event stabilizes to ≤ G1 and 
corticosteroid is reduced to a dose ≤10 mg 
of prednisone per day (or equivalent) then 
MEDI4736 treatment can be resumed at 
the next scheduled dose 
- 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 coordinating investigators and promptly start systemic steroids 
prednisone  1-2 mg/kg/day or i.v. equivalent   
- Consider skin biopsy if persistent for > 1-2 weeks or recurs 
G3 
Hold MEDI4736 until resolution to ≤ G1 or 
baseline 
 If temporarily holding the MEDI4736 does 
not provide improvement of the G3 skin 
rash  to ≤ G1 or baseline within 30 days, 
then permanently discontinue MEDI4736  
For G3 or G4: 
- Consult dermatology  
-  Promptly initiate empiric i.v. 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. 
CONT. 
G4 
Permanently discontinue MEDI4736  

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- Once improving, gradually taper steroids and consider prophylactic antibiotics, 
antifungals and anti-PCP treatment (please refer to current NCCN guidelines for 
treatment of  cancer-related infections [Category 2B recommendation]) 
- Discuss with coordinating investigators 
Endocrinopathy (e.g. hyperthyroidism, hypothyroidism, hypopituitarism, adrenal insufficiency, etc.) 
(Depending on the type of endocrinopathy, refer to CTCAE version 4.03 for defining the CTCAE severity/Grade) 
Any Grade 
 
 
- 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  
G1 
 
No dose modification 
For G1: (including those with asymptomatic thyroid stimulating hormone (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 
G2  
 
 
For 
G2 
endocrinopathy 
other 
than 
hypothyroidism, hold MEDI4736 dose until  
subject is clinically stable 
• If  toxicity worsens then treat as G3 or G4  
• If toxicity improves to baseline then treat at 
next scheduled treatment date 
• Once event stabilizes to ≤ G1 and 
corticosteroid is reduced to a dose ≤10 mg 
of prednisone per day (or equivalent) then 
MEDI4736 treatment can be resumed at 
For G2: (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. 1-2 mg/kg/day 
methylprednisolone or i.v. equivalent) and prompt initiation of treatment with 
relevant hormone replacement (e.g. levothyroxine, hydrocortisone, or sex 
hormones).  
 CONT. 

 
 
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Grade (CTCAE v4.03) 
Dose Modifications 
Toxicity Management 
the next scheduled dose 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement 
can 
be 
retreated 
with 
MEDI4736 on the following conditions:  
1. the event stabilizes and is controlled 
2. the subject is clinically stable as per 
investigator or treating physician’s clinical 
judgement 
3. doses of prednisone are ≤ 10 mg/day 
or equivalent 
- Once improving, gradually taper steroids and consider prophylactic antibiotics, 
antifungals and anti-PCP treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B recommendation]) 
- For patients with normal endocrine work up (lab or MRI scans), repeat labs/MRI 
as clinically indicated 
G3 or G4 
 
For G3 or G4 endocrinopathy other than 
hypothyroidism, hold MEDI4736 dose until 
endocrinopathy symptom(s) are controlled 
Resume MEDI4736 administration if control-
led at the next scheduled dose 
MEDI4736 treatment can be resumed at the 
next scheduled dose once event stabilizes 
to ≤ G1 and corticosteroid is reduced to a 
dose ≤10 mg of prednisone per day (or 
equivalent) 
For G3 or G4: 
- Consult endocrinologist 
- Isolated hypothyroidism may be treated with replacement therapy without 
treatment interruption and without corticosteroids 
- Promptly initiate empiric i.v. 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 and consider 
prophylactic antibiotics, antifungals and anti-PCP treatment (please refer to 
current NCCN guidelines for treatment of  cancer-related infections [Category 
2B recommendation]) 
- Discuss with coordinating investigators 
 
 
Immune mediated Neurotoxicity  
(to include but not limited to limbic encephalitis, autonomic neuropathy; excluding Myasthenia Gravis and Guillain-Barre) 
Depending on the type of neurotoxicity , refer to CTCAE version 4.03 for defining the severity/Grade 
Any Grade 
 
 
- 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 
G1 
 No dose modifications 
See “Any Grade” recommendations above. 

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Dose Modifications 
Toxicity Management 
G2 
For 
acute 
motor 
neuropathies 
or  
neurotoxicity, hold MEDI4736 dose until 
resolution to ≤ G1 
For sensory neuropathy/neuropathic pain, 
consider holding MEDI4736 dose until 
resolution to ≤ G1 
• If toxicity worsens then treat as G3 or 
G4  
• If toxicity improves to baseline then treat 
at next scheduled treatment date 
• Once event stabilizes to ≤ G1 and 
corticosteroid is reduced to a dose ≤10 
mg 
of 
prednisone 
per 
day 
(or 
equivalent) then MEDI4736 treatment 
can be resumed at the next scheduled 
dose 
- Discuss with the coordinating investigators  
- Obtain neurology consult  
- Sensory neuropathy/neuropathic pain may be managed by appropriate 
medications (e.g. gabapentin, duloxetine, etc.) 
- Promptly start systemic steroids prednisone 1-2 mg/kg/day or i.v. equivalent  
- If no improvement within 3-5 days despite 1-2 mg/kg/day prednisone or i.v. 
equivalent consider additional workup and promptly treat with additional 
immunosuppressive therapy (e.g. IVIgG)  
 
G3 
Hold MEDI4736 dose until resolution to ≤ G1 
Permanently discontinue MEDI4736 if G3 
irAE does not resolve to ≤ G1 within 30 
days. 
For G3 or G4: 
- Discuss with coordinating investigators 
- Obtain neurology consult 
- Consider hospitalization 
- Promptly initiate empiric i.v. methylprednisolone 1 to 2 mg/kg/day or equivalent  
- If no improvement within 3-5 days despite i.v. corticosteroids, consider 
additional workup and promptly treat with additional immunosuppressants (e.g. 
IVIgG)  
- Once stable, gradually taper steroids  
G4 
 
Permanently discontinue MEDI4736 
Immune-mediated peripheral neuromotor syndromes, such as Guillain-Barre and Myasthenia Gravis 
Any Grade 
 
- The prompt diagnosis of immune-mediated peripheral neuromotor 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 

 
 
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Grade (CTCAE v4.03) 
Dose Modifications 
Toxicity Management 
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 IVIgG and followed by plasmapheresis if not responsive to IVIgG 
G1 
No dose modification 
- Discuss with the coordinating investigators 
- 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 
G2 
Hold MEDI4736 dose until resolution to ≤ G1 
Permanently discontinue MEDI4736 if it does 
not resolve to ≤ G1 within 30 days or if 
there are signs of respiratory insufficiency 
or autonomic instability 
 
- Discuss with the coordinating investigators  
- Care should be taken to monitor patients for sentinel symptoms of a potential 
decompensation as described above 
- Obtain a neurology consult  
- Sensory neuropathy/neuropathic pain may be managed by appropriate 
medications (e.g. gabapentin, 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:  
- Important to consider here that the use of steroids as the primary treatment of 

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Guillain-Barre is not typically considered effective. Patients requiring treatment 
should be started with IVIgG and followed by plasmapheresis if not responsive 
to IVIgG 
G3 
Hold MEDI4736 dose until resolution to ≤ G1 
Permanently discontinue MEDI4736 if G3 
irAE does not resolve to ≤ G1 within 30 
days or if there are signs of respiratory 
insufficiency or autonomic instability 
For severe or life threatening (G3 or G4) events:  
- Discuss with coordinating investigators 
- 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 plasmapharesis or IVIgG 
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 IVIgG and 
followed by plasmapheresis if not responsive to IVIgG 
G4 
Permanently discontinue MEDI4736  
 
 
 

 
 
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10.8.2 Infusion-related reactions associated with MEDI4736 
Please also consider the most current version of the IB. 
Grade (CTCAE 
v4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
 
- 
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.) 
G1 
The infusion rate of MEDI4736 may be decreased by 
50% or temporarily interrupted until resolution of the 
event 
- 
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 
G2 
 
The infusion rate of MEDI4736 may be decreased 50% 
or temporarily interrupted until resolution of the event  
Subsequent infusions may be given at 50% of the initial 
infusion rate 
G3/4 
Permanently discontinue MEDI4736 
- 
Manage severe infusion-related reactions per institutional standards (e.g. 
intramuscular epinephrine, followed by i.v. diphenhydramine and ranitidine, 
and i.v. glucocorticoid) 
 
10.8.3 Non-immune mediated reactions associated with MEDI4736 
Please also consider the most current version of the IB. 
Grade (CTCAE 
v4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: dose modifications are not required for AEs not 
deemed to be related to study treatment (i.e. events 
due to underlying disease) or for laboratory 
abnormalities not deemed to be clinically significant 
Treat accordingly as per institutional standard  
G1 
No dose adjustment  
Treat accordingly as per institutional standard  
G2 
Hold MEDI4736 until resolution to ≤ G1 or baseline 
Treat accordingly as per institutional standard  

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Grade (CTCAE 
v4.03) 
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G3 
Hold MEDI4736 until resolution to ≤ G1 or baseline 
For AEs that down-grade to ≤ G2 within 7 days or 
resolve to ≤ G1 or baseline within 14 days, resume 
MEDI4736 administration at next scheduled dose. 
Otherwise, discontinue MEDI4736 
Treat accordingly as per institutional standard  
 
 
G4 
Discontinue MEDI4736  
(Note for G4 labs: decision to discontinue would be 
based on accompanying clinical signs/symptoms and 
as per treating investigator’s clinical judgment and in 
consultation with the coordinating Investigators)  
Treat accordingly as per institutional standard  
 
 

 
 
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11 
SAFETY REPORTING  
11.1 
Definition of serious adverse event (SAE) 
11.1.1 SAEs during trial treatment 
SAE to be reported are any of the events listed in the table below and occurring between 
registration and up to 90 days after the last dose of MEDI4736 or until the initiation of alternative 
anticancer therapy. In case trial treatment is interrupted before any dose of MEDI4736 is 
administered, SAE are to be reported until 30 days from last dose of chemotherapy: 
Criteria fulfilling the condition for a SAE 
SAE 
Comments 
Fatal 
All events resulting in death. 
Life-threatening 
The patient was at immediate risk of death from the event as it occurred.  
It does not include an event that, had it occurred in a more serious form, 
might have caused death. 
Requires inpatient 
hospitalization 
(> 24 hours) 
Events not considered to be SAE are hospitalizations > 24 hours and 
occurring under the following circumstances:  
- elective surgery (planned before entry into the trial), 
- protocol-related treatments, procedures or monitoring, 
- social reasons (e.g. in rehabilitation home), 
- disease progression. 
Prolongs 
hospitalization 
Prolongation of an existing hospitalization. 
Disabling 
Includes persistent or relevant disability or incapacity. 
Secondary 
malignancy 
Any new malignancy other than a relapse of the current tumor. 
Congenital anomaly Birth defect in neonate/infant or stillbirth. 
Other medically 
significant condition 
Important events that are not immediately life-threatening or do not result in 
death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed above. 
11.1.2 SAEs after the end of trial treatment 
During the follow-up phase (starting 90 days after the last dose of MEDI4736; or 30 days after the 
last dose of chemotherapy in case trial treatment was interrupted before any dose of MEDI4736 
was administered), the following events have to be reported as SAE: 
SAE 
Comments 
Fatal 
Defined as above, but only events possibly, probably or definitely related to
(late effects of) trial treatment/procedure. 
Life-threatening 
Defined as above, but only events possibly, probably or definitely related to
(late effects of) trial treatment. 
Disabling 
Defined as above, but only events possibly, probably or definitely related to 
(late effects of) trial treatment. 
Secondary 
malignancy 
Any new malignancy other than a relapse of the current tumor. 
Congenital anomaly 
Birth defect in neonate/infant or stillbirth. 
Other medically 
significant condition 
Defined as above, but only events possibly, probably or definitely related to
(late effects of) trial treatment. 

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11.2 
Definition of serious adverse reaction (SAR) 
SARs are all SAEs considered to be possibly, probably or definitely related to the trial treatment. 
11.3 
Definition of suspected unexpected serious adverse reactions 
(SUSARs) 
SUSARs are serious adverse reactions that are related to medication and assessed as unexpected 
on the basis of the applicable product information (cisplatin/docetaxel) or the IB (MEDI4736). 
11.4 
Reporting of individual SAEs by the investigator 
Any SAE must be reported by submitting the completed initial report section of the trial-specific 
SAE form within 24 hours of becoming aware of the event. This form can be downloaded from the 
SAKK website (www.sakk.ch  Members  Trials  Lung Cancer  SAKK 16/14  CRFs). 
Reporting is done by sending the SAE form by fax to:    
Fax: +41 31 508 41 42 
The SAE outcome must be reported within 2 weeks after initial report by submitting the follow-up 
report (e.g. initial SAE form, updated with follow-up information) to the SAKK CC by fax. In case 
the SAE is reported as ongoing after 14 days, the follow-up report has to be submitted again with 
the final outcome. The investigator is responsible for following all SAEs until resolution, until the 
patient returns to baseline status or until the condition has stabilized with the expectation that it will 
remain chronic. 
The originals of the SAE forms (both initial and follow-up reports) are kept at the sites in the 
Investigator’s file.  
11.5 
Reporting of individual SAEs and SUSARs by the sponsor 
The SAKK CC ensures that all reporting requirements and timelines for reporting, as defined in the 
Swiss HRA and its applicable ordinances are followed. 
The SAKK CC will forward any SAE which is fatal or resulted in death to the involved EC. 
The SAKK CC will report every SUSAR to all principal investigators, to the involved ECs and to 
Swissmedic in accordance with the Swiss HRA. 
Additionally, SAKK CC will forward each individual SAE and SUSAR to the coordinating 
investigator and to AstraZeneca. 
11.6 
Reporting of safety signals 
In case the investigator receives external safety reports/letters related to the IMP, he/she must 
report to the sponsor within 7 days. The SAKK CC will forward these reports/letters to all 
investigators and to the local and lead ECs if applicable.   
11.7 
Pregnancy 
Pregnancy itself or pregnancy of a patient’s partner is not regarded as an AE unless there is 
suspicion that the trial IMP may have interfered with the effectiveness of a contraception 
medication. In the case of pregnancy occurring during the trial treatment or during 90 days after the 
last dose of MEDI4736, the investigator must report the event to the SAKK within 24 hours of 
knowledge of the event by completing the SAKK pregnancy reporting form. This form (available on 
the SAKK website (www.sakk.ch  Members  Trials  Lung Cancer  SAKK 16/14  CRFs) 
has to be filled in immediately and faxed to the SAKK CC. The investigator shall ensure that the 
case is followed up until the end of the pregnancy and supply a final report on the outcome to the 

 
 
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SAKK CC. In addition, the investigator has to report any fetal anomaly, stillbirth, miscarriage or any 
other significant medicinal event concerning the pregnancy as SAE (see section 11.1.1).  
Patients who become pregnant during trial treatment will be transferred to the follow-up phase of 
the trial (see section 9.7). 
In case the female partner of a male patient becomes pregnant while the patient is on trial 
treatment or in the follow-up period of the trial, the patient should, with his partner’s consent, notify 
the investigator. It is recommended that the investigator shall ensure that the case is followed up 
until the end of the pregnancy and supply a final report on the outcome to the SAKK CC. 
The SAKK CC will forward within 1 working day each individual pregnancy report to the 
coordinating investigator and to AstraZeneca after receipt from the site. SAKK CC will endeavor to 
collect follow-up information and distribute final reports on pregnancy outcome to AstraZeneca in 
due time.  
11.8 
Periodic reporting on safety  
The SAKK CC ensures that the reporting requirements and timelines for reporting, as defined in 
the respective applicable laws, are followed.  
A development safety update report (DSUR) will be provided to the local investigators for filing into 
the investigator’s file. The SAKK CC will submit the DSUR to the involved ECs, to Swissmedic and 
to AstraZeneca. 
 

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EVALUATIONS AND INVESTIGATIONS BEFORE, 
DURING AND AFTER TRIAL TREATMENT 
Assessments and investigations must be done within the defined time as indicated below. 
At the start of each therapy cycle (with chemotherapy or immunotherapy), assessments may be 
done one day before or on the day of therapy administration (d-1 or d1 of each cycle) unless 
otherwise specified in text below.  
During the therapy cycle, weekly assessments may be done within ± 1 day of the indicated day.  
A schedule of assessments and treatments is provided in Appendix 8. An adaptable scheduler (MS 
Excel file) can be downloaded from the SAKK website (www.sakk.ch  Members  Trials  Lung 
Cancer  SAKK 16/14). 
12.1 
Pretreatment evaluations and procedures 
Informed consent must be obtained before registration and prior to any trial-specific procedures. 
12.1.1 The following investigations have to be performed before registration:  
• Histological confirmation of NSCLC  
• Confirmation of the availability of tumor material (preferably histology, cytology allowed) at 
diagnosis for Central Pathology 
12.1.2 The following investigations have to be performed within 42 days before 
registration  
• Brain MRI or CT to exclude brain metastasis 
• Pulmonary function tests according to ESTS guidelines, as depicted in Appendix 7 [75] 
• Echocardiography to evaluate cardiac function 
12.1.3 The following investigations have to be performed within 28 days before 
registration  
• PET/CT with contrast enhanced CT scan of thorax and upper abdomen (incl. the assessment 
of number and size of lymph nodes) 
• Tumor staging to confirm stage T1-3N2M0 (stage IIIA/N2) disease according to the process 
chart depicted in Appendix 6. One of the following investigations has to be performed: 
o Mediastinoscopy 
o Endobronchial ultrasound (EBUS) with FNA 
o Bronchoscopy with FNA 
o Esophageal ultrasound with FNA 
• 12-lead ECG (in triplicate, 2-5 minutes apart)  
12.1.4 The following investigations have to be performed within 14 days before 
registration 
• Medical history, including baseline symptoms, concomitant corticosteroids, smoking habits, 
weight loss over 6 months, Charlson Comorbidity Index [82] 
• Physical examination, including assessment of WHO performance status, weight, height and 
blood pressure 
• Hematological values: hemoglobin, absolute neutrophils count, platelets count, WBC 
• Hepatic function: bilirubin, AST/ALT, AP 
• Metabolic function (serum or plasma): sodium (Na), potassium (K), magnesium (Mg) 
• Renal function: serum creatinine and calculated creatinine clearance (according to the formula 
of Cockcroft-Gault, see Appendix 3) 

 
 
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• Thyroid function test: thyroid-stimulating hormone (TSH); free T3 and free T4 only if TSH 
abnormal 
• Urine analysis*: bilirubin, blood, glucose, ketones, pH, protein, specific gravity, color and 
appearance (*microscopy should be used as appropriate to investigate white blood cells (WBC) and 
use the high power field for red blood cells)  
Within 14 days prior to registration until d1 of treatment (but before the first dose of treatment) 
• Mandatory: samples for translational research projects 
o 30 ml heparinized blood, 10 ml serum blood and 2.5 ml PAXgene blood (see 
section 18.4) 
o Note: histology or cytology samples for (retrospective) central review must be 
shipped to Central Pathology at the latest 30 days following registration (see 
section 17.1.3)  
• Optional: (only for patients who indicated their consent in main PIS/IC) 
o Stool (see section 18.4)  
Within 7 days prior to registration:  
• Serum pregnancy test (for women of childbearing potential only) 
12.2 
Evaluations during neoadjuvant chemotherapy  
Visits will take place weekly during the 3 cycles of neoadjuvant chemotherapy. 
On day 1 of each cycle  
d1, 22 and 43 
• Physical examination including assessment of WHO performance status, weight and blood 
pressure 
• Hepatic function: AST/ALT  
• Renal function: creatinine and calculated creatinine clearance (according to the formula of 
Cockcroft-Gault, see Appendix 3)  
• Metabolic function (serum or plasma): Na, K, Mg 
On day 1 of each cycle and weekly thereafter  
d1, 8, 15, 22, 29, 36, 43, 50 and 57 
• Hematological values: hemoglobin, absolute neutrophils count, platelets count, WBC 
• AEs 
During cycle 3 of neoadjuvant chemotherapy  
Between d50-d63 (corresponds to weeks 8-9) 
• Radiological assessment with PET/CT with contrast enhanced CT scan of thorax and upper 
abdomen [83]. 
Note:  
o Patients who permanently discontinue neoadjuvant chemotherapy due to AE and proceed to 
MEDI4736 therapy have to undergo a radiological re-assessment with PET/CT with contrast 
enhanced CT scan of thorax and upper abdomen within one week before starting MEDI4736. 
Further investigations may be performed according to local standards. 
 
 

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Evaluations during neoadjuvant MEDI4736 therapy 
Visits will take place weekly during the two cycles of neoadjuvant treatment with MEDI4736. 
On day 1 of cycle 1  
d64 (week 10) 
• 12-lead ECG (in triplicate, 2-5 minutes apart) prior treatment administration 
• Thyroid function test: TSH; free T3 and free T4 only if TSH abnormal 
• Urine analysis*: bilirubin, blood, glucose, ketones, pH, protein, specific gravity, color and 
appearance (*microscopy should be used as appropriate to investigate WBC and use the high power 
field for red blood cells) 
• Mandatory: samples for translational research projects 
o 30 ml heparinized blood, 10 ml serum blood and 2.5 ml PAXgene blood (see 
section 18.4) 
On day 1 of each cycle  
d64 (week 10) and d78 (week 12) 
• Physical examination including assessment of WHO performance status and weight  
• Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) measured within 
one hour prior to start of MEDI4736 administration, at 30 minutes during the infusion (± 5 
minutes), at the end of infusion (± 5 minutes), and at 30 minutes (± 5 minutes) post-infusion.  
• After the first infusion (cycle 1, day 64) vital signs must also be measured 60 minutes (± 5 
minutes) post-infusion. 
On day 1 of cycle 1 and weekly thereafter 
d64, 71, 78 and 85 
• Hematological values: hemoglobin, absolute neutrophils count, platelets count, WBC 
• Clinical chemistry (serum or plasma): creatinine, AST/ALT, Na, K, Mg 
• AEs 
Further investigations may be performed according to local standards. 
12.4 
Evaluations at surgery  
Surgery must take place 2-4 weeks after the last infusion of MEDI4736.  
The following assessments have to be done during the week preceding the surgery. 
• Physical examination including assessment of WHO performance status, weight and blood 
pressure 
• Hematological values: hemoglobin, absolute neutrophils count, platelets count, WBC 
• Clinical chemistry (serum or plasma): creatinine, AST/ALT, Na, K, Mg 
• Coagulation parameters: prothrombin time (PT), partial thromboplastin time (PTT), 
international normalized ratio (INR) 
• Thyroid function test: TSH; free T3 and free T4 only if TSH abnormal 
• AEs 
• 12-lead ECG (additional echocardiography at the local investigator’s discretion) 
• Pulmonary function tests (according to ESTS guidelines) 
• PET/CT with contrast enhanced CT scan of thorax and upper abdomen (may be done up to 2 
weeks preceding surgery) 
• Mandatory: samples for translational research projects 
o 30 ml heparinized blood, 10 ml serum blood and 2.5 ml PAXgene blood (see 
section 18.4) 

 
 
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After surgery: 
• AEs  
• Mandatory: samples for central pathology review and translational research projects  
o Resected tumor specimen must be sent to Central Pathology (see section 
17.1.3) 
During radiation therapy: 
For patients with R1/R2 resection (including patients with extracapsular spread of lymph node 
metastasis) undergoing radiotherapy, the investigator must collect and record the following 
assessments during the entire course of the radiation therapy: 
• AEs 
12.5 
Evaluations during adjuvant MEDI4736 therapy 
Adjuvant treatment with MEDI4736 should start within 4-6 weeks after surgery (or within 2 weeks 
after the completion of radiotherapy, when applicable) and will be administered for a maximum of 1 
year (26 cycles).  
Visits will take place on day 1 of each cycle. 
On day 1 of each cycle 
• Physical examination including assessment of WHO performance status and weight  
• Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) measured within 
one hour prior to start of MEDI4736 administration, at 30 minutes during the infusion (± 5 
minutes), at the end of infusion (± 5 minutes), and at 30 minutes (± 5 minutes) post-infusion.  
• AEs 
On day 1 of cycle 1 and every other cycle thereafter 
• Hematological values: hemoglobin, absolute neutrophils count, platelets count, WBC  
• Clinical chemistry (serum or plasma): creatinine, AST/ALT, Na, K, Mg  
• Thyroid function tests: TSH; free T3 and free T4 only if TSH abnormal 
• Urine analysis*: bilirubin, blood, glucose, ketones, pH, protein, specific gravity, color and 
appearance (*microscopy should be used as appropriate to investigate WBC and use the high power 
field for red blood cells) 
On day 1 of cycle 1 and cycle 9 
• 12-lead ECG (in triplicate, 2-5 minutes apart) prior treatment administration 
On day 1 of cycle 5 
• Mandatory: samples for translational research projects 
o 30 ml heparinized blood, 10 ml serum blood and 2.5 ml PAXgene blood (see 
section 18.4) 
• 
Optional (only for patients who indicated their consent in main PIS/IC): 
o Stool (see section 18.4; distribute the collection tube to the patient at cycle 4).  
Every 3 months after the start of adjuvant treatment, starting 1 month after surgery  
i.e. month 1, 4, 7, 10 (± 1 week) after surgery 
• Contrast enhanced CT scan of thorax and upper abdomen  
For all patients without previous disease progression/relapse: a contrast enhanced CT scan of 
thorax and upper abdomen has to be performed at 12 months post-registration (+ 4 weeks), 
unless such a CT scan is already performed within the 6 weeks preceding the 12-month 
post-registration time-point during the regular schedule of assessment (i.e. month 1, 4, 7, 10 
after surgery). This tumor assessment is crucial for the evaluation of the primary endpoint (12 
months EFS). 

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12.6 
Evaluations at the end of treatment 
Assessments are to be done within 1 month following the last dose of MEDI4736 in case of 
treatment completion as per protocol or after premature treatment termination (for any of the 
reason as mentioned in 9.7). 
• 12-lead ECG (in triplicate, ≥2-5 minutes apart) 
• Hematological values: hemoglobin, absolute neutrophils count, platelets count, WBC 
• Clinical chemistry (serum or plasma): creatinine, AST/ALT, Na, K, Mg 
• Thyroid function tests: TSH; free T3 and free T4 only if TSH abnormal 
• X-ray 
• AEs 
• Mandatory: samples for translational research projects 
o 30 ml heparinized blood, 10 ml serum blood and 2.5 ml PAX blood (see 
section 18.4) 
12.7 
Evaluations at recurrence 
At the time of tumor progression/relapse (only if it occurs during adjuvant trial treatment or within 
30 days after the end of adjuvant treatment)  
• Mandatory: samples for translational research projects 
o 30 ml heparinized blood and 10 ml serum blood (see section 18.4) 
• Optional: (requires additional patient informed consent) 
o Tumor re-biopsy (preferred) or cytology (see section 17.1.3) 
12.8 
Evaluations in the follow-up phase  
Patients will be followed-up lifelong. Follow-up visits will take place: 
- every 3 months (± 2 weeks) during the first two years after the end of trial therapy,  
- every 6 months (± 1 month) during the next three years until 5 years, 
- yearly (± 1 month) until patient death (unless clinically indicated otherwise). 
Patients without recurrence who are transferred to the follow-up phase before completion of trial 
treatment are followed as patients completing therapy without progression. 
12.8.1 Patients without recurrence 
• Physical examination 
• Contrast enhanced thorax CT scan alternating with chest X-ray 
(every 3 months within 2 years after end of therapy; afterwards, every 6 months until 5 years 
after the end of therapy or until disease progression/relapse).  
Five years after the first follow-up visit, no further imaging is requested by the protocol. 
• For all registered patients without previous disease recurrence: a contrast enhanced CT 
scan of thorax and upper abdomen has to be performed at one year post-registration (+ 
4 weeks), unless already performed within the 6 weeks preceding the 12-month post-
registration time-point during the regular schedule of assessment as described above. 
This assessment is crucial for the evaluation of the primary endpoint (12 months EFS). 
Hematological and blood chemistry analyses may be done according to local standards. 
12.8.2 Patients after recurrence 
After the patient experienced progression, no trial-specific clinical assessments are requested. 
Further treatments and investigations are at the discretion of the treating physician. 
• Survival status 
• Reporting of subsequent therapies 

 
 
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13 
CRITERIA OF EVALUATION AND DEFINITION OF 
ENDPOINTS 
13.1 
Criteria of evaluation 
The following population sets will be used for the analysis: 
• 
Full analysis set (FAS): is defined as all patients who received at least one dose of 
chemotherapy, excluding patients with major eligibility violations (as defined in the Statistical 
analysis Plan (SAP)).  
• 
Full analysis set-2 (FAS-2): is defined as all patients who received at least one dose of 
chemotherapy and at least one dose of anti-PD-L1 antibody MEDI4736, excluding patients with 
major eligibility violations (as defined in the SAP). 
• 
Per protocol (PP) set: is defined as a subset of patients of the FAS population excluding 
patients who did not receive full trial treatment (at least one dose of chemotherapy, followed by 
at least one dose of neoadjuvant MEDI4736, surgery and then at least one dose of adjuvant 
MEDI4736) or patients who had major protocol violations (as defined in the SAP). 
• 
Safety set: is defined as all patients who took at least one dose of the trial treatment after 
registration.  
In case of uncertainty, the coordinating investigator together with the trial team will decide, prior to 
the analysis and without looking at any efficacy data, if a patient can be included in the FAS, FAS-2 
or PP set. 
The patients who do not comply with the FAS criteria will not be taken into consideration for the 
efficacy endpoints. 
13.2 
Definition of Endpoints 
13.2.1 Primary endpoint 
EFS at 12 months 
EFS at 12 months is defined as absence of events at 12 months after registration. EFS and event 
definition are given in section 13.2.2 below. 
13.2.2 Secondary endpoints  
EFS 
EFS is defined as time from registration to one of the following events, whichever occurs first: 
• 
Relapse or progression according to RECIST 1.1 criteria (see Appendix 1). 
• 
Second tumor  
• 
Death due to any cause 
Patients not experiencing an event will be censored at the date of last tumor assessment before 
starting a subsequent treatment, if any. 
OS 
OS is defined as time from registration until death due to any cause. 
Patients not experiencing an event will be censored at the last date they were known to be alive. 
OR after neoadjuvant chemotherapy  
OR after neoadjuvant chemotherapy is defined as complete response (CR) or partial response 
(PR) after the end of neoadjuvant chemotherapy. 
Response will be evaluated according to RECIST 1.1 criteria. 
Patients without response assessment after the end of neoadjuvant chemotherapy will be regarded 
as having a non-evaluable response (NE) and shall be considered as failures for this endpoint. 

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OR after neoadjuvant immunotherapy 
OR after neoadjuvant immunotherapy is defined as complete response (CR) or partial response 
(PR) after the end of neoadjuvant immunotherapy. Response will be evaluated according to 
RECIST 1.1 criteria. 
Patients without response assessment after the end of neoadjuvant immunotherapy will be 
regarded as having a non-evaluable response (NE) and shall be considered as failures for this 
endpoint. 
pCR 
pCR is defined as complete absence of any residual tumor in the primary tumor or in the involved 
lymph nodes or any suspicion of metastasis after the surgery of the patient. 
Patients who were not operated will not be taken into consideration for this endpoint. Results from 
Central Pathology will be used. 
Major pathological response (10% or less residual viable tumor [84]) 
Major pathologic response is defined as the presence of 10% or less of the residual viable tumor 
after surgery. 
Patients who were not operated will not be taken into consideration for this endpoint. Results from 
Central Pathology will be used. 
Nodal down-staging to < ypN2 
Nodal down-staging to < ypN2 is defined as the case where after the surgery the remaining node 
status of the patients according to the TNM cancer staging system is less than N2 (N0/1). 
Patients who were not operated will not be taken into consideration for this endpoint. 
Complete resection 
Complete resection is defined as fulfillment of all the following criteria, according to [74]: 
- 
free resection margins proved microscopically (R0 resection) 
- 
mediastinal nodal dissection 
- 
no extracapsular mediastinal nodal involvement 
- 
no involvement of nodal resection margins (nodal stations 2 and 9) 
Patients who were not operated will not be taken into consideration for this endpoint. 
Pattern of recurrence (local, loco-regional, distant) 
Pattern of recurrence is defined as location of first tumor progression or relapse. Patterns can be 
local (area of primary tumor or mediastinum), loco-regional or distant. 
A separate category will include the combination of the above patterns. 
Cases of patients with secondary malignancy or patients with no progression/relapse will not be 
taken into consideration for this endpoint. 
AEs 
All AEs (incl. abnormal vital signs) will be assessed according to NCI CTCAE v4.03 (see section 
10.2). 
Postoperative 30-day mortality 
Postoperative 30-day mortality is defined as the case when a patient’s death occurs within 30 days 
from the thoracic surgery to remove the primary tumor. 
Patients who were not operated will not be taken into consideration for this endpoint. 
 
 

 
 
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14 
DOCUMENTATION 
14.1 
CRFs and reports 
CRFs specifically created for this trial are used for documentation. It is very important to adhere to 
the schedule of visits prescribed in the protocol for all patients.  
The eCRFs have to be completed online in the web-based EDC system (www.sakk.ch/edc) in a 
timely manner. The data should be entered into the eCRFs within a month from the patient’s visit 
or medical examination.  
Sites must use a patient identification list in order to allow identification of a patient. This list must 
be kept at the site in the investigator’s file. 
14.2 
Notes for special handling of CRFs 
Eligibility CRF: 
• 
The completed form ER in the web-based EDC system has to be printed and signed by the 
treating investigator (authorized physician according to the staff list). A copy of the signed 
form ER has to be sent to SAKK CC by email or fax within one month after the patient’s 
registration. The original signed form (or a copy thereof, in case the original was sent to SAKK 
CC), is kept at the site in the Investigator’s file. 
• 
If it is not possible to enter the eligibility form online for technical reasons, complete the paper 
CRF version and fax it in due time to the SAKK CC, which will perform the registration of the 
patient (see also section 7).  
SAE and pregnancy report forms: 
• 
Trial-specific SAE report forms and the pregnancy report forms have to be submitted by fax to 
SAKK CC within 24 hours of becoming aware of the SAE or pregnancy (see section 11 for 
SAE reporting and pregnancy reporting). Originals of SAE and pregnancy report forms are kept 
at the site in the Investigator’s file. 
AESI report forms: 
• 
Non-serious AESIs are reported in the web-based EDC system on an AE form (the tick-box 
whether the event is an AESI must be checked).  
• 
Serious AESIs are reported within 24 hours of becoming aware of the event using the trial-
specific SAE report form mentioned above, in case the AESI complies with the definition for 
seriousness. 
14.3 
Source data 
Additionally to other source data, the following data entered directly into trial documents are 
considered to be source data:  
• 
patient screening and enrollment list, 
• 
patient identification list,  
• 
drug inventory log. 
 

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STATISTICAL CONSIDERATIONS 
15.1 
Introduction 
The primary endpoint of this trial is EFS at 12 months after registration, with the intention to show 
promising efficacy results of the proposed therapeutic scheme compared to the standard of care. 
In the standard of care, EFS at 12 months was 48% (primary analysis of trial SAKK 16/00) [35]. 
Final results of trial SAKK 16/96 were similar. An EFS rate at 12 months of at least 65% is required 
in order to consider the proposed therapeutic scheme as promising. 
15.2 
Sample size estimation 
• 
Software package: R 3.2 (FixDes {OptInterim}) 
• 
Number of treatment arms: 1 
• 
Type of design: Single stage design based on EFS  rate at a specific time-point  
• 
Null hypothesis: EFS at 12 months ≤ 48% [35] 
• 
Alternative hypothesis: EFS at 12 months ≥ 65% 
• 
Type I error: 0.05 
• 
Power: 0.8 
• 
Number of interim analyses for the primary endpoint: 0 
• 
Expected accrual rate: 2 patients per month 
• 
Expected proportion of non-evaluable patients: 5% (4 patients) 
• 
Minimum sample size needed for the primary endpoint estimation: 64 
• 
Total sample size: 68 
• 
Expected accrual duration: 3 years 
• 
Minimal follow-up time for primary analysis: 12 months from registration 
• 
Expected trial duration until primary analysis (accrual duration + minimal follow up): 4 years 
15.3 
Interim safety analysis 
An interim safety analysis may be performed after the first 25 included patients according to the 
following rule. The 30-day postoperative mortality rate will be calculated as soon as a period of 30 
days after the patients’ surgeries is completed. In case of a postoperative 30-day mortality >10%, a 
safety interim analysis will be performed and the independent data monitoring committee (IDMC) 
appointed by the SAKK Board will have to evaluate the safety of the trial and suggest appropriate 
measures (a detailed description of the interim data monitoring procedure will be specified in a 
dedicated IDMC charter). During the safety analysis, trial accrual will be suspended. 
The SAKK Board will decide on trial continuation or premature termination based on the 
recommendations of the IDMC. 
15.4 
Statistical analyses 
The primary analysis will take place only after all patients who comply with the FAS criteria have 
been followed at least for a period of 12 months after registration or until they experience an event, 
if this occurs first. 
All efficacy endpoints will be analyzed using the FAS unless otherwise specified. Supportive 
analyses based on the FAS-2 and PP set will be performed. All safety endpoints will be analyzed 
using the safety set. 
For the primary endpoint, the point estimate of EFS at 12 months together with its 90% confidence 
interval will be presented using the Kaplan-Meier estimators of the survival function. 

 
 
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Generally for each categorical variable the results will be summarized by frequencies and 
percentages. For each continuous variable the results will be summarized by descriptive statistics. 
All time-to-event endpoints shall have the median value estimated using the Kaplan-Meier method, 
along with a 95% confidence interval (CI). The number and type of events of each endpoint shall 
be presented descriptively by frequency and percentage. 
Laboratory values will be expressed as absolute values and as grading (ordinal categorical 
variables) according to NCI CTCAE v4.03. 
AEs will be presented by type and Grade in listing tables showing frequency and percentage of the 
within-patient worst grades. In addition, Grade ≥ 3 AEs and AEs with relation to treatment at least 
probable will be summarized separately.  
No adjustment will be made for multiple testing. 
Full analysis details will be outlined in the SAP.  
15.5 
Handling of missing data and drop-outs 
No imputation of missing data will be performed. 
A row denoted “Missing” will be included in count tabulations if necessary to account for drop-outs 
and missing values. As mentioned in section 13.1, patients not fulfilling the FAS criteria will not be 
taken into consideration for the efficacy endpoints.  
16 
QUALITY OF LIFE  
Not applicable  
 
 
 

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PATHOLOGY 
In order to uniformly assess the pathological response to neoadjuvant treatment (chemotherapy 
and immunotherapy), a central histopathological review will be performed. For that purpose, 
surgical specimens will be reviewed. 
Histological diagnosis is highly recommended, however cytology specimens only are acceptable. 
Biopsy of the primary tumor is recommended. However, if biopsy of the primary tumor is technically 
or due to the expected complications not feasible, a radiologically highly suspicious lymph node 
may be used for resection or biopsy to obtain histological material. 
17.1 
Local pathology 
17.1.1 Task for the local investigator 
The local investigator at each participating site is responsible to inform the local surgeon and the 
local pathologist about the protocol, the trial-specific requirements and the sample handling for 
central pathological review and investigations and sample banking.  
It is the task of the local investigator to determine the disease stage according to the TNM 
classification (7th edition, October 2009, Appendix 2) and to order the tumor material by the local 
pathologist (see 17.1.3). 
17.1.2 Task for the local pathologist 
The main task of the local pathologist is the diagnostic work-up of biopsy and resection specimens 
in a routine manner considering the following instructions: 
Baseline biopsy or cytology at diagnosis (pre-treatment) 
• 
The local pathologist must diagnose and subtype NSCLC by using as little tumor material as 
possible (we only recommend p40 and TTF1), so that enough can be sent to Central Pathology 
for review and translational studies. 
• 
Diagnostic workup and NSCLC subtyping should be performed according to the WHO 
classification (4th edition, 2015) [85]. 
• 
Immunohistochemistry should only be performed if necessary and should be restricted to a 
minimum panel of markers. 
Resection specimen after neoadjuvant treatment 
• 
The local pathologist must examine the resection specimen in accordance with the protocol of 
the College of American Pathologists (which is available under the following link:  
http://www.cap.org/ShowProperty?nodePath=/UCMCon/Contribution%20Folders/WebContent/
pdf/lung-13protocol-3300.pdf). 
• 
The percentage of vital tumor tissue compared to the tumor bed should be evaluated 
macroscopically and microscopically and should be documented in the pathology report.   
• 
In addition to the vital tumor, the whole tumor bed (fibrosis/necrosis) should be measured and 
at least one block per cm of the tumor bed should be embedded (not only the vital tumor 
areas). If no vital tumor is visible the whole tumor bed has to be examined histologically. 
• 
Pathological TNM staging must be done according to the latest TNM classification (7th edition, 
October 2009 (see Appendix 2). 
Biopsy or cytology at recurrence (post-surgery) 
Only for patients who separately consented to the optional translational research (if 
recurrence is within the time of adjuvant treatment or within 30 days after completion of adjuvant 
treatment) 
Re-biopsy is highly recommended, however cytology specimens only are acceptable. 
• 
The local pathologist must confirm recurrence in a routine manner by using as little tissue as 
possible, so that enough tissue can be sent to Central Pathology for translational studies. 
• 
Predictive marker analyses, if necessary, should be performed in a routine manner. 

 
 
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17.1.3 Required material for pathological review 
The local investigator will order and ship the required following material to Central Pathology, 
together with the “Pathology sample cover letter” provided on the SAKK website (www.sakk.ch  
Members section  Trials  Lung Cancer  SAKK 16/14  trial tools): 
Baseline biopsy or cytology at diagnosis (pre-treatment) 
• 
if NSCLC is confirmed (preferably by histology) by the local pathologist, the local 
investigator will order the following material from the biopsy after registration of the patient: 
o max 5 cytology specimen containing tumor, preferably from the primary tumor (and 
the formalin-fixed and paraffin-embedded (FFPE) cell block, if available).  
o Or in case a histology sample is available: one hematoxylin and eosin (HE)-stained 
slide and the FFPE tumor tissue block or alternatively 10 unstained slides. 
o A copy of the local pathology report coded with the patient’s UPN (patient 
information such as name and date of birth must be erased).  
Resection specimens after neoadjuvant treatment 
• 
The local investigator will inform the responsible surgeon that the patient is enrolled in the 
trial. 
• 
The surgeon will send the resection specimen to the local pathologist in a routine manner 
with a note on the local pathology order form that the patient is enrolled in the trial (SAKK 
16/14). 
o HE-stained histological slides from all tumor-containing blocks of the tumor and the 
tumor bed. 
o One representative FFPE block from the primary tumor site or the tumor bed in case 
of complete tumor regression and of one mediastinal lymph node metastasis if 
available, or alternatively 10 empty sections from representative FFPE blocks 
(blocks are preferred). 
o A copy of the local pathology report, coded with the patient’s UPN (patient 
information such as name and date of birth must be erased). 
Biopsy or cytology at recurrence (post-surgery) 
Only for patients who separately consented to the optional translational research (if 
recurrence is within the time of adjuvant treatment or 30 days thereafter) 
• 
The local investigator will inform the responsible pneumologist/radiologist that the patient is 
enrolled in the trial. 
• 
The pneumologist/radiologist will take a biopsy (preferred) or cytology and send it to the 
local pathologist in a routine manner with a note on the local pathology order form that the 
patient is enrolled in the trial (SAKK 16/14). 
o 5 cytology specimen containing tumor (and the FFPE cell block, if available).  
o Or in case a histology sample is available: one HE-stained slide and the FFPE 
tumor tissue block or alternatively 10 unstained slides (blocks are preferred). 
o A copy of the local pathology report, coded with the patient’s UPN (patient 
information such as name and date of birth must be erased). 
Return of diagnostic samples: Any diagnostic sample can be returned to the site for diagnostic 
purposes and upon request from the local investigator or pathologist. Patients and their treating 
physicians have the right to be informed of the results of the central pathology review and 
investigations. Central Pathology will forward this information to any investigator whose patient or 
their treating oncologist expresses their wish to be informed. 
Reimbursement for the local pathologist 
The work of the local pathologist will be financially compensated by SAKK according to the SAKK 
guidelines on the pricing for Pathology (see “Principles of Translational Research in SAKK Trials”). 
Reconciliation listings 

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The local pathologist will be requested to provide at regular intervals a listing of all shipped 
samples to Central Pathology and SAKK CC for reconciliation. Timing for the reconciliation will be 
determined by the SAKK CC and communicated to the sites during trial conduct. 
17.1.4 Labeling and handling 
All material has to be clearly labeled with: 
SAKK 16/14 
Patient UPN  
Date of sampling 
Sample ID of local pathology institute 
Site 
17.1.5 Shipment 
Samples, including the accompanying documents, have to be shipped within one month of 
registration/ patient surgery/ biopsy or cytology at recurrence (if applicable) with priority postal mail 
to:  
 
Dr. med. Spasenija Savic  
 
Trial SAKK 16/14 
 
Institute of Pathology, USB 
 
Schönbeinstrasse 40 
 
CH – 4031 Basel 
 
17.2 
Central pathology 
17.2.1 Task for the central pathologist 
The central pathologist will review the shipped tumor material and lead the pathological 
investigation with the samples. Examinations will be performed in accordance with the WHO 
classification (4th edition, 2015) and the protocol of the College of American Pathologists. 
The review data will be entered in the EDC system by the central pathologist.  
Baseline biopsy or cytology at diagnosis (pre-treatment) and biopsy or cytology at 
recurrence (post-surgery) if available 
• 
The NSCLC subtype will be confirmed (acc. to WHO classification, 4th edition, 2015) [85]. 
• 
The ratio of cancer versus non-cancer tissue will be assessed 
• 
The feasibility for translational studies will be assessed 
Resection specimen after neoadjuvant treatment 
• 
The pathological response to neoadjuvant treatment (% of vital tumor) will be confirmed 
• 
The ratio of cancer versus non-cancer tissue will be assessed 
• 
The feasibility for translational studies will be assessed. 
Reconciliation listings 
The central pathologist will be requested to send at regular intervals (in general, twice yearly) a list 
of all received samples to SAKK CC for information and reconciliation. Timing for the reconciliation 
will be communicated to the pathologist during trial conduct. 
17.3 
Pathology samples banking 
In case the patient consented to the storage of the tumor material in the trial-associated Biobank, 
the tumor samples will be kept at the Institute of Pathology, University Hospital Basel, for a 
maximum of 10 years after the publication of the primary analysis, for future research in connection 
with NSCLC and according to the trial-specific Biobank Regulation (see section 18.7 for further 
considerations and procedures with respect to sample banking). Any new research on these 
samples that is not planned in this protocol must first be approved by the SAKK board and by the 
relevant Ethics committee. 
In case the patient did not consent to the biobanking of his/her tumor material, any leftover material 
will be returned to the site after the mandatory translational research part of the trial is performed. 
Any diagnostic sample can be returned to the site in case of need for diagnostic purposes. 

 
 
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18 
TRANSLATIONAL RESEARCH  
Tumor samples from diagnostic biopsy or cytology and surgical resection as well as blood and 
stool samples obtained at defined time points during the conduct of the trial will allow an 
observational exploratory translational research.  
Any research question not included in the protocol has to be formulated in written. The additional 
project has to consider the funding of the research and must be approved by the SAKK Board and 
be submitted to the relevant Ethics Committees and regulatory authorities for authorization.  
18.1 
Determination of a pre- and post-therapeutic „Tumor Immune 
Profile“ (mandatory) 
Patient participation in the translational projects described in this section is mandatory. Patient 
consent for translational research with their biological material and clinical data collected at 
baseline and during trial treatment, will be obtained prior to patient’s inclusion into the trial (with the 
use of the main PIS/IC form, mandatory for trial participation).  
18.1.1 Rationale 
Recent studies established that the balance between cancer progression and regression is 
strongly influenced by complex interactions between the tumor and the microenvironment. It is 
known that in some cancers the infiltration of T cells into the tumor microenvironment correlates 
strongly with tumor regression and patient survival [86, 87]. This has also been substantiated in 
mouse models which clearly highlight the concept of cancer immuno-surveillance and cancer 
immuno-editing [88, 89]. However, in addition to T cells, there is also a highly heterogeneous 
population of other immune cells that infiltrate tumors and interact with tumor cells. These complex 
interactions between tumors and their microenvironment create the immune landscape, i.e. the so-
called tumor immunome, which is thought to considerably contribute to tumor progression or 
regression. The tumor immunome has started to be investigated in more detail only very recently. 
There is for example growing evidence of a prognostic impact of tumor-infiltrating B cells and 
dendritic cells in NSCLC [90-92].  
The PD-1:PD-L1/2 pathway is a major mechanism of immune escape. Blockade of the PD-1:PD-
L1/2 pathway has recently been shown to exert remarkable therapeutic activity in patients with 
advanced NSCLC, melanoma, prostate, renal cell and colorectal cancer [93, 94]. It remains to be 
investigated whether PD-L1 expression on immune cells of the tumor microenvironment or on 
tumor cells is more relevant as predictive marker for anti-PD-L1 immunotherapies. Moreover, the 
definition of a “positive” PD-L1 expression is variable across studies and may impact on trial 
results. In a clinical trial with the anti-PD-1 antibody nivolumab 68 tumor specimens from 41 
patients were analyzed [93]. The only independent marker for response to therapy was PD-L1 
expression by ≥5% of the tumor cells. PD-L1 expression by tumor-infiltrating immune cells had no 
significant impact on objective clinical response rate, though there was a significant correlation with 
clinical benefit. The presence of tumor-infiltrating lymphocytes (TILs) did not correlate with 
objective response to therapy, while infiltration of B-cells correlated positively with the grade of 
immune infiltration and PD-1 expression by T-cells. The presence of TILs was associated with PD-
L1 expression, reflecting an immune active microenvironment.  Results from several trials indicate 
that the ratios of the different functional immune cell subsets may be of greater importance than 
their absolute numbers [94]. However, apart from the CD4:CD8-ratio, no subgroup analysis was 
performed. Another limiting factor of most of the trials is the small sample size (only 12 subjects 
with NSCLC of whom only 3 had squamous cell histology). Furthermore, since several lines of 
evidence indicate, that PD-L1 expression as well as immune cell infiltration vary widely within 
different tumor entities and stages [95-97], the heterogeneous composition of tumors in the study 
population makes it difficult to draw firm conclusions with regard to specific tumor entities. 
18.1.2 Objectives 
In this trial we aim to:  
- 
compare the tumor immunome before (treatment-naive) and after neoadjuvant chemo- and 
immunotherapy.  

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- 
investigate efficacy outcome parameters (EFS, OR, OS) in relation to tissue expression of PD-
L1.   
- 
investigate biomarkers for anti-PD-L1 treatment and their relation to efficacy endpoints of 
interest (EFS, OS and OR after neoadjuvant immunotherapy) in NSCLC. Historical control 
samples from previous SAKK trials will be used. 
18.1.3 TR projects 
• 
Immunohistochemistry   
Tumor material from each patient before treatment and at the time of resection will be centrally 
collected in the Institute of Pathology at the University Hospital Basel. Immunohistochemistry 
(IHC) will be used to quantify protein levels of PD-1 and PD-L1. PD-L1 will be scored based on 
the previously published scoring method [98, 99]: IHC 0 = <1%, IHC 1 = ≥1% but <5%, IHC 2 
= ≥5% but < 10, IHC 3 = ≥10%. IHC 2/3 will be considered as “PD-L1 positive”. Tumor cells 
and immune cells will both be evaluated. In addition, we will calculate the H-score for tumor 
cells, i.e. intensity (0-3) x percentage of stained carcinoma cells = IHC-score 0-300. In addition 
to PD-L1 an IHC panel of lineage marker proteins will be used to quantify the different 
categories of associated immune cells. Furthermore, tissue samples will be evaluated for the 
percentage of stromal TILs as recently recommended by an international working group [100]. 
Based on recent reports on the predictive role of CD8 expression at the invasive tumor margin 
[101], immunohistochemical analyses will specifically focus on the invasive tumor margin. 
• 
High-throughput mRNA sequencing and next-generation sequencing  
We plan to perform a global gene expression profile of immune cells within tumor material at 
the time of diagnosis and at the time of surgical resection by using high-throughput mRNA 
sequencing. This analysis will include clonality assessment of the T cell receptor (T cell 
repertoire), neo-antigens and neo-epitopes as well as the tumor microenvironment. In 
particular, the latter will allow to obtain a global genetic profile of the tumor immune landscape 
to dissect the highly complex and diverse network of cancer infiltrating immune cell subsets. 
Next-generation sequencing (NGS) of genomic tumor DNA will be used to evaluate a panel of 
genes that are commonly mutated in NSCLC. NGS allows identification of driver mutations 
and of inactivation of tumor suppressor genes. Mutational analysis will be correlated to the 
tumor immunome.  
• 
Multiparameter flow cytometry of immune cell populations  
Multiparameter flow cytometry of peripheral blood will allow us to obtain a view of the cellular 
landscape in the peripheral blood of NSCLC patients. Frequency and phenotype of 
lymphocyte subpopulations in the peripheral blood before, during and after neoadjuvant 
therapy will be investigated. The following cell types will be investigated using standard 
staining panels: T cells (including T follicular helper cells, effector T cells, regulatory T cells), B 
cells (including memory B cells, regulatory B cells), natural killer-(T) cells, myeloid cells 
(including TAMs and MDSCs). Furthermore, the expression of potentially inhibitory receptors 
on T cells will be assessed using commercially available antibodies including anti-CTLA-4, -
PD-1, -BTLA, -CD160, -Tim-3, -2B4, -LAG3, -CD200R, -LilrB2, -NKG2A, -KIRs, -Siglecs and -
CD57, which are considered key players in regulating T cell activation/inhibition [102]. We will 
further analyze the expression of these molecules on T cell subpopulations with respect to 
their activation status (e.g. CD25, CD69, CD137, ICOS, KLRG-1, OX40), their differentiation 
stage (e.g. CD45RA, CCR7, CD27, CD28, CD57, FoxP3), and their functional capacity (e.g. 
Ki-67, perforin, Granzyme B). In particular, the analysis will determine the expression pattern 
of those receptors on different T cell subsets, ranging from naïve to memory/effector status. 
Induction of cytotoxicity will be determined by measuring degranulation (CD107a) and 
Granzyme B expression. Secretion of effector cytokines such as IFN-γ, TNF-α, TGF-β, IL-2, 
IL-10 and IL-35 which are gradually lost during T cell exhaustion, will be measured by 
intracellular cytokine staining and ELISA assays. In order to compare T cell activation and 
function on naïve and memory subsets, markers for CD45RA and CCR7 will be included in all 
stainings.  
 

 
 
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• 
Multiplexed cytokine detection with magnetic immunoassays (Serum) 
We will use the Luminex MagPix system to quantitatively measure the changes of different 
cytokines in the peripheral blood of NSCLC patients following treatment. We will measure the 
amounts of 32 different cytokines known to play roles in innate and adaptive immunity. 
18.2 
Re-biopsies/cytologies in patients with tumor progression  or 
relapse during adjuvant MEDI4736 treatment (optional)  
In a separate optional research project, patients experiencing tumor progression or relapse during 
adjuvant MEDI4736 therapy or within 30 days after the last dose of adjuvant MEDI4736 therapy 
will be offered to undergo a re-biopsy or cytology of the tumor. Participation in this research project 
is non-mandatory and will be individually discussed with each patient. Patient consent will be 
obtained with the use of a separate patient informed information and consent form. 
18.2.1 Objective 
In order to better understand potential mechanisms associated with resistance towards checkpoint 
inhibition, we aim at investigating the immunome (by high-throughput sequencing and multi-
parameter flow cytometry as described in section 18.1.3 above) as well as genomic aberrations in 
the tumor using NGS at the time of tumor progression.  
18.3 
Microbiome (optional)  
Participation in this research project is optional. Patients will be informed prior trial entry and 
written patient consent will be obtained using the main patient information sheet and consent form. 
18.3.1 Rationale 
Recent data illustrate the complex interplay of microbial activity and function with the immune 
system. It was demonstrated that gut bacteria bolster the effects of chemotherapy as well as 
immunotherapy in mice [64, 65]. More recently, the influence of gut microbiota on the effect of 
immune checkpoint inhibitors has been demonstrated in an animal model [66]. Another study 
confirms the influence of gut microbiota on the activity of anti-CTLA-4 therapy also in melanoma 
patients [67]. This study showed that ipilimumab modifies the abundance of immunogenic 
Bacteroides species in the gut of melanoma patients, which in turn impacts its anticancer efficacy. 
Moreover, it has been shown that therapy with immune checkpoint inhibitors lead to the 
development of antibodies to components of the enteric flora [103]. 
18.3.2 Objectives 
We aim at confirming the hypothesis that the gut microbiota is required for the anticancer effects of 
PD-L1 blockade. For this purpose we will collect stool samples from patients to analyze the gut 
microbiota composition by high throughput sequencing of feces in therapy-naïve patients and 
during therapy with MEDI4736. We aim at validating the relevance of the gut microbiota 
composition for efficacy of immune checkpoint inhibitors. Furthermore, we aim at understanding 
how immune checkpoint inhibition changes the host microbiome and how these changes correlate 
with the response of the disease to therapy. 
18.4 
Samples and scheduling of sampling 
Except for PAXgene Blood RNA collection tubes and OMNIgene•GUT stool collection kits, no tube 
or shipping material will be provided by the SAKK CC. Sites have to use their own disposables. 
Refer to the corresponding “TR useful tool” on the SAKK website for further information.   
Mandatory samples 
• 
Diagnostic tumor samples (histological or cytological) and tumor resection specimens 
which were sent to Central Pathology for the assessment of the pathological response to 
neoadjuvant treatment will be used for research projects. 
See sections 17.1.4 and 17.1.5 for the handling, labeling and shipment of tumor samples. 

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• 
Peripheral blood (30 ml, heparinized), serum (10 ml, native blood) and preserved blood 
(2.5 ml, PAXgene) will be collected by venipuncture during trial conduct: 
o At baseline (prior to the start of neoadjuvant chemotherapy) 
o Prior to the start of neoadjuvant MEDI4736 therapy 
o Prior to surgery 
o Prior to the 5th application of adjuvant MEDI4736 therapy 
o At the end of trial treatment (also in case of premature trial treatment end for other 
reasons than PD/relapse), or  
o At the time of tumor progression or relapse (if within the time of adjuvant MEDI4736 
treatment or within 30 days thereafter) 
See also section 12. 
Optional samples 
• 
Tumor biopsy at the time of tumor progression/relapse or metastasis if within the time of 
adjuvant treatment or 30 days thereafter (requires additional patient informed consent). 
• 
Stool from patients who consented to the optional translational project (requires specific 
consent in main PIS/IC) 
o at baseline (prior to the start of neoadjuvant chemotherapy)  
o Prior to the 5th application of adjuvant MEDI4736 therapy 
Note: Be reminded to distribute the stool collection tube to the patient at cycle 4 of 
adjuvant immunotherapy.  
In addition, the patient is to be instructed that the stool should be collected towards the 
end of the 2-weeks cycle and that he/she should bring back the tube at the next visit (e.g. 
cycle 5).  
Remaining samples of blood and tumor tissue material may be stored in a biobank after completion 
of the planned research projects (see 18.7). Any stool material left after completion of the planned 
investigation will be discarded. 
18.5 
Handling and labeling 
Blood and stool samples have to be clearly labeled with:   
  
SAKK 16/14 
Patient UPN 
Site  
Sampling date 
Blood samples have to be sent immediately upon collection. However, they should not be sent on 
Friday or during the weekend. In such cases, the blood can be kept at 4°C until shipment on 
Monday. Otherwise the samples can be stored and shipped at room temperature.  
Stool should be shipped within one week upon return of the sample by the patient (as stool is 
stable in the collection tube for 2 weeks, ensure that the sample will reach the laboratory no later 
than 2 weeks after it is collected). 
18.6 
Shipment 
Samples have to be sent to: 
Laboratory of Cancer Immunology 
 
 
Sacha Rothschild / Franziska Uhlenbrock   
 
Trial SAKK 16/14  
 
Department of Biomedicine 
 
Hebelstrasse 20 / Labor 416 
 
CH – 4031 Basel 
 
Shipment modalities are described in the corresponding “TR useful tool” which is posted on 
www.sakk.ch  Members  Trials  Lung Cancer  SAKK 16/14  trial tools). 

 
 
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18.7 
Sample biobanking 
In case the patient consented to the storage of his/her biological material in the trial-associated 
Biobank, PBMCs (isolated from heparinized blood using FICOLL), serum samples and the 
PAXgene-preserved blood will be stored in the Laboratory for Cancer Immunology, Department of 
Biomedicine, University Hospital Basel according to the trial-specific Biobank Regulation, for future 
research in connection with NSCLC. Samples will be stored until publication of the primary analysis 
and up to 10 years thereafter. 
In case the patient did not consent to the biobanking of his/her blood samples, any leftover material 
will be destroyed after the mandatory translational research part of the trial is performed. 
The tumor material from consenting patients will be kept at the Institute of Pathology, University 
Hospital Basel, until publication of the primary analysis and up to 10 years thereafter, for future 
research in connection with NSCLC and according to the corresponding Biobank Regulation (see 
also section 17.3). 
The banking of material must conform to the HRA and its corresponding ordinance HFV/ORH, and 
to the recommendations from the Swiss Ethics Committees on research involving humans. It is 
regulated by specific Biobank Regulations. The patient will have no commercial rights to the data, 
information, discoveries, or derivative materials gained or produced from the samples. 
The patient retains the right to have their stored material irreversibly anonymized at any time by 
contacting the principal investigator. The SAKK will be responsible for the anonymization of the 
sample(s) at the request of the patient. However, data which is already obtained from this material 
can be used for the intended analysis.  
The SAKK will be responsible for the destruction of the sample(s) at the end of the storage period. 
The investigator will provide the sponsor with the required trial code and patient identification 
(UPN) so that any remaining sample can be located and destroyed. 
Any new research on these samples that is not planned in this protocol must first be approved by 
the SAKK board and by the relevant Ethics committee. 
19 
ECONOMIC EVALUATION  
Not applicable 
 
 

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ETHICAL CONSIDERATIONS 
This protocol was written and the trial will be carried out in accordance with the principles 
enunciated in the current version of the Declaration of Helsinki, the guidelines of Good Clinical 
Practice (GCP) issued by ICH, the applicable Swiss HRA and its associated ordinances and the 
requirements from the Swiss regulatory bodies  [106].  
The protocol, the patient information sheets and informed consent forms (PIS/ICs), as well as all 
other trial-related documents shall be submitted to all involved ECs and to the competent authority 
in agreement with local legal requirements for formal authorization. Any amendment to the 
protocol, the CRFs or the PIS/ICs will be submitted for authorization to these institutions. 
The decision of the ECs and competent authority with regard to the conduct of the trial will be 
made in written to the Sponsor prior to trial initiation. Any substantial amendment to the protocol 
(except for safety reasons) can only be implemented at a site after obtaining written authorization 
by the regulatory bodies. Patient recruitment can only take place after the site has officially been 
opened for accrual by the SAKK CC. 
Sites have to adhere to the Swiss HRA and all applicable local regulatory guidelines. 
20.1 
Risks/benefits 
NSCLC stage IIIA(N2) is a potentially curable disease with poor cure rates still. In this trial we 
investigate the addition of the immune checkpoint inhibitor MEDI4736 to standard therapy. 
Therefore, all patients receive the standard of care which consists in three cycles of neoadjuvant 
chemotherapy with cisplatin/docetaxel followed by surgical resection of the tumor. We know from 
previous trials that immune checkpoint inhibition with anti-PD-L1 antibodies is an active treatment 
leading to tumor responses and long lasting tumor stabilization in metastatic disease. Therefore, 
there is a strong rationale to use these agents also in the curative setting to improve the outcome 
of the disease. 
Patients will be exposed to the risk of additional occurrence of toxicities which are associated with 
the investigational product. Yet, the rate of grade 3 and 4 toxicities with MEDI4736 is below 5% 
and investigation product has shown so far a relatively safe profile.  
The neoadjuvant use of MEDI4736 delays surgery, with the consequence that it holds the risk of 
tumor progression before surgery in patients not responding to the treatment. However, it is known 
from past trials that patients progressing within six weeks after platinum-based induction 
chemotherapy have an adverse prognosis. The benefit of an earlier surgical tumor resection in this 
patient subgroup is questionable. Our trial will closely monitor disease status during neoadjuvant 
treatment to offer the best-of-care off-trial therapy to patients who will progress before surgery.   
To address this risk further, as this trial is the first one to investigate the neoadjuvant use of 
immune checkpoint inhibition in potentially curable NSCLC patients, we implemented an interim 
safety analysis. This analysis will be performed after the first 25 included patients. The 30-day 
postoperative mortality rate will be calculated as soon as a period of 30 days after the patient 
surgeries is completed. In case of a postoperative 30-day mortality >10%, an IDMC will have to 
evaluate the safety and suggest appropriate measures. 
20.2 
Trial categorization 
Clinical trial with IMP.  
MEDI4736 is an investigational product without marketing authorization for any indication. 
MEDI4736 is currently under investigation in 30 ongoing clinical trials either as monotherapy or as 
combination therapy for advance stage solid tumors. According to the Swiss HRA and its 
corresponding ordinance KlinV/Oclin on clinical trials, this trial is classified as category C. 
20.3 
Patient information and informed consent 
The informed consent procedure must conform to the ICH-GCP guidelines.  

 
 
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All patients will be informed of the aims and procedures of the trial, the possible AEs, how to react 
in case an AE occurs, and possible hazards to which they will be exposed. They will be informed 
as to the strict confidentiality of their patient data and biological material, but they need to know 
that their medical records may be reviewed for trial purposes by authorized individuals other than 
their treating physician. 
The investigator must provide the patient with sufficient opportunity to consider whether or not to 
participate and minimize the possibility of coercion or undue influence. The information provided 
shall be in a language intelligible to the patient and may not include any content that appears to 
waive any of the patient’s legal rights, or appears to release the investigator, the sponsor, or the 
institution from liability for negligence. 
It will be emphasized that participation is voluntary and that the patient is allowed to refuse further 
participation in the trial whenever he/she wants. This will not prejudice the patient's subsequent 
care.  
Informed consent will be obtained before registration and prior to any protocol-specific procedures.  
Informed consent shall be obtained on a written form approved by the local EC and signed and 
personally dated by the patient and the investigator. The patient information sheet as well as a 
copy or original of the signed and dated informed consent will be handed to the patient. Inclusion of 
legally incompetent patients is not permitted in this trial. 
In case new results become available that shift the risk/benefit ratio, the patient should re-consent. 
In this trial, the collection of tumor material and blood sampling for translational research purposes 
is mandatory. The patient will be made aware of the mandatory translational aspects of the trial. 
Patients refusing to accept mandatory translational research projects (and the associated 
collection of their biological samples) cannot participate in the trial.  
Participation to the translational research project with stool is optional. Patient’s consent for the 
optional collection of stool will be sought when the patient is informed about the trial (using the 
main PIS/IC). Patient’s refusal will have no consequence on their participation in the trial. 
Patient’s consent to the banking of his/her blood and tumor material for future research projects 
and to the additional collection and banking of tumor sample at recurrence is optional and will not 
impact on the patient’s participation in the trial. Separate information and consent forms will be 
presented to the patients for this purpose. 
20.4 
Premature withdrawal 
Patients have the right to refuse further treatment for any reason and at any time. In that case, they 
will be transferred to the follow-up phase. Patients who decide to withdraw from the trial (i.e. refuse 
further data collection) will be informed that all data and biological material collected until the time 
point of their withdrawal will be used. For the patient’s security, a last examination should be 
performed.   
Patients may be withdrawn at any time from trial treatment at the discretion of the treating 
investigator due to an SAE or based on any other relevant medical condition. The patient will then 
be transferred to the follow-up phase. 
 
 

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ADMINISTRATIVE CONSIDERATIONS 
21.1 
Insurance 
The SAKK will indemnify patients for damages they have suffered as participants in the trial. For 
this purpose, SAKK has taken out a special insurance for clinical trials with Chubb Insurance 
Company of Europe SE, Zollikerstrasse 141, 8034 Zürich. 
21.2 
Financing and support 
This trial is funded by SAKK and the pharmaceutical company AstraZeneca. The study medicinal 
product MEDI4736 (durvalumab) is provided by AstraZeneca. 
21.3 
Monitoring and auditing 
All source data must be accessible for auditing and monitoring. CRAs and auditors will maintain 
patient confidentiality. 
21.3.1 Monitoring strategy 
This trial will be monitored. The SAKK is following a risk-adapted monitoring strategy according to 
the concept developed by the ADAMON group [110] and the TransCelerate position paper . Based 
on the risk analysis, level 4 monitoring strategy has been chosen. The different monitoring 
activities as well as the frequency of the visit are described in a trial-specific monitoring plan.  
21.3.2 Auditing/inspecting 
Authorities have the right to perform inspections, and the SAKK has the right to perform on-site 
auditing during working hours upon reasonable prior notice.  
21.4 
IDMC 
An IDMC appointed by the SAKK Board may evaluate the safety of the trial and suggest 
appropriate measures if necessary (see section 15). A detailed description of the interim data 
monitoring procedure will be specified in a dedicated IDMC charter. 
21.5 
Quality control and quality assurance 
Several procedures ensure the quality of the trial in compliance with applicable regulatory 
requirements, GCP and the protocol: 
• 
Written standard operating procedures are implemented 
• 
Personnel involved in conducting the trial is qualified by education, training and experience  
• 
An updated staff list must be kept at the site  
• 
Validation of database and statistical analysis 
• 
Quality control principles are implemented 
• 
On-site and central monitoring to evaluate protocol compliance (SDV, verification of informed 
consent etc.) by personnel designated by the SAKK 
• 
Data captured online will be validated in real-time, yielding errors (for inacceptable data) and 
warnings (for possibly inconsistent data - these warnings may be overruled by the user).  
• 
Audit trail of changes 
• 
Medical data review by the coordinating investigator or a delegated person (all CRFs will be 
reviewed and checked on medical content)  
• 
Central management of deviations and implementation of corrective and preventive measures 
• 
Central pathology review 
• 
IDMC  
• 
Safety monitoring 

 
 
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• 
Accountability of MEDI4736 
• 
Internal audit procedures 
21.6 
Trial activation procedure 
The procedure for trial activation at a site is described in the final protocol letter, which is sent to all 
sites which committed to participate in the trial. All participating sites must follow the instructions 
which are given in this letter for the preparation of site documents. Upon receipt of the sites 
documents, the SAKK CC will submit them to the involved ECs and Swissmedic. 
Any site which is interested to participate in the trial, but has not committed yet, has to contact the 
SAKK CC first.     
The investigator will only be allowed to register patients into the trial after the ECs and 
Swissmedic authorized the trial at the site and the SAKK CC opened the site for accrual. 
21.7 
Local trial records 
21.7.1 Investigator’s file 
All trial-related correspondence should be filed in the investigator’s file. A suggested table of 
contents (according to ICH E6, chapter 8) is provided on the SAKK website (www.sakk.ch  
Members  Trials  Lung Cancer  SAKK 16/14  trial tools). 
21.7.2 Useful tools  
CRFs, drug order forms and accountability logs, documents required for EC approval, the excel 
schedule of assessments, and any other trial tool can be downloaded from the SAKK website 
(www.sakk.ch  Members  Trials  Lung Cancer  SAKK 16/14  trial tools). 
21.7.3 Record retention 
The site will retain all essential documents according to ICH-GCP. This includes copies of the 
patient trial records, which are considered as source data, patient informed consent statement, 
laboratory printouts, drug inventory and destruction logs, and all other information collected during 
the trial. These documents were stored until at least 15 years after the termination of the trial. The 
end of this retention period will be communicated to the sites by the SAKK CC. For the patient trial 
records, which are entered into the EDC system, the sponsor guarantees the access and 
availability of the data at any time for at least 15 years after the termination of the trial.  
In the event that the principal investigator retires or changes employment, custody of the records 
may be transferred to another competent person who will accept responsibility for those records. 
Written notice of such transfer will be given to the SAKK CC. The SAKK will notify the concerned 
regulatory authorities. 
21.8 
Trial registration 
The SAKK will register the trial at www.clinicaltrials.gov and on the Swiss National Clinical Trials 
Portal (SNCTP) at www.kofam.ch/www.humanforschunginfo.ch. 
21.9 
List of participating sites 
A list of sites and investigators that have agreed to participate in the trial are given in a separate 
document which can be downloaded from www.sakk.ch ( Members  Trials  Lung Cancer  
SAKK 16/14  trial tools).  
21.10 Modifications of the protocol 
21.10.1 Substantial amendment 
Any amendment which may have an impact on the conduct of the trial, the potential benefit of the 
trial, or may affect patient safety, including changes of trial objectives, trial design, patient 

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population, sample sizes, trial procedures, or significant administrative aspects. Such an 
amendment must be accepted by the SAKK Board and must have the authorization of the 
respective EC and competent authority (if applicable) prior to implementation. 
21.10.2 Safety amendment  
A safety amendment is a special kind of substantial amendment which is released when it is 
necessary to eliminate immediate hazards to trial participants. A safety amendment requires 
immediate implementation at local sites and is submitted in parallel for authorization to the ECs 
and the competent authority (if applicable).  
21.10.3 Non substantial amendment 
Non-substantial amendments such as minor corrections and/or clarifications that have no effect on 
the way the trial is conducted have to be submitted to the ECs once a year, together with the 
submission of the annual development safety update report. Non-substantial amendments which 
affect the evaluation of the competent authority have to be submitted to the authority as soon as 
possible. 
21.11 Trial termination 
The SAKK CC is responsible for submitting the information about trial termination to the Swiss 
authorities according to the Swiss HRA.  
 
22 
PUBLICATION 
The results of the trial will be published according to the current version of the SAKK publication 
guidelines (available on the SAKK website). The SAKK publication guideline guarantees the 
freedom of reporting of the participating physicians. 
 
23 
CONFIDENTIALITY 
23.1 
Copyright 
The information contained in this protocol is copyright protected by the SAKK (Swiss Group for 
Clinical Cancer Research). This information is given for the needs of the trial and must not be 
disclosed to persons outside of the SAKK without prior written consent of the SAKK CC. 
23.2 
Confidentiality 
Trial-related data of the patient will be provided in a coded manner to the SAKK CC. The names of 
the patients will not be disclosed to the SAKK CC. A unique patient number (UPN) will be attributed 
to each patient registered into the trial.  
Identification of patients must be guaranteed at the site. For this purpose, sites are requested to 
use the patient screening and enrollment and the patient identification lists specifically produced for 
the trial. In order to avoid identification errors, the year of birth and the UPN have to be provided on 
the CRFs. Patient confidentiality will be maintained according to the applicable legislation. Patients 
must be informed of, and agree to, data and material transfer and handling, in accordance with 
Swiss data protection law. 
All information concerning the IMP supplied by AstraZeneca in connection with this trial and not 
previously published is considered confidential and proprietary information.  

 
 
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Seoul 
and 
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and 
clarified 
in 
Washington 
and 
Tokyo). 
2013, 
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http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R
1__Guideline.pdf. 
106. 
HRA, Bundesgesetz über die Forschung am Menschen (Humanforschungsgesetz, HFG) vom 30. 
September 2011 (Stand am 1. Januar 2014) / Loi fédérale relative à la recherche sur l'être humain 
(Loi relative à la recherche sur l'être humain, LRH) du 30 septembre 2011 (Etat le 1er janvier 2014), 
810.30., Goverment, Editor, http://www.admin.ch/opc/de/official-compilation/2013/3215.pdf. 
107. 
Verordnung über klinische Versuche in der Humanforschung (Verordnung über klinische Versuche; 
KlinV) vom 20. September 2013 (Stand am 1. Januar 2014) / Ordonnance sur les essais cliniques 
dans le cadre de la recherche sur l'être humain (Ordonnance sur les essais cliniques, OClin) du 20 
septembre 
2013 
(Etat 
le 
1er 
janvier 
2014), 
810.305., 
Government, 
Editor, 
http://www.admin.ch/opc/de/classified-compilation/20121176/201401010000/810.305.pdf. 
108. 
Organisationsverordnung zum Humanforschungsgesetz (Organisationsverordnung HFG, OV-HFG) 
vom 20. September 2013 (Stand am 1. Januar 2014) / Ordonnance d'organisation concernant la loi 
relative à la recherche sur l'être humain (Ordonnance d'organisation concernant la LRH, Org LRH) 
du 
20 
septembre 
2013 
(Etat 
le 
1er 
janvier 
2014), 
810.308., 
Government, 
Editor, 
http://www.admin.ch/opc/de/classified-compilation/20121179/201401010000/810.308.pdf. 
109. 
Verordnung 
über 
die 
Humanforschung 
mit 
Ausnahme 
der 
klinischen 
Versuche 
(Humanforschungsverordnung, HFV) vom 20. September 2013 (Stand am 1. Januar 2014) / 
Ordonnance relative à la recherche sur l'être humain à l'exception des essais cliniques (Ordonnance 
relative à la recherche sur l'être humain, ORH) du 20 septembre 2013 (Etat le 1er janvier 2014), 
810.301, http://www.admin.ch/opc/de/official-compilation/2013/3381.pdf. 
110. 
Brosteanu, O., et al., Risk analysis and risk adapted on-site monitoring in noncommercial clinical 
trials. Clin Trials, 2009. 6(6): p. 585-96. 
111. 
TransCelerate position paper. May 30, 2013. , http://www.transceleratebiopharmainc.com/wp-
content/uploads/2013/10/TransCelerate-RBM-Position-Paper-FINAL-30MAY2013.pdf. 
112. 
TNM Classification of Malignant Tumours (UICC). 7 ed, ed. D.L.H. SobinOctober 2009. 
113. 
Cockcroft, D.W. and M.H. Gault, Prediction of creatinine clearance from serum creatinine. Nephron, 
1976. 16(1): p. 31-41. 
114. 
Oken, M.M., et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J 
Clin Oncol, 1982. 5(6): p. 649-55. 
115. 
The Criteria Committee of the New York Heart Association: Physical capacity with heart disease, in 
Disease of the Heart and Blood Vessels, Nomenclature and Criteria for Diagnosis, ed. 6, L. Boston, 
Brown & Co, Editor 1964. p. 110-114.  
 
 
 
 

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APPENDICES 
 
Appendix 1 
Tumor response assessment according to RECIST 1.1 
All patients will be evaluated for response according to the revised Response Evaluation Criteria in 
Solid Tumors (RECIST v1.1) [112]. 
App 1.1 
Methods of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
• 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. CT should generally be performed using a ≤ 5 mm contiguous 
reconstruction algorithm. MRI is acceptable for certain situations. 
• 
Clinical lesions will only be considered measurable when they are superficial (e.g. skin 
nodules) and ≥ 10 mm. In the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is recommended. 
• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
• 
Ultrasound is not useful in assessment of lesion size and should not be used as method 
of assessment. 
• 
FDG-PET is generally not foreseen for regular response assessments. It may, however, 
be used to detect or confirm the appearance of new lesions. Attenuation correction CT 
scans performed as part of a PET/CT scan frequently show lower resolution; therefore, 
dedicated CT scans are preferred. However, if the site can demonstrate that the CT 
performed as part of a PET/CT is of the same diagnostic quality as a diagnostic CT (with 
i.v. and oral contrast), then the CT portion of the PET/CT can be used for RECIST 
measurements. 
App 1.2 
Definition of measurability  
Measurable disease is defined as the presence of at least one measurable lesion.  
• 
Measurable lesions:  
o Non-nodal lesions that can be accurately measured in at least one dimension with 
longest diameter ≥ 10 mm using CT scan, assuming the slice thickness is ≤ 5 mm. 
As a general rule, the longest diameter must be at least twice the slice thickness of 
the imaging. In the case of chest X-ray, the lesion must be ≥ 20 mm. Clinically 
assessed lesions must be ≥ 10 mm. 
o Lymph nodes that can be accurately measured with a short axis of ≥ 15 mm using 
CT scan, assuming the slice thickness is ≤ 5 mm. 
• 
Non-measurable lesions: all other lesions, i.e. : 
o small non-nodal lesions (longest diameter < 10 mm in CT scan) 
o small lymph nodes (short axis ≥ 10 and < 15 mm) 1 
o bone lesions2 
o leptomeningeal disease  
o ascites 
o pleural/pericardial effusion 
o inflammatory breast disease 
o lymphangitis cutis/pulmonis 
o cystic lesions3  
o tumor lesions situated in a previously irradiated area, or subjected to other 
locoregional therapy4 

 
 
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o abdominal masses/abdominal organomegaly identified by physical exam that are 
not measurable by reproducible imaging techniques 
1  
Lymph nodes that have a short axis <10 mm are considered non-pathological and should not be 
recorded or followed 
2  
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, can be 
considered as measurable lesions if the soft tissue component meets the definition of measurability 
described above. 
3  
Cystic lesions thought to represent cystic metastases may be considered as measurable lesions. 
However, if non-cystic lesions are present, these are preferred as target lesions.  
4  
May be considered measurable if there has been demonstrated progression in the lesion. 
App 1.3 
Selection of lesions 
Selection of target lesions 
Measurable lesions up to a maximum of 5 lesions representative of all involved organs, and up to 2 
per organ, should be identified as target lesions and measured and recorded at baseline.  
Target lesions (TL) should be selected on the basis of their size and their suitability for accurate 
repetitive measurements. A sum of diameters for all target lesions will be calculated and reported 
as the baseline sum of diameters. Lymph nodes selected as TL should always have the short 
axis recorded. All other lesions should always have their longest diameters recorded. This sum 
will be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease. 
Selection of non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions (NTL) and should 
also be recorded at baseline. Measurements are not required, but the presence or absence of 
each should be noted throughout follow-up. It is possible to record multiple NTL as a single item on 
the CRF (e.g. "multiple liver metastases"). 
App 1.4 
Evaluation of lesions 
Evaluation of Target Lesions 
All TL will be measured at each tumor assessment, and the sum of their diameters will be 
compared to previous assessments in order to assign the response status as specified below.  
• 
Complete Response (CR): Disappearance of all TL. Lymph nodes selected as TL must each 
have reduction in the short axis to < 10 mm in order for the response to be considered 
complete. 
• 
Partial Response (PR): At least a 30% decrease in the sum of diameters of TL taking as 
reference the baseline sum of diameters. 
• 
Progression (PD): At least a 20% increase in the sum of diameters of TL, taking as reference 
the smallest sum recorded on study. In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD. 
Note: All TL, including lymph nodes, should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g. 2 mm). If the radiologist does not feel 
comfortable assigning an exact measure and reports a lesion as "too small to measure", a default 
value of 5 mm should be recorded. If a TL is thought likely to have disappeared, "0 mm" is noted. 
Evaluation of Non-Target Lesions  
• 
Complete Response (CR): Disappearance of all NTL; lymph nodes selected as NTL must be 
non-pathological in size (< 10 mm). 
• 
Non-CR/non-PD: Persistence of one or more NTL (non-CR). 

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• 
Progression (PD): unequivocal progression of existing NTL. Unequivocal means: comparable in 
magnitude to the increase that would be required to declare PD for measurable disease or an 
overall substantial increase in tumor burden that merits treatment discontinuation. 
Determination of new lesions 
The appearance of any new malignant lesions denotes disease progression. The finding of a new 
lesion should be unequivocal, i.e. not attributable to differences in scanning technique or findings 
thought to represent something other than tumor. If a new lesion is equivocal, e.g. because of its 
small size, the patient will stay on treatment (if the decision on PD is based on this lesion only). If 
the repeat scans confirm there is definitely a new lesion, then progression should be declared 
using the date of the previous scan. 
Lesions found in a new location not included in the baseline scan (e.g. brain metastases) are 
considered new lesions. 
Note: the "re-appearance" of a previously "disappeared" target or non-target lesion does not in 
itself necessarily qualify as PD; this is the case only if the overall evaluation meets the PD criteria, 
or if the patient was previously in CR. 
Additional considerations 
• 
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
• 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
App 1.5 
Determination of overall response 
Based on the responses of TL, NTL, and the presence or absence of new lesions, the overall 
response will be determined at each tumor assessment, according to the table below:  
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated (NE)* 
No 
PR 
PR 
Non-PD or not all evaluated* 
No 
PR 
SD 
Non-PD or not all evaluated* 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In selected circumstances, certain non-target organs may be evaluated less frequently. For 
instance, bone scans may need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
Note: a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression, sometimes reported as “symptomatic deterioration”, is not a 
response outcome in itself. Every effort should be made to document objective progression even 
after discontinuation of treatment. 

 
 
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Appendix 2 
TNM Classification 
According to UICC 2009 [112] 
Primary tumor (T) 
TX Primary tumor cannot be assessed, or the tumor is proven by the presence of malignant cells in sputum 
or bronchial washing but is not visualized by imaging or bronchoscopy  
T0 
No evidence of primary tumor 
Tis Carcinoma in situ 
T1 
Tumor ≤ 3 cm in greatest dimension, surrounded by lung or visceral pleura, no bronchoscopic evidence 
of invasion more proximal than the lobar bronchus (not in the main bronchus); superficial spreading of 
tumor in the central airways (confined to the bronchial wall )  
 
 
T1a Tumor ≤ 2 cm in the greatest dimension 
T1b Tumor > 2 cm but ≤ 3 cm in the greatest dimension 
T2 
Tumor > 3 cm but ≤ 7 cm or tumor with any of the following:  
• 
Invades visceral pleura 
• 
Involves the main bronchus ≥ 2 cm distal to the carina 
• 
Associated with atelectasis/obstructive pneumonitis extending to hilar region but not involving 
the entire lung 
T2a Tumor > 3 cm but ≤ 5 cm in the greatest dimension 
T2b Tumor > 5 cm but ≤ 7 cm in the greatest dimension 
T3 
Tumor > 7 cm or one that directly invades any of the following:  
• 
Chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or 
parietal pericardium; 
Or tumor in the main bronchus < 2 cm distal to the carina but without involvement of the carina 
Or associated atelectasis/obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the 
same lobe 
T4 
Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, 
recurrent laryngeal nerve, esophagus, vertebral body, or carina; or separate tumor nodule(s) in a 
different ipsilateral lobe  
Regional lymph nodes (N) 
NX Regional lymph nodes cannot be assessed 
N0 No regional node metastasis 
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, 
including involvement by direct extension  
N2 Metastasis in the ipsilateral mediastinal and/or subcarinal lymph node(s) 
N3 Metastasis in the contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or 
supraclavicular lymph nodes  
Distant metastasis (M) 
MX Distant metastasis cannot be assessed 
M0 No distant metastasis 
M1 Distant metastasis 
M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural (or 
pericardial) effusion 
M1b Distant metastasis 
 
• c: stage given by clinical examination of a patient. The c-prefix is implicit in absence of the p-
prefix. 
• p: stage given by pathologic examination of the surgical specimen. 
• y: stage assessed after neoadjuvant therapy. 

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Appendix 3 
Calculation of creatinine clearance 
Creatinine clearance should be calculated according to the formula of Cockcroft-Gault [113]. 
Cockcroft-Gault formula: 
 
Constant is 1.04 for females and 1.23 for males  
 
 
Appendix 4 
WHO performance status  
Performance status should be calculated according to the ECOG/WHO definition [114]. 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g. light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
 
 
Appendix 5 
New York Heart Association (NYHA) classification  
From the Criteria Committee of the New York Heart Association [115]. 
Class I 
Patients have cardiac disease but without significant limitations of physical activity. 
Ordinary activity does not cause undue fatigue, palpitations, dyspnea (shortness of 
breath), or anginal pain. 
Class II 
Patients have slight limitations of physical activity. They are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitations, dyspnea or anginal pain. 
Class III 
Patients have marked limitations of physical activity. They are comfortable at rest, 
however less than ordinary physical activity results in fatigue, palpitations, dyspnea 
or anginal pain. 
Class IV 
Patients are unable to carry out any physical activity without symptoms referred to 
above. Some Class IV patients may have symptoms at rest. 
 
= 
Creatinine clearance (ml/min) 
(140 - age) x weight (in kg) x constant 
serum creatinine (in µmol/L) 

 
 
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Appendix 6 
Process chart for mediastinal lymph node staging 
 

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Appendix 7 
Process chart for lung function tests 
Algorithm for the assessment of cardiopulmonary reserve before lung resection in lung cancer patients based on the ESTS guidelines [75] 
 
 
FEV1: Force expiratory volume in 1 s.; DL,CO: diffusing capacity of the lung for carbone monoxide; VO2: oxygen comsumption; ppo: predictive postoperative 
# if peak VO2: is not available, cardiopulmonary exercice testing can be replaced by stair climbing; however, if altitude reaching stair climbing is < 22m, 
cardiopulmonary exercice testing with peak VO2 measurement is highly recommended. 
¶   refer to guidelines 
 
 

 
 
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Appendix 8 
Schedule of assessments and treatments 
An adaptable scheduler is available on www.sakk.ch ( Members  Trials  Lung Cancer  SAKK 16/14) 
During trial treatment 
 

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a) Refer to protocol sections 9 & 10 for the timelines of cycles, permitted delays, etc. 
b) Last cycle: after max. 1 year of adjuvant MEDI4736 (i.e. max.26 cycles) or at premature termination of adjuvant treatment 
c) Week 8 or 9 
d) CT scans have to be performed every 3 months (during adj. immunotherapy), starting 1 month after surgery 
e) If CT scan is within 6 weeks before EFS at 12 months (i.e. 12 months from registration), no need to repeat at 12 months - otherwise, it is imperative to repeat a CT assessment 
at 12 months [+ 4 weeks] from registration 
f) Assessments have to be done every other cycle during adjuvant MEDI4736 
g) For women in child-bearing age 
h) For patients undergoing RT: radiotherapy should start 4-6 weeks after surgery; the first infusion of adjuvant MEDI4736 should take place within 2 weeks after completion of 
radiotherapy 
i) In  case end of treatment is due to recurrence during adj. immunotherapy: collect blood for mandatory TR and consider consenting the patient for optional TR (+ tumor re-
biopsy/cytology)  
k) Baseline samples can be collected from 14 days prior registration until the first day of trial treatment (prior first dose of  treatment)  
l) Stool Instruct the patient about stool collection at cycle for adjuvant MEDI4736 (refer also to protocol section 18.4)  
 
 

 
 
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After trial treatment