Clinical trial NCT02046733
Conditions: Limited Stage Small Cell Lung Cancer Small Cell Lung Cancer
Keywords: SCLC CTLA-4
Sponsor: ETOP IBCSG Partners Foundation
Start date: 2015-12-18; Completion date: 2022-02-01
Enrollment: 222 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Despite the fact that the majority of the patients with limited disease SCLC will respond very well to the standard treatment, a great proportion will relapse within 12 - 24 months.

Several studies in patients with lung cancer suggested a possible favourable association between the increased presence of immunologically active cells in the tumour and survival. Nivolumab and ipilimumab are proteins, which help your immune system to attack and destroy cancer cells by your immune cells. Early clinical trials with nivolumab and ipilimumab have shown activity in a broad range of cancers, including SCLC.

The aim of the current study is to investigate the efficacy (how well the treatment works) and tolerability (how severe the side effects are) of the standard treatment (chemotherapy and radiotherapy) alone, compared with the standard treatment followed by nivolumab and ipilimumab in patients with limited SCLC.

Detailed description:
At the time of diagnosis, 30% of patients with small cell lung carcinoma (SCLC) will have limited stage disease, now called stage I-IIIB (IASLC). The outcome of limited disease SCLC is still poor, with a median survival of 16 to 24 months with current forms of treatment and only 15-25% long term survivors.

Combining chemotherapy and thoracic radiotherapy is the standard treatment approach in limited-stage SCLC with a combination of platinum compounds (cis- or carboplatin) and etoposide and cisplatin (PE) as the backbone regimen. Concurrent chemo-radiotherapy is superior to sequential treatment and early thoracic irradiation starting with first or second cycle of chemotherapy appears beneficial. Hyperfractionated accelerated radiotherapy has been shown to be more efficacious than radiotherapy given in a long overall treatment time. However, availability and routine-use of hyperfractionated radiotherapy remains a matter of debate. Therefore, in this trial, both radiotherapy schedules of accelerated twice-daily administration or once-daily radiotherapy are accepted. The choice of schedule is a stratification factor for randomisation.

The adaptive immune response is triggered via effector T-cells, antigen-presenting cells (APCs) and co-stimulatory signals mediated by T cell receptors such as CD28. The interplay of these signals results in the activation and clonal proliferation of T cells.

T-cell proliferation is tightly regulated in order to avoid autoimmunity. The balance between co-stimulatory signals mediated by CD28 and co-inhibitory signals via so called immune checkpoint receptors is crucial for the maintenance of self-tolerance and to protect tissues from damage during normal immune response. After activation, T-cells express the immune checkpoint receptors cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1).

CTLA-4- and PD-1 expressing T-cells play a critical role in maintaining self-tolerance but are also responsible for non-responsiveness to tumour antigens. Cancer cells escape from im-mune surveillance by expressing immune checkpoint receptors. The goal of immune check-point inhibitor therapies is not to activate the immune system to attack particular targets on tumour cells, but rather to remove inhibitory pathways that block effective antitumour T cell responses.

Ipilimumab is a monoclonal antibody that binds to CTLA-4 and inhibits the interactions with the ligands B7.1 and B7.2, Nivolumab is a monoclonal antibody that targets PD-1. Engagement of PD-1 by its natural ligands, PD-L1 and PD-L2, results in an inhibition of T cell proliferation, survival and cyto-kine secretion. Nivolumab abrogates this interaction between PD-1 and its ligands.

The two antibodies, nivolumab and ipilimumab, do not only target different immune cell receptors, they also regulate distinct inhibitory pathways and have therefore non-overlapping mechanisms of action. Anti-CTLA-4 therapies seem to drive T-cells into tumours, resulting in an increased number of intratumour T-cells and a concomitant increase in IFN-y. This in turn can induce the expression of PD-L1 in the tumour microenvironment, with subsequent inhibition of antitumour T-cell responses, but may also increase the chance of benefit from anti-PD-1 and anti-PD-L1 therapies. A combination treatment with anti-CTLA-4 (e.g. ipili-mumab) plus anti PD-1 (e.g. nivolumab) or anti-PD-L1 antibodies should enable the creation of an immunogenic tumour microenvironment with subsequent clinical benefit for patients.

Nivolumab monotherapy has been approved for the treatment of advanced melanoma (FDA, EMA, and Japan) and previously treated squamous NSCLC (FDA, positive CHMP opin-ion). Nivolumab and ipilimumab improved PFS compared to nivolumab or ipilimumab alone in a study in melanoma (CA209067).

In a randomised open-label phase I/II trial (CheckMate 032), evaluating nivolumab with or without ipilimumab in pretreated SCLC patients with progressive disease and sensitive or refractory to platinum based chemotherapy, based on an interim analysis a response rate of 33% and disease stabilisation in 22% was observed for the combination of nivolumab and ipilimumab compared to 18% response rate and 20% stable disease with nivolumab mono-therapy.

Both, nivolumab monotherapy and nivolumab plus ipilimumab combination treatment were tolerable for the treatment of SCLC, and no new safety profile was identified compared to the profile of nivolumab with or without ipilimumab in other anti-cancer therapies.

Nivolumab plus ipilimumab will be administered as a consolidation treatment after comple-tion of a standard treatment including chemo-radiotherapy and prophylactic cranial irradia-tion (PCI).

Arms: arm 1: \- Induction: Nivolumab at a dose of 1 mg/kg i.v. followed (on the same day) by Ipilimumab at a dose of 3 mg/kg i.v. once every 3 weeks, 4 cycles

\- Maintenance: Nivolumab 240 mg i.v. once every 2 weeks, for a maximum of 12 months from start of maintenance arm 2: no further treatment; tumour assessment, follow-up documentation and collection of biological material will be done according to the same schedule as Arm 1.
Interventions: intervention 1: Ipilimumab intervention 2: Nivolumab
Intervention descriptions: intervention 1: Induction phase: i.v. 3 mg/kg, once every 3 weeks × 4 cycles, to start within 6-8 weeks (42-56 days) from start of chemotherapy cycle 4, and not more than 2 weeks (14 days) after the date of randomisation) intervention 2: Induction phase: Nivolumab i.v. 1 mg/kg, once every 3 weeks × 4 cycles, to start within 6-8 weeks (42-56 days) from start of chemotherapy cycle 4, and not more than 2 weeks (14 days) after the date of randomisation) Maintenance Phase: Nivolumab 240 mg i.v once every 2 weeks for a maximum of 12 months from start of maintenance (the first dose of maintenance nivolumab will be administered 3 weeks after the last IMP doses of induction Phase).

Protocol documents:
Prot_000.pdf: 
ETOP/IFCT 4-12 STIMULI V 2.0   03Aug2015 
 
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ETOP/IFCT 4-12 STIMULI 
 
 
 
 
A randomised open-label phase II trial of consolidation with nivolumab 
and ipilimumab in limited-stage SCLC after chemo-radiotherapy 
 
STIMULI: Small cell lung carcinoma Trial with nivolumab and Ipili-
MUmab in LImited disease  
 
 
Sponsor: European Thoracic Oncology Platform (ETOP) 
 
 
 
 
EudraCT number: 2013-002609-78 
 
 
BMS number: CA184-310 
 
 
 
 
 
ETOP c/o IBCSG Coordinating Centre, Effingerstrasse 40, CH- 3008 Bern 
Phone: +41 31 389 93 91 
Fax: +41 31 389 93 92 
 
 
 
Version 2.0 
 
 


ETOP/IFCT 4-12 STIMULI V 2.0   03Aug2015 
 
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Contacts 
 
Trial Chair 
Solange Peters, MD-
PhD 
 
 
 
 
Address 
 
 
Tel:  
 
Fax: 
Email: 
Département d'Oncologie 
Centre Hospitalier Universitaire Vaudois  
1011 Lausanne, Switzerland 
+41 79 556 01 92 
+41 21 314 67 89 (assistant) 
+41 21 314 07 37 
solange.peters@etop-eu.org 
Trial Chair 
Dirk De Ruysscher, 
MD, PhD 
 
Address 
 
 
Email: 
Maastro clinic 
Dr Tanslaan 12 
6229 ET Maastricht, The Netherlands 
dirk.deruysscher@maastro.nl  
Trial Co-Chair 
Sanjay Popat, MD 
Address 
 
 
Tel:  
Fax: 
Email: 
Royal Marsden Hospital 
Fulham Road 
London SW3 6JJ, United Kingdom 
+44 207 808 2132 
+44 207 808 2688 
sanjay.popat@rmh.nhs.uk 
Trial Co-Chair 
Martin Reck, MD 
 
 
 
Address 
 
 
Tel:  
Fax: 
Email: 
Krankenhaus Großhansdorf 
Woehrendamm 80 
22927 Grosshansdorf, Germany 
+49 4102 6012101 
+49 4102 6017101 
dr.martin.reck@web.de 
Trial Co-Chair IFCT 
Cécile Le Pechoux, 
MD 
Address 
Tel:  
Fax: 
Email: 
Department of Radiotherapy 
Institut Gustave Roussy, Villejuif, France 
Tel: 33 (0)1 4211 4757 
Fax: 33 (0)1 4211 5253 
Cecile.LEPECHOUX@igr.fr 
Trial Co-Chair IFCT 
Jean-Louis Pujol, 
MD 
Address 
 
 
 
 
Tel, Fax: 
Email: 
Montpellier Adacemic Hospital  
Hôpital Arnaud de Villeneuve  
Thoracic Oncology Unit  
Avenue du Doyen Giraud  
34295 Montpellier CEDEX, France  
+33 4 67 33 61 36  
jl-pujol@chu-montpellier.fr 
ETOP Chairman 
Rolf Stahel, MD 
Address 
 
 
 
 
Tel:  
Fax: 
Email:  
Laboratory of Molecular Oncology 
Clinic of Oncology 
University Hospital Zuerich  
Häldeliweg 4 
CH-8044 Zürich, Switzerland  
+41 44 634 28 71 
 +41 44 634 28 72 
rolf.stahel@usz.ch 
Co-Chair Translational 
Research 
Adrian Liston, PhD  
Address 
 
 
 
Tel:  
Fax: 
Email:  
KU Leuven 
Department of Microbiology and Immunol-
ogy, O&N2 bus 1026 
Herestraat 49, B-3000 Leuven, Belgium 
+32 (0) 163 30934 
+32 (0) 163 30591 
adrian.liston@vib.be 


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Co-Chair Translational 
Research 
Daniel Speiser, MD 
 
 
George Coukos, MD 
PhD  
Address 
 
Email: 
Email: 
 
 
 
Tel:  
Fax:  
Clinical Tumour Biology & Immunotherapy 
Group 
d.e.speiser@gmail.com 
George.Coukos@chuv.ch 
Department of Oncology and Ludwig Centre 
for Cancer Research, Univ. of Lausanne 
Av. P.-Decker 4, CH-1011 Lausanne 
+41 21 314 01 82 
+41 21 314 74 77 
Translational Research 
Coordinator 
Rosita Kammler 
Address 
 
 
 
Tel:  
Fax: 
Email:  
ETOP Coordinating Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 389 93 83 
+41 31 389 92 29 
rosita.kammler@ibcsg.org 
Statistics 
Urania Dafni, ScD 
 
 
 
 
 
Zoi Tsourti, PhD 
Address 
 
 
Tel:  
Fax: 
Email: 
Email: 
Frontier Science Foundation – Hellas 
118-120 Papadiamantopoulou Str. 
15773, Zografou, Athens, Greece 
+302107710902 
+302107710903 
udafni@frontier-science.gr 
ztsourti@frontier-science.gr 
Project Manager 
 
 
 
 
 
 
 
Data Management 
Mark Finlayson, PhD 
 
 
 
 
 
 
Anne-Christine 
Piguet, PhD 
Address 
 
 
 
Tel:  
Fax: 
Email:  
Tel: 
Email: 
ETOP Coordinating Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 389 92 21 
+41 31 389 92 29 
STIMULI@etop-eu.org 
+41 31 389 91 87 
ETOPDataManagement@etop-eu.org 
Drug supply 
Barbara Ruepp, 
PharmD 
Address 
 
 
 
Tel:  
Fax: 
Email:  
ETOP Drug Supply Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 389 93 91 
+41 31 389 92 29 
drugsupply@etop-eu.org 
Safety and Regulatory 
Affairs 
Barbara Ruepp, 
PharmD 
Address 
 
 
 
Tel:  
Fax: 
Email:  
ETOP Safety and Regulatory Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 389 93 91 
+41 31 389 92 29 
regulatoryoffice@etop-eu.org 
ETOP Coordinating 
Office 
Anita Hiltbrunner 
Rudolf Maibach, 
PhD 
Mark Finlayson, PhD 
Address 
 
 
Tel:  
Fax: 
Email: 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 389 93 91 
+41 31 389 92 29 
anita.hiltbrunner@etop-eu.org 
rudolf.maibach@etop-eu.org 
STIMULI@etop-eu.org 
Remote Data Entry 
system 
Anne-Christine Pi-
guet, PhD 
 
Technical assistance 
 
ETOPDataManagement@etop-eu.org 
 
 
richard.king@etop-eu.org 
In collaboration with Bristol-Myers Squibb  




ETOP/IFCT 4-12 STIMULI V 2.0   03Aug2015 
 
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Protocol Signature Page 
 
A randomised open-label phase II trial of consolidation ipilimumab in limited-
stage SCLC after chemo-radiotherapy 
 
ETOP/IFCT 4-12 STIMULI 
 
 
Approved by: 
 
 
 
 
 
 


ETOP/IFCT 4-12 STIMULI V 2.0   03Aug2015 
 
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Principal Investigator Protocol Amendment 1 Signature Page 
 
A randomised open-label phase II trial of consolidation with nivolumab and 
ipilimumab in limited-stage SCLC after chemo-radiotherapy 
 
ETOP/IFCT 4-12 STIMULI 
 
I have read the amended protocol and agree that it contains all necessary details for conducting 
this trial. I will conduct the trial as outlined in the following protocol and in compliance with 
GCP, and will apply due diligence to avoid protocol deviations. I will provide copies of the 
protocol and all drug information relating to pre-clinical and prior clinical experience fur-
nished to me by ETOP, to all physicians responsible to me who participate in this trial. I will 
discuss this material with them to assure that they are fully informed regarding the drug and 
the conduct of the trial. I agree to keep accurate records on all patient information including 
patient's informed consent statement, drug shipment and return forms, and all other infor-
mation collected during the trial for a minimum period of 15 years. 
 
 
Name of Principal Investigator:___________________________________________ 
 
 
Institution’s name and place:___________________________________________ 
 
 
 
_____________________________________________________ ______________ 
 
 
Signature 
Date 
 


ETOP/IFCT 4-12 STIMULI V 2.0   03Aug2015 
 
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TABLE OF CONTENTS  
Section 
Page 
 
1. 
Protocol summary .................................................................................................... 10 
2. 
Trial schedule ........................................................................................................... 16 
3. 
List of abbreviations ................................................................................................ 19 
4. 
Background and rationale ........................................................................................ 22 
4.1. 
Disease background ............................................................................................. 22 
4.2. 
Treatment of stage I-III SCLC ............................................................................. 23 
4.3. 
Targeted agents in small cell lung carcinoma ..................................................... 25 
4.4. 
Immunotherapy .................................................................................................... 25 
4.5. 
Immune checkpoint receptors .............................................................................. 26 
4.6. 
Immune checkpoint inhibitors ............................................................................. 27 
4.7. 
Overall risk/benefit assessment ........................................................................... 32 
4.8. 
Rationale for trial design ..................................................................................... 34 
5. 
Objectives and endpoints ......................................................................................... 35 
5.1. 
Primary objective ................................................................................................. 35 
5.2. 
Secondary objectives ........................................................................................... 35 
5.3. 
Co-primary endpoints .......................................................................................... 35 
5.4. 
Secondary endpoints ............................................................................................ 35 
6. 
Trial design, duration and termination ..................................................................... 35 
7. 
Patient selection ....................................................................................................... 37 
7.1. 
Inclusion criteria for enrolment ........................................................................... 37 
7.2. 
Exclusion criteria for enrolment .......................................................................... 38 
7.3. 
Inclusion criteria for randomisation .................................................................... 39 
7.4. 
Exclusion criteria for randomisation ................................................................... 39 
8. 
Patient screening, enrolment and randomisation ..................................................... 40 
8.1. 
Screening ............................................................................................................. 40 
8.2. 
Randomisation and stratification ......................................................................... 40 
9. 
Investigational Medicinal Products ......................................................................... 40 
9.1. 
Description of the Investigational Medicinal Products ....................................... 41 
9.2. 
Packaging and labelling ....................................................................................... 41 
9.3. 
Receipt of the drugs ............................................................................................. 41 
9.4. 
Storage and handling ........................................................................................... 42 
9.5. 
Unused trial drug supplies ................................................................................... 42 
10. 
Trial treatments ........................................................................................................ 42 
10.1. 
Overview of treatment sequence ......................................................................... 42 
10.2. 
Chemotherapy dosage, administration and schedule ........................................... 43 
10.3. 
Chemotherapy delay and dose modification for toxicity..................................... 46 
10.4. 
Thoracic radiation ................................................................................................ 48 
10.5. 
Prophylactic cranial irradiation (PCI) .................................................................. 52 
10.6. 
Nivolumab and ipilimumab combination treatment ............................................ 52 
10.7. 
Nivolumab and ipilimumab delay and discontinuation for toxicity during 
consolidation phase ............................................................................................. 53 
10.8. 
Immune-related Adverse Events (irAEs): definition, monitoring and treatment 56 
10.9. 
Prohibited and restricted therapies during trial treatment ................................... 59 
10.10. Pregnancy prevention .......................................................................................... 60 
10.11. Treatment duration .............................................................................................. 60 
11. 
Safety of Investigational Medicinal Products .......................................................... 62 


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11.1. 
Ipilimumab........................................................................................................... 62 
11.2. 
Nivolumab ........................................................................................................... 65 
11.3. 
Safety profile of nivolumab and ipilimumab combination therapy ..................... 69 
11.4. 
Early analysis for treatment related pneumonitis ................................................ 70 
11.5. 
Cisplatin ............................................................................................................... 70 
11.6. 
Carboplatin .......................................................................................................... 72 
11.7. 
Etoposide ............................................................................................................. 76 
12. 
Adverse events and reporting .................................................................................. 78 
12.1. 
Adverse event reporting ....................................................................................... 78 
12.2. 
Targeted Adverse Events for chemo-radiotherapy .............................................. 79 
12.3. 
Definition of immune-related Adverse Events (irAE) ........................................ 80 
12.4. 
Drug-induced liver injury (DILI): ....................................................................... 81 
12.5. 
Definition of Serious Adverse Event (SAE)........................................................ 82 
12.6. 
Definition of Serious Adverse Drug Reaction (SADR) ...................................... 83 
12.7. 
Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) ........ 83 
12.8. 
Reporting SAEs and protocol-specified significant events ................................. 83 
12.9. 
Pregnancy ............................................................................................................ 84 
13. 
Response evaluation ................................................................................................ 85 
13.1. 
RECIST 1.1 criteria ............................................................................................. 85 
13.2. 
CT Schedule for tumour assessment ................................................................... 85 
13.3. 
Determination of time point response ................................................................. 85 
13.4. 
Determination of best overall response ............................................................... 86 
13.5. 
Storage of imaging............................................................................................... 86 
14. 
Endpoints definition ................................................................................................. 86 
14.1. 
Progression-free survival ..................................................................................... 86 
14.2. 
Overall survival ................................................................................................... 86 
14.3. 
Objective response ............................................................................................... 87 
14.4. 
Time to treatment failure ..................................................................................... 87 
14.5. 
Toxicity ................................................................................................................ 87 
15. 
Biological material and translational research ......................................................... 87 
15.1. 
Mandatory evaluations ........................................................................................ 87 
15.2. 
FDG-PET CT ....................................................................................................... 88 
15.3. 
Optional evaluations ............................................................................................ 88 
15.4. 
Submission of material ........................................................................................ 89 
15.5. 
Banking of biological material ............................................................................ 90 
16. 
Trial procedures ....................................................................................................... 90 
16.1. 
Trial phases .......................................................................................................... 91 
16.2. 
Baseline evaluations ............................................................................................ 92 
16.3. 
During chemo-radiotherapy ................................................................................. 93 
16.4. 
Before randomisation .......................................................................................... 93 
16.5. 
Before start of consolidation phase ..................................................................... 94 
16.6. 
During consolidation phase (induction and maintenance) .................................. 94 
16.7. 
Evaluations at progression ................................................................................... 95 
16.8. 
End of treatment visit .......................................................................................... 95 
16.9. 
Evaluations in the follow-up phase before progression ....................................... 96 
16.10. Evaluations after progression / in follow-up ....................................................... 96 
17. 
Case report forms and documentation ..................................................................... 96 
17.1. 
Case report forms schedule .................................................................................. 96 
18. 
Statistical considerations ....................................................................................... 100 
18.1. 
Primary objective ............................................................................................... 100 


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18.2. 
Sample size determination ................................................................................. 100 
18.3. 
Co-primary endpoint: OS and PFS .................................................................... 100 
18.4. 
Evaluation of primary and secondary objectives ............................................... 101 
18.5. 
Early safety evaluation ...................................................................................... 102 
19. 
Criteria for termination of the trial ........................................................................ 102 
19.1. 
General criteria for termination of the trial ....................................................... 102 
19.2. 
Discontinuation of protocol treatment for individual patients ........................... 102 
19.3. 
Withdrawal of consent ....................................................................................... 103 
20. 
Ethics aspects, regulatory approval, and Patient Informed Consent ...................... 103 
20.1. 
Ethical Review Board/Ethics Committee .......................................................... 104 
20.2. 
Regulatory approval procedures ........................................................................ 104 
20.3. 
Informed consent ............................................................................................... 104 
21. 
Governance and administrative issues ................................................................... 105 
21.1. 
Final report ........................................................................................................ 105 
21.2. 
Steering Committee ........................................................................................... 105 
21.3. 
Independent Data Monitoring Committee ......................................................... 105 
21.4. 
Publication ......................................................................................................... 105 
21.5. 
Clinical trial insurance ....................................................................................... 105 
21.6. 
Quality assurance ............................................................................................... 106 
21.7. 
Protocol adherence ............................................................................................ 106 
21.8. 
Data protection .................................................................................................. 106 
21.9. 
Record retention ................................................................................................ 107 
22. 
References .............................................................................................................. 107 
Appendices: 
1. Template for patient information and informed consent form  
2. RECIST criteria V1.1 
3. ETOP Publication Guidelines  
Index of tables 
Table 1: AEs in a randomised placebo-controlled phase II trial in stage IV SCLC comparing 
chemotherapy to concurrent or sequential chemotherapy and ipilimumab ........................... 28 
Table 2: Chemotherapy administration using option 1 schedule (cisplatin day 1 only) ........ 44 
Table 3: Chemotherapy administration using option 2 schedule (cisplatin days 1-3) ........... 45 
Table 4: Chemotherapy administration using option 3 schedule (carboplatin day 1 only) ... 45 
Table 5: Dose modifications of cisplatin/etoposide for haematological toxicity .................. 46 
Table 6: Dose modifications of carboplatin/etoposide for haematological toxicity .............. 46 
Table 7: Dose modifications of cisplatin/etoposide for hepatic toxicity ............................... 47 
Table 8: Dose modifications of carboplatin/etoposide for hepatic toxicity ........................... 47 
Table 9: Dose modifications of cisplatin/etoposide for renal toxicity ................................... 48 
Table 10: Dose modifications of carboplatin/etoposide for renal toxicity ............................ 48 
Table 11: Summary of irAE safety data for 10 mg/kg ipilimumab in melanoma ................. 62 
Table 12: Drug-related AEs ≥5% (any grade) and all Grade 3-5 AEs – SCLC patients 
treated with nivolumab monotherapy or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg 
combination therapy............................................................................................................... 67 
Table 13: Summary statistics of nivolumab steady-state exposure ....................................... 68 
Table 14: Summary of AE safety data for etoposide ............................................................. 76 
Table 15: Determination of time point response.................................................................... 85 
Table 16: Case report forms ................................................................................................... 96 
 


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1. 
Protocol summary 
 
ETOP/IFCT 4-12 STIMULI 
 
 A randomised open-label phase II trial of consolidation with nivolumab 
and ipilimumab in limited-stage SCLC after chemo-radiotherapy  
 
Small cell lung carcinoma Trial with nivolumab and IpiliMUmab in LIm-
ited disease 
 
Sponsor: European Thoracic Oncology Platform (ETOP) 
Pharma Partner: Bristol-Myers Squibb 
Population: Radically treated limited-stage SCLC following completion of thoracic radio-
therapy concomitant to chemotherapy and PCI 
Design: Open-label, randomised, two-arm, phase II international multi-centre clinical trial 
with early interim analysis for safety 
 
Sample size: 260 randomised under the amendment 1, approximately 325 enroled in chemo-
radiotherapy part. 
Randomisation: stratified by twice-daily vs once-daily radiotherapy and PET-CT done vs 
not done. 
Chemo-Radiotherapy:
cis-/carboplatin + etoposide 
4 cycles
Biomaterial for translational research:
Consolidation vs observation:
induction
maintenance
max 1 year
combination
nivolumab
nivolumab/ipilimumab
observation
Screening:
LD SCLC
PCI
Tumour
evaluation:
PD
off
Voluntary re-biopsy: 
→ FFPE block
yes
no
R

3
6
9
3
6
9
18
12
after randomisation
RT (Thoracic Radiotherapy):
CT scans for tumour assessment
accelerated schedule preferred 
- up to 18 months: 
every 9 weeks
start: day 1 of chemo cycle 1 or
- up to 2 years: 
every 12 weeks 
day 1 of chemo cycle 2 
- years 3 & 4: 
every 6 months
- at 5 years
0
Week
Serum
At progression:
Whole blood
Whole blood
Whole blood
RT
RT
from start of chemotherapy
-2
CT
Serum
Serum
Serum
FDG-PET-CT
or CT 
Brain MRI 
or CT
Biopsy: 
FFPE block 
or slides
27 ∙∙∙
CT

14
16


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Rationale: 
At the time of diagnosis, 30% of patients with small cell lung carcinoma (SCLC) will have 
limited stage disease, now called stage I-IIIB (IASLC). The outcome of limited disease SCLC 
is still poor, with a median survival of 16 to 24 months with current forms of treatment and 
only 15-25% long term survivors. 
Combining chemotherapy and thoracic radiotherapy is the standard treatment approach in 
limited-stage SCLC with a combination of platinum compounds (cis- or carboplatin) and 
etoposide as the backbone regimen. Concurrent chemo-radiotherapy is superior to sequential 
treatment and early thoracic irradiation starting with first or second cycle of chemotherapy 
appears beneficial. Hyperfractionated accelerated radiotherapy has been shown to be more 
efficacious than radiotherapy given in a long overall treatment time. However, availability 
and routine-use of hyperfractionated radiotherapy remains a matter of debate. Therefore, in 
this trial, both radiotherapy schedules of accelerated twice-daily administration or once-daily 
radiotherapy are accepted. The choice of schedule is a stratification factor for randomisation. 
Several studies in patients with NSCLC suggested an association of increased tumour infil-
tration of immune cells with improved survival. In recent years, a continuously improved 
identification of antigenic targets, the addition of immunoadjuvants, and the production of 
more efficient delivery systems have resulted in more efficient vaccines, able to elicit a potent 
immune response, leading to the development of immunotherapy as a fundamentally new 
treatment of NSCLC.  
The adaptive immune response is triggered via effector T-cells, antigen-presenting cells 
(APCs) and co-stimulatory signals mediated by T-cell receptors such as CD28. The interplay 
of these signals results in the activation and clonal proliferation of T-cells. 
T-cell proliferation is tightly regulated in order to avoid autoimmunity. The balance between 
co-stimulatory signals mediated by CD28 and co-inhibitory signals via so called immune 
checkpoint receptors is crucial for the maintenance of self-tolerance and to protect tissues 
from damage during normal immune response. After activation, T-cells express the immune 
checkpoint receptors cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell 
death protein 1 (PD-1). 
CTLA-4- and PD-1 expressing T-cells play a critical role in maintaining self-tolerance but are 
also responsible for non-responsiveness to tumour antigens. Cancer cells escape from immune 
surveillance by expressing immune checkpoint receptors. The goal of immune checkpoint 
inhibitor therapies is not to activate the immune system to attack particular targets on tumour 
cells, but rather to remove inhibitory pathways that block effective antitumour T-cell re-
sponses. 
Ipilimumab is a monoclonal antibody that binds to CTLA-4 and inhibits the interactions with 
the ligands B7.1 and B7.2, 
Nivolumab is a monoclonal antibody that targets PD-1. Engagement of PD-1 by its natural 
ligands, PD-L1 and PD-L2, results in an inhibition of T-cell proliferation, survival and cyto-
kine secretion. Nivolumab abrogates this interaction between PD-1 and its ligands. 


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The two antibodies, nivolumab and ipilimumab, do not only target different immune cell re-
ceptors, they also regulate distinct inhibitory pathways and have therefore non-overlapping 
mechanisms of action. Anti-CTLA-4 therapies seem to drive T-cells into tumours, resulting 
in an increased number of intratumour T-cells and a concomitant increase in IFN-. This in 
turn can induce the expression of PD-L1 in the tumour microenvironment, with subsequent 
inhibition of antitumour T-cell responses, but may also increase the chance of benefit from 
anti-PD-1 and anti-PD-L1 therapies. A combination treatment with anti-CTLA-4 (e.g. ipili-
mumab) plus anti-PD-1 (e.g. nivolumab) or anti-PD-L1 antibodies should enable the creation 
of an immunogenic tumour microenvironment with subsequent clinical benefit for patients. 
Nivolumab monotherapy has been approved for the treatment of advanced melanoma (FDA, 
EMA, and Japan) and previously treated squamous NSCLC (FDA, positive CHMP opinion). 
Nivolumab and ipilimumab improved PFS compared to nivolumab or ipilimumab alone in a 
study in melanoma (CA209067). 
In a randomised open-label phase I/II trial (CheckMate 032), evaluating nivolumab with or 
without ipilimumab in pretreated SCLC patients with progressive disease and sensitive or 
refractory to platinum based chemotherapy, based on an interim analysis a response rate of 
33% and disease stabilisation in 22% was observed for the combination of nivolumab and 
ipilimumab compared to 18% response rate and 20% stable disease with nivolumab mono-
therapy. 
Both, nivolumab monotherapy and nivolumab plus ipilimumab combination treatment were 
tolerable for the treatment of SCLC, and no new safety profile was identified compared to the 
profile of nivolumab with or without ipilimumab in other anti-cancer therapies. 
Nivolumab plus ipilimumab will be administered as a consolidation treatment  after comple-
tion of a standard treatment including chemo-radiotherapy and prophylactic cranial irradiation 
(PCI). 
 
Objectives and endpoints:  
The primary objective is to evaluate if patients treated with chemo-radiotherapy and prophy-
lactic cranial irradiation followed by consolidation treatment (nivolumab plus ipilimumab) 
have a better outcome in terms of progression-free survival and overall survival, compared to 
patients treated with chemo-radiotherapy and prophylactic cranial irradiation without consol-
idation treatment. 
Co-primary endpoints:  
 Overall survival 
 Progression-free survival determined by RECIST 1.1 
 
Secondary endpoints:  
 Objective response determined by RECIST 1.1 
 Time to treatment failure 
 Adverse events graded according to CTCAE V4.0 
 


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Most important eligibility criteria (see protocol section 7 for complete list):  
Inclusion criteria at enrolment: 
 Histologically or cytologically confirmed small cell lung carcinoma 
 Untreated (with the exception of 1 cycle of chemotherapy given prior to enrolment) 
limited stage disease (LD) as defined by stage I-IIIB based on 7th TNM classifica-
tion (IASLC classification for SCLC proposal). M0 proven by  
o Whole body FDG-PET CT including a contrast-enhanced CT of thorax and 
upper abdomen (incl. liver, kidney, adrenals); 
OR contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, 
adrenals) and bone scan;  
AND 
o Brain MRI (or contrast enhanced CT of the brain). 
 
Within 28 days before start of chemotherapy 
 
 Age ≥18 years 
 ECOG performance status 0-1 
 Adequate haematological, renal, hepatic and lung function 
 Pulmonary function FEV1 of 1.0L or >40% predicted value and DLCO >40% pre-
dicted value 
Exclusion criteria at enrolment: 
 Patients with mixed small-cell and non-small-cell histologic features 
 Patients with pleural or pericardial effusions proven to be malignant 
 Documented history of severe autoimmune or immune mediated symptomatic dis-
ease that required prolonged (more than 2 months) systemic immunosuppressive 
treatment (e.g steroids) such as ulcerative colitis and Crohn´s disease, rheumathoid 
arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythemato-
sus, or autoimmune vasculitis (eg, Wegener’s granulomatosis) 
 Patients with an autoimmune paraneoplastic syndrome requiring concurrent immu-
nosuppressive treatment are excluded. 
 Interstitial lung disease or pulmonary fibrosis  
 Women who are pregnant or in the period of lactation  
 Patients with any concurrent anticancer systemic therapy (except for chemotherapy 
cycle 1) 
 HIV, Hepatitis B or Hepatitis C infection 
 Patients who have had in the past 5 years any previous or concomitant malignancy 
EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ 
carcinoma of the cervix or bladder, in situ ductal carcinoma of the breast. 
 Previous radiotherapy to the thorax (prior to inclusion)  
 Planned mean lung dose >20 Gy or V20 >35% 
Inclusion criteria at randomisation: 
 Chemo-radiotherapy completed per protocol: 4 cycles of chemotherapy, 85% of PTV 
of thoracic radiotherapy, as well as completed, mandatory PCI 
 Non-PD after chemo-radiotherapy and PCI 


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Treatment arms: 
 
Experimental arm: 
Induction phase: 
to start within 6-8 weeks (42-56 days) after the start of chemotherapy cycle 4, and not more 
than 2 weeks (14 days) after the date of randomisation 
- Nivolumab at a dose of 1 mg/kg i.v. over a period of 30 minutes 
 followed (on the same day) by 
- Ipilimumab at a dose of 3 mg/kg i.v. over a period of 90 minutes 
 once every 3 weeks (+/- 3 days, without dosing delay), 4 cycles 
 
Maintenance phase: 
to start 3 weeks (21 days) after the last IMP dose of induction phase 
- Nivolumab 240 mg i.v. over a period of 30 minutes, once every 2 weeks (+/- 2 days, with-
out dosing delay), for a maximum of 12 months from start of maintenance phase. 
 
Observation arm: 
No further treatment 
 
Statistical considerations:  
Hyperfractionated accelerated radiotherapy has been shown to be more efficacious than radi-
otherapy given in a long overall treatment time. By giving twice-daily fractionation (BID), 
late reacting normal tissues are spared compared to the tumour, with as a consequence more 
temporarily acute oesophagitis. 
The value of twice daily (BID) radiotherapy given early and concurrently to chemotherapy 
was examined in landmark trials and in a meta-analysis which will be our benchmark data. 
After a median follow-up of over 8 years, 2-year overall survival (OS) for BID and QD radi-
otherapy, respectively, were 47% and 41%. Assuming that half of included patients will re-
ceive BID and QD respectively, the median OS is therefore expected to be 20.7 months in the 
observation. Median progression-free survival (PFS) is expected to be 13.1 months. 
PFS and OS will be evaluated as co-primary endpoints. Hazard ratios of 0.70 for OS and 0.57 
for PFS are to be detected with adequate power. The overall one-sided significance level of 
0.05 for the logrank test is divided into 0.04 for OS and 0.01 for PFS.  
A trial duration of 7.5 years from enrolment of the first patient is necessary for the required 
212 deaths to be observed. The main analysis of PFS will be performed when 148 PFS events 
have occurred, which is expected at approximately 45 months. The achieved power is 78% 


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for OS at the end of the study, and 80% for PFS at 45 months. A total number of 260 patients 
is required to be randomised.  
It is expected that after the chemo-radiotherapy phase, about 20% of treated patients will have 
progressed or will not receive PCI and can therefore not be randomised. Thus, approximately 
325 patients will be enroled in order to randomise 260 patients under amendment 1, at an 
estimated accrual time of 3 years. 
Total trial duration: 7.5 years from enrolment of the first patient 
Translational research:  
Serum levels of TNF α/β, IL6 and circulating antibodies will be determined centrally in every 
patient at enrolment, at the time of randomisation, 9 and 18 weeks after randomisation and at 
the time of progression. 
A biobank will be created with centralised samples for translational research. 
Whole blood, PBMCs (in selected centres) and diagnostic FFPE blocks  will be collected from 
patients consenting to translational research. If no blocks can be submitted, 5-10 sections with 
a minimum thickness of 15-20μm from the tumour block or cell block can be submitted in-
stead, and, when feasible, also 5 freshly cut sections at 4-5 μm thickness. Immune-related 
gene expression profile and deep sequencing will be considered in peripheral blood and tu-
mours, and immunohistochemistry will allow characterising tumour microenvironment. Im-
munomonitoring with blood cell subtyping and quantification, including FACS analysis, will 
be performed on PBMCs (selected centres only). 
Progressing patients will be asked for a voluntary biopsy. 
Pre-chemo-radiotherapy FDG-PET to assess background FDG avidity in the tumour, the hilar 
and mediastinal lymph nodes (if involved at staging) and the lungs will be optional. 
 
 


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2. 
Trial schedule 
 
Screening1 
Enrolment 
Chemo-ra-
diotherapy2 
Before ran-
domisation3 
Consolidation treatment4 
 
PD 
End of 
Treatment 
visit 
Follow-up8 
Induction5,7 
Maintenance6,7 
Before 
PD 
After 
PD 
Written informed consent 
before any trial specific 
evaluations and intervention 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
 
 
 
 
FFPE tumour material 
optional 
 
 
 
 
 
optional (en-
couraged) re-
biopsy 
 
 
 
Serum samples  
for translational research 
TNF /, IL6,  
circulating antibodies 
 
 
 
 
9 weeks after ran-
domisation 
18 weeks after 
randomisation 
 
 
 
 
Whole blood 
for translational research: 
RNA profiling (all sites), 
PBMCs (selected sites) 
 
optional 
 
optional 
optional 
 
9 weeks after ran-
domisation 
optional 
 
18 weeks after 
randomisation 
 
 
 
 
Physical exam: PS / blood 
pressure / body weight / 
height 
 
 
every cycle 
 
every cycle 
every cycle 
 
 
 
 
Pulmonary function:  
FEV1 / DLCO 
 
 
 
 
 
 
 
 
 
 
HIV / Hepatitis B/C 
 
 
 
 
 
 
 
 
 
 
Haematology9 
 
 
every cycle 
only haemoglo-
bin, platelets, 
neutrophils 
 
every cycle 
every cycle 
 
 
 
 
Renal function: 
serum creatinine, calculated 
creatinine clearance 
 
 
every cycle 
 
every cycle 
every cycle 
 
 
 
 
Hepatic function:  
ALT, AST, AP, bilirubin 
 
 
only AST & bil-
irubin 
 
every cycle 
every cycle 
 
 
 
 
Na, K 
 
 
 
 
every cycle 
every cycle 
 
 
 
 
TSH, with reflex free T3/410 
 
 
 
 
1st and 3rd cycle 
at 1st cycle, then 
every 3 cycles 
 
 
 
 


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Screening1 
Enrolment 
Chemo-ra-
diotherapy2 
Before ran-
domisation3 
Consolidation treatment4 
 
PD 
End of 
Treatment 
visit 
Follow-up8 
Induction5,7 
Maintenance6,7 
Before 
PD 
After 
PD 
Ca, LDH, glucose, amyl-
ase, lipase10 
 
 
 
 
every cycle 
every 3 cycles 
 
 
 
 
Pregnancy test 11: 
 
 
 
 
every 6 weeks 
every 6 weeks 
 
 
 
 
Tumour assessments be-
fore randomisation12 
 
 
 
 
 
 
 
 
 
 
Tumour assessments after 
randomisation13 
 
 
 
 
 
 
 
 
 
 
Adverse events14 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
Cis- or carboplatin + 
etoposide 
 
 
 
 
 
 
 
 
 
 
Radiotherapy15 
 
 
 
 
 
 
 
 
 
 
Prophylatic cranial irradi-
ation 
 
 
cycle 4 
 
 
 
 
 
 
 
Nivolumab plus ipili-
mumab 
 
 
 
 
 
 
 
 
 
 
Nivolumab 
 
 
 
 
 
 
 
 
 
 
Second-line therapy and 
survival 
 
 
 
 
 
 
 
 
 
 
 
 
Mandatory evaluation / intervention 
1  
≤ 28 days prior enrolment; if the first chemotherapy cycle has been administered before enrolment, baseline evaluations must have been done within 35 days before start of first chemotherapy 
cycle. 
2 
Chemotherapy consists of platinum compound (cis- or carboplatin) and etoposide combination and is given for 4 cycles (1 cycle = 21 days). Chemotherapy should start within 7 days after 
enrolment. If the start of chemotherapy cannot be delayed, a maximum of 1 chemotherapy cycle can be administered before enrolment. 
3 
Randomisation should take place 5 - 6 weeks from day 1 of chemotherapy cycle 4 (between days 35 and 42 of cycle 4). All examinations have to be done within 7 days prior randomisation 
(except for tumour assessment, which has to be done within 14 days before randomisation). 
4 
Consolidation treatment should start 6-8 weeks (42-56 day) from start of chemotherapy cycle 4, and not more than 2 weeks (14 days) after the date of randomisation. 
5 
Induction phase: nivolumab (1 mg/kg i.v. over a period of 30 minutes) followed (on the same day) by ipilimumab (3 mg/kg i.v. over a period of 90 minutes), once every 3 weeks (+/- 3 days, 
without dosing delay), for 4 cycles. 
6 
Maintenance phase: nivolumab (240 mg i.v. over a period of 30 minutes), once every 2 weeks (+/- 2 days, without dosing delay) until PD, for a maximum of 1 year from start of maintenance 
phase. The first dose of maintenance nivolumab will be administered 3 weeks after the last IMP doses of induction phase. 


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7 
Observation arm: patients should be documented 9 and 18 weeks (+/- 3 days) after randomisation and thereafter every 18 weeks (+/- 1 week), according to local standard of follow-up, 
until PD or for maximum15 months after randomisation. The following laboratory values are to be measured: haematology, renal function, hepatic function, Na and K. Beyond 15 months 
after randomisation or upon PD patients will enter the follow-up phase. 
 
CT scans for tumour assessment are done at the same schedule as for patient in the experimental arm (see footnote 13). 
8 
Follow-up:  
Before PD: Patients who completed consolidation treatment (in the observation arm this corresponds to 15 months after randomisation) or discontinue IMP treatment before tumour progres-
sion should have physical examination at regular intervals (blood pressure, performance status and weight). In the first 18 months after randomisation this has to be done together with the 
CT scans according to the schedule indicated in footnote 13, then every 12 (+/- 1) weeks until PD for a maximum of 4.5 years after the enrolment of the last patient. 
 
After PD: Patients with tumour progression will end trial treatment and should have documented survival, and further lines of treatment every 12 weeks (+/-1 week) starting from date of 
progression during the first year after randomisation, then every 6 months (+/- 4 weeks) up to 4.5 years  after the enrolment of the last patient. 
9 
Haematology: haemoglobin, platelets, complete white blood cell count [leucocytes, neutrophils, eosinophils, basophils (or total granulocytes), lymphocytes, monocytes] 
10 
Only patients in experimental arm. In case of abnormal TSH value, also free T3 and T4 has to be measured. 
11 
Pregnancy test: Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days 
before beginning of chemotherapy. The test has to be repeated within 7 days before randomization and then every 6 weeks during consolidation treatment. Pregnancy tests should be repeated 
at approximately 30 days and approximately 70 days after consolidation treatment stop. 
12 
Tumour assessments before randomisation 
 
At baseline: brain MRI (or contrast enhanced CT of the brain), AND whole body FDG-PET CT including a contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals). 
If FDG-PET CT is not available, contrast enhanced CT of the thorax and upper abdomen (incl. liver, kidney, adrenals) and bone scan is required for tumour assessment at baseline. 
 
Within 14 days prior to randomisation: contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals) 
13 
Tumour assessments after randomisation 
 
For both treatment arms, CT of thorax and upper abdomen (incl. liver, kidney, adrenals) have to be done as indicated below: 
 
 
- up to 18 months: 
every 9 weeks 
weeks after randomisation: 
9, 18, 27, 36, 45, 54, 63, 72, 81 (+/- 1 week) 
 
 
- up to 2 years: 
every 12 weeks 
 
“ 
93, 105 (+/- 1 week) 
 
 
- years 3 and 4: 
every 6 months (26 weeks) 
 
“ 
131, 157, 183, 209 (+/- 1 week) 
 
 
- at 5 years: 
 
 
“ 
260 (+/- 1 week) 
 
In case of clinical suspicion of distant metastases, immediate adequate diagnostic procedures including CT-scan, whole body PET-CT, bone scans and MRI (as appropriate) should be used. 
 
Early progression at 9 weeks: Patients with tumour volume increase documented by CT scan 9 weeks after randomisation, but without appearance of new lesions or rapid clinical deterioration 
should continue to be treated with IMP and clinically observed with a stringent imaging schedule 4 weeks later to determine whether there has been a decrease in the tumour size or disease 
stabilisation, or alternatively continued PD which would terminate the trial treatment. 
 
Patients who discontinue study treatment for reasons other than progressive disease: Restaging should be repeated at time of discontinuation, except if already performed within 6 weeks 
prior to the last dose of study treatment. 
14 
Adverse events: All adverse events that occur within 100 days of the last administered study medication or within 100 days after the last visit in the observation arm must be documented. 
Symptoms present at baseline and at randomisation will be recorded on the adverse event forms as well. 
15 
Thoracic radiation will be administered concurrently to chemotherapy and should preferentially start at the same time as the first chemotherapy cycle (e.g. day 1 of cycle 1), if the patient 
 
can be enroled before chemotherapy start. Otherwise, radiotherapy should optimally start at day 1 of cycle 2, i.e. in treatment week 4. As a latest start of radiotherapy day 1 of cycle 3 is 
 
allowed, but should be exceptional. 


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3. 
List of abbreviations 
AE 
Adverse Event 
ALT 
Alanine transaminase 
ANC 
Absolute Neutrophil Count 
AP 
Alkaline phosphatase 
APC 
Antigen presenting cell 
AST 
Aspartate transaminase 
AUC 
Area Under the Curve 
BID 
Bis In Die (lat.), twice-daily  
BMS 
Bristol-Myers Squibb 
BOR 
Best Overall Response 
BORR 
Best Overall Response Rate 
CNS 
Central Nervous System 
CR 
Complete response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte Antigen-4 
CTV 
Clinical Target Volume 
DLCO 
Diffusing Capacity for Carbon Monoxide 
DVH 
Dose Volume Histogramm 
EC 
Ethics Committee 
ECL  
Electrochemiluminescent 
eCRF 
Electronic Case Report Form 
ED 
Extensive Stage Disease 
EGFR 
epidermal growth factor receptor 
EP 
Etoposide - Cisplatinum 
ERB 
Ethical Review Board 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography 
FFPE 
Formalin Fixed, Paraffin Embedded 
GFR 
Glomerular Filtration Rate 
GI 
Gastrointestinal 
GTV 
Gross Tumour Volume  
IASLC 
International Association for the Study of Lung Cancer 
IB 
Investigator's Brochure 
IC 
Informed Consent 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IMRT 
Intensity Modulated Radiotherapy 


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INR 
International Normalised Ratio 
IMP 
Investigational Medicinal Product 
irAE 
Immune-related Adverse Events 
irBORR 
Best Overall Response Rate by irRC 
irPFS 
Immune-related Progression Free Survival 
irRC 
Immune-related Response Criteria 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-Releasing System 
Hb 
Hemoglobin 
LD 
Limited Stage Disease 
LF 
Lost to Follow-up 
LFT  
Liver Function Test  
LLN 
Lower Limit of Normal Lab Value 
LS 
Limited Stage 
MIP 
Maximum Intensity Projection  
MLD 
Mean Lung Dose 
MRI 
Magnetic Resonance Imaging 
NE 
Not Evaluable 
NCCN 
National Comprehensive Cancer Network 
NSCC 
Nonsquamous-Cell Carcinoma 
NSCLC 
Non-Small Cell Lung Carcinoma 
OAR 
Organs at Risk 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral blood mononuclear cell 
PCI 
Prophylactic Cranial Irradiation 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Protein 1 
PD-L1 
Programmed Cell Death Ligand 1 
PE 
Cisplatin/Etoposide 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PPK 
Population Pharmacokinetic 
PR 
Partial Response 
PS 
Performance Status 
QD 
Quaque Die, once daily 
PTV  
Planning Target Volume 
RDE 
Remote Data Entry 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RT 
Radiotherapy 


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SAE 
Serious Adverse Event 
SADR 
Serious Adverse Drug Reaction 
SCC 
Squamous-Cell Carcinoma 
SCLC 
Small cell lung carcinoma 
SD 
Stable Disease 
SER 
Start of any Treatment to the End of Radiotherapy 
SIAD 
Syndrome of Inappropriate Diuresis 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUV 
Standard uptake volume 
TIL 
Tumour Infiltrating Lymphocyte 
Treg 
Regulatory T-cells (CD4+CD25+) 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal lab value 
VALG 
Veterans Administration Lung Study Group 
VEGF 
Vascular endothelial growth factor 
WBRT 
Whole Brain Radiotherapy 
WC 
Withdrawal of Consent 


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4. 
Background and rationale 
4.1. 
Disease background 
Lung cancer accounts for 12% of all incident cases of cancer. 13% of these lung cancer cases 
are small cell lung carcinoma (SCLC) [1]. Over 90% of SCLC patients are current or past 
smokers, although some very exceptional cases have been described in never-smokers [2, 3]. 
The median age at diagnosis exceeds 70 years and most patients have at least one cardiovas-
cular, respiratory, or metabolic co-morbidity [4]. The incidence of SCLC has been decreasing 
over the past 30 years in developed countries, most probably related to changes in smoking 
pattern [5].  
SCLC is defined as “a malignant epithelial tumour consisting of small cells with scant cyto-
plasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous 
nucleoli” [6]. There are two categories: more than 90% is ‘typical’, the others being ‘com-
bined’ when at least 10% large cells are admixed. 
Cytogenetic analysis of SCLC has identified several abnormalities in DNA copy number. 
Several important genetic and molecular changes have been described, including the identifi-
cation of autocrine growth loops, proto-oncogene activation, and loss or inactivation of tu-
mour-suppressor genes [7]. One of the most frequent genetic alterations in SCLC is the dele-
tion of the chromosome region 3p(14-23) occurring in virtually all SCLCs. This region of 
deletion includes the tumour suppressor gene FHIT. The mutational pattern evident in SCLC 
is distinct from that in NSCLC with a near universal loss of the tumour suppressor retinoblas-
toma gene RB1 and more frequent mutation of TP53. Tyrosine kinase signalling genes in-
cluding K-RAS and EGFR are rarely mutated.  
The typical SCLC patient is a 70 year old male heavy (ex-)smoker with pulmonary and car-
diovascular comorbidity, presenting with rapid onset symptoms due to either local tumour 
growth (cough, wheezing, dyspnoea, haemoptysis), invasion in either chest wall, superior 
vena cava, oesophagus or recurrent nerve, distant spread (pain, fatigue, anorexia, neurological 
complaints) or a paraneoplastic syndrome [8, 9]. The duration of symptoms is short, being 
approximately 8–12 weeks prior to presentation. Preferential metastatic sites of dissemination 
are the brain, liver, adrenal glands, bone and bone marrow. SCLC is the most frequent cause 
of paraneoplastic syndromes, most commonly the syndrome of inappropriate diuresis (SIAD) 
and Cushing syndrome. 
In 1957, the Veterans Administration Lung Study Group (VALG) adopted a dichotomized 
staging classification [10]. Limited stage (LS) was defined as a tumour volume encompassa-
ble in a single radiation portal. All other disease spread was classified as extensive stage. Of 
course, this definition dates from before the CT-era, contemporary staging and radiotherapy 
techniques. The International Association for the Study of Lung Cancer recommends staging 
of SCLC according to the 7th edition of the TNM-classification of lung cancer [11]. This 
recommendation is based on a retrospective analysis of data from 8000 SCLC patients, show-
ing that survival of LS-patients with mediastinal lymph node involvement (stage III) signifi-
cantly differs from those without (stage I) or with N1-lymph node involvement (stage II) [12]. 
Patients with pleural effusion have an intermediate prognosis between stage III and those with 


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haematogenous spread (stage IV). The implication of this recommendation is that patients 
with cytologically negative effusions are now classified as having stage III. Although its sim-
plicity makes the VALG-classification attractive for use in routine clinical practice, clinicians 
and cancer registrars are nevertheless strongly encouraged to use the TNM-classification. 
Moreover, it should be emphasised that the definition of “limited stage” also differs signifi-
cantly between clinical studies, and that most series did not use the strict VALG-classification.  
4.2. 
Treatment of stage I-III SCLC 
Because SCLC is a systemic disease, chemotherapy is and remains the backbone of the treat-
ment. Adequate local therapy nevertheless improves long-term survival significantly when 
delivered together with systemic treatment. Importantly, the COCIS meta-analysis [13] of 
individual patient data showed that carboplatin-based regimens appear to be equally effective 
in terms of OS, PFS, and ORR compared with cisplatin-based combinations for the first-line 
therapy of SCLC, differing only in their toxicity profiles. Carboplatin-based regimens were 
associated with more cases of Grade 3 to 4 haematologic toxicities. Cisplatin-based therapies 
were associated with more nonhaematologic toxicities of any grade. No evidence of signifi-
cant differences in OS between cisplatin and carboplatin according to sex, stage, performance 
status, or age were apparent. Despite the fact that only a small group of patients had limited 
disease in the trials considered in COCIS, and that probably no definite conclusions can be 
drawn in this subgroup of patients with a rather poor prognostic profile, carboplatin is widely 
accepted as an option in extensive and limited disease SCLC, as evidenced for example in the 
NCCN guidelines (www.nccn.org). 
4.2.1. 
Resection 
Immediate surgery may be considered in the rare biopsy-proven T1N0M0 tumours, but only 
after thorough mediastinal staging confirming node negativity before proceeding with resec-
tion. Most patients with resected SCLC presented with a solitary pulmonary nodule without 
pathological diagnosis and thus had small volume disease. Adjuvant chemotherapy is recom-
mended and is followed by prophylactic cranial irradiation (PCI) in most of the retrospective 
series, with 5-year survival rates up to 57% [14]. The role of post-induction surgery has never 
been fully developed because the overwhelming majority of patients with non-metastatic 
SCLC present with irresectable stage III.  
4.2.2. 
Chest radiotherapy 
A meta-analysis from individual patient data provided evidence that the addition of chest ra-
diotherapy to chemotherapy improved survival [15]. An improvement of 5.4% in the absolute 
survival at three years was observed in favour of groups having received chest irradiation. 
The 5-year survival rate remained disappointingly low at 10-15%. The question which chem-
otherapy should be combined with chest radiotherapy was investigated in randomised trials. 
Etoposide-cisplatinum (EP) was compared to a combination of cyclophosphamide, etoposide 
and vincristine [16]. Among stage I-III patients, a significant superior survival was observed 
with EP. In a small randomised study, the substitution of cisplatin by carboplatin – both in 
combination with etoposide and chest radiotherapy – resulted in the same survival [17]. As in 


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stage IV SCLC, several drugs have been added to EP or new regimens explored, including 
irinotecan, without improving the outcome [18-22].  
Data on the optimal radiation dose and fractionation comes mostly from retrospective and 
phase II prospective studies. In patients receiving either sequential chemo-radiation or alter-
nating schedules, in non-randomised studies, a major improvement in local control may be 
achieved when the dose was increased from 35 to 40 Gy, with possibly a modest further gain 
with an escalation to 50 Gy [23]. However, it is unclear whether also in the setting of concur-
rent chemo- and radiotherapy, radiation dose escalation above 45-50 Gy is beneficial. The 
current standard of a dose of 45 Gy in 30 twice-daily fractions of 1.5 Gy, delivered concur-
rently with chest radiotherapy [24, 25] is at present being compared to higher doses in two 
on-going phase III trials in the US and Europe (CONVERT). 
The definition of the target volumes for radiotherapy is important, for decreasing the volume 
of the organs at risk (OAR) which are irradiated will also reduce the side-effects. In a pro-
spective study in stage I-III SCLC in which only CT-positive mediastinal lymph nodes were 
included in the target volume, a higher than expected isolated recurrence rate of 11% was 
observed [26]. Irradiation of only FDG-PET positive nodes was tested in a phase II study [27]. 
Only 3% isolated nodal failures were observed, with intriguingly only 13% of Grade 3 esoph-
agitis, which compares favourably with the expected 30%. These results were subsequently 
confirmed in a retrospective series from MD Anderson [28]. 
Many phase III trials have investigated the optimal timing of chest radiation (reviewed in 
[29]). At 5 years, the survival was significantly higher when chest radiotherapy was given 
early, i.e. within 30 days after the initiation of platinum-based chemotherapy, representing a 
5-year survival rate of 20% for early versus 14% for late thoracic radiotherapy. In a pivotal 
phase III trial [30], decreasing the overall treatment time of chest radiotherapy from 5 weeks 
(2 Gy once-daily) to 3 weeks (1.5 Gy twice-daily), whilst keeping the total radiation dose to 
45 Gy, increased the 5-year survival from 16 to 26%. In both arms of the trial, chest radio-
therapy was delivered concurrently with cisplatin and etoposide chemotherapy. Early concur-
rent chemotherapy with accelerated radiation resulted in approximately 30% Grade 3 acute 
esophagitis, which contrasts with about 15% in early concurrent non-accelerated radiotherapy 
and approximately 5% in sequential schedules. In this trial, elective mediastinal radiotherapy 
was used. It should be stressed that lung toxicity was not different according to the timing of 
radiotherapy. Because a time-interaction between chest radiation and chemotherapy was sus-
pected, it was hypothesised that accelerated repopulation was triggered by the first dose of 
any effective cytotoxic agent and that in order to obtain local tumour control, the last tumour 
clonogen should be killed by the end of radiotherapy. It follows from these two assumptions 
that the long-term survival should decrease with increasing time between the Start of any 
treatment to the End of Radiotherapy (SER). A meta-analysis of published data, which was 
subsequently updated, showed superior long-term survival if the SER was kept below 30 days 
[31, 32]. These results are consistent with the hypothesis that there is accelerated proliferation 
of tumour clonogens triggered by radiotherapy and/or chemotherapy.  


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In conclusion, for stage I-III SCLC, current evidence supports early administration of 45 Gy 
with concurrent EP at systemic doses. If for reasons of fitness or availability, this scheme 
cannot be offered, chest radiotherapy should follow induction chemotherapy.  
4.2.3. 
Prophylactic Cranial Irradiation (PCI) 
As whole brain radiotherapy (WBRT) for symptomatic brain metastases for patients with 
SCLC yields a response rate of 50% and a median survival of 4-5 months [33], several phase 
III studies have been undertaken to investigate the effect of PCI on brain recurrence and sur-
vival in patients with stage I-III SCLC. In a meta-analysis based on individual patient data, it 
was shown that the addition of PCI resulted in a significant increase in the 3-year survival rate 
(15% without PCI versus 21% with PCI) [34]. PCI also increased the disease-free survival 
and reduced the cumulative incidence of brain metastases. There was a trend toward a greater 
effect in patients with shorter time intervals between induction therapy and PCI, suggestive 
of a benefit of early versus late administration of PCI. In this meta-analysis, only patients with 
a complete remission on a chest X-ray were included. Because at the present time, combined 
chemotherapy and radiotherapy has become standard treatment and therefore radiological as-
sessment of response is notoriously inaccurate for post-radiation changes cannot be distin-
guished from active tumour. In currently ongoing phase III trials, patients without progressive 
disease are therefore being offered PCI. From this meta-analysis, a PCI dose and fractionation 
of 25 Gy delivered in 10 once-daily fractions became standard. In a large phase III trial, pa-
tients with stage I-III SCLC in complete remission on the basis of chest X-rays after induction 
chemotherapy were randomised to either this standard or a higher PCI-dose (36 Gy) [35]. No 
beneficial effect on survival of the higher dose was observed, but neurotoxicity was increased 
[36]. Based on these results, the current recommendation of 25 Gy in ten 2.5 Gy fractions 
remains the standard of care of PCI.  
In summary, PCI should be planned for all SCLC patients not-progressing after induction 
therapy. However, it should be used with caution in patients with significant medical comor-
bidities, poor performance status, or impaired neurocognitive function. 
4.3. 
Targeted agents in small cell lung carcinoma 
Many targeted therapies have been evaluated in the treatment of SCLC, but, in contrast to 
advanced-stage NSCLC, none of these have been successful (reviewed in [37]). Small mole-
cule inhibitors of different receptor tyrosine kinases (EGFR, c-kit, VEGFR) were studied in 
phase II trials with or without chemotherapy but did not show significant activity. Two large 
randomised phase III trials failed to show a significant benefit of adding thalidomide to stand-
ard chemotherapy. Adding two different matrix metalloproteinase inhibitors to standard 
chemotherapy demonstrated no improved survival, and even decreased quality of life. Vac-
cine therapy targeted against the ganglioside family of antigens on the SCLC surface has 
failed to show any benefit. 
4.4. 
Immunotherapy 
Several studies in patients with NSCLC suggested an association of increased immune cell 
infiltration into tumours with improved survival. In recent years, improved identification of 


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antigenic targets, the addition of immunoadjuvants, and the production of more efficient de-
livery systems have resulted in more efficient vaccines, able to elicit a potent immune re-
sponse, leading to the development of immunotherapy for the treatment of NSCLC [38]. Dif-
ferent vaccines are in late-stage development in different NSCLC treatment settings. For 
early-stage NSCLC, the MAGE-A3 vaccine is in phase III testing and results from the com-
pleted trial are awaited. For locally advanced stage, the L-BLP25 vaccine has been tested as 
a consolidation treatment after chemo- radiotherapy in stage III. Butts and colleagues have 
reported at ASCO 2013 the absence of a survival benefit related to vaccination in the whole 
population, but identified a potential survival benefit in the subgroup of patients having ben-
efitted of a concomitant strategy of chemo-radiotherapy (as compared to sequential), deserv-
ing a confirmatory trial. For advanced NSCLC, several compounds are currently investigated 
in randomised controlled trials: belagenpumatucel-L, the EGF vaccine, and the TG4010 vac-
cine [39, 40]. 
4.5. 
Immune checkpoint receptors  
The adaptive immune response requires two signals between the antigen-presenting cells 
(APCs) and the effector T-cells. The first signal is mediated by the T-cell receptor and the 
major histocompatibility complex classes I or II antigenic peptide. The second signal is a co-
stimulatory signal mediated by CD28 on the T-cell surface through binding of the B7 family 
members on APCs. Both signals result in the activation and clonal proliferation of T-cells.  
In order to avoid autoimmunity, T-cell proliferation is tightly regulated. The balance between 
co-stimulatory signals mediated by CD28 and co-inhibitory signals via so called immune 
checkpoint receptors is crucial for the maintenance of self-tolerance and to protect tissues 
from damage during normal immune response. After activation, T-cells express cytotoxic T-
lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1, cluster of dif-
ferentiation 279 [CD279]), both so called immune checkpoint receptors.  
CTLA-4 binds members of the B7 family with a much higher affinity than CD28 and down-
regulates the T-cell response. It has been shown in pre-clinical models that one reason for the 
poor immunogenicity of many tumours such as lung cancer is CTLA-4 activity and that in 
vivo administration of antibodies to CTLA-4 can enhance antitumour immunity [41]. 
CD4+CD25+ regulatory T-cells (Treg) that express FOXP3 represent a group of T lympho-
cytes that is essential for maintaining self-tolerance [42]. The transcription factor FOXP3 re-
presses IL2 transcription and up-regulates expression of CTLA-4. FOXP3+CD25+CD4+ 
Treg cells constitutively express cell surface CTLA-4. CTLA4 thus maintains the immune 
system homeostasis by functioning as a major feedback inhibitor of T-cell activation. 
PD-1 is another immune checkpoint receptor expressed on activated T-cells. Its physiological 
role is to dampen the immune response in order to protect against excessive inflammation and 
development of autoimmunity. PD-1 is expressed in response to inflammation and is found 
in many tumours. Compared with CTLA-4, PD-1 modulates a later stage of the immune re-
sponse. Instead of affecting the initial stage of T-cell activation (priming) in the regional 
lymph node, PD-1 regulates the activation of T-cells in peripheral tissues. Like CTLA-4, PD-
1 can be found on Treg lymphocytes and also on B lymphocytes and natural killer cells. PD-


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1 binds to its ligands PD-L1 (B7-H1) and PD-L2 (B7-DC), which are expressed on antigen 
presenting cells but more importanly, also on cancer cells. 
While CTLA-4- and PD-1 expressing Tregs may play a critical role in maintaining self-toler-
ance, they also play a role in non-responsiveness to tumour antigens.  
It is a recognised feature of cancer cells to escape immune surveillance by expressing ligands 
binding to immune checkpoint receptors and the development of therapies to enhance immu-
nogenic activity towards tumours is a rational treatment strategy. The goal of checkpoint in-
hibitor therapies is not to activate the immune system to attack particular targets on tumour 
cells, but rather to remove inhibitory pathways that block effective antitumour T-cell re-
sponses. 
Tregs have been shown to be present in tumours and coexist with primed effector T-cells. 
Blockade of Tregs function via anti-CTLA-4 and anti-PD-1 has the potential to remove Tregs 
suppression and enhance antitumour immunogenicity [43, 44]. 
 
The abscopal effect, a systemic antitumour response, describes an immune-mediated phenom-
enon where localised irradiation causes tumour response not only in the treated tumour but 
also in tumours outside the radiation therapy field. Local radiotherapy causes the tumour-cell 
to undergo apoptosis or necrosis and to subsequently release tumour antigens. But especially 
in poorly immunogenic cancer this radiation alone is not sufficient to trigger antigenic signals, 
and a second co-stimulatory signal is required to elicit systemic antitumour immune responses 
[45]. The combination of radiotherapy with immune modulators such as checkpoint inhibitors 
may have the capability to escalate antitumour responses to a level that could suppress or 
eliminate systemic metastasis [46-53]. 
4.6. 
Immune checkpoint inhibitors 
4.6.1. 
Ipilimumab 
Ipilimumab is a fully human monoclonal anti-CTLA-4-antibody. It has already been approved 
by the US Food and Drug Administration for the treatment of metastatic melanoma.  Ipili-
mumab showed promising results in a first-line NSCLC phase II study combining car-
boplatin/paclitaxel chemotherapy with ipilimumab [54]. In that randomised, double-blind 
phase II trial, 204 chemotherapy-naive non-small-cell lung carcinoma patients were randomly 
assigned to receive paclitaxel and carboplatin with either placebo (control) or ipilimumab in 
one of the following two regimens: concurrent ipilimumab (four doses of ipilimumab plus 
paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and carboplatin) 
or phased ipilimumab (two doses of placebo plus paclitaxel and carboplatin followed by four 
doses of ipilimumab plus paclitaxel and carboplatin). Phased ipilimumab, concurrent ipili-
mumab, and control treatments were associated with a median immune-related progression-
free survival (irPFS) of 5.7, 5.5, and 4.6 months, respectively, a median PFS of 5.1, 4.1, and 
4.2 months, respectively, and a median OS of 12.2, 9.7, and 8.3 months. Overall rates of 
Grade 3 and 4 immune-related adverse-events (AEs) were 15%, 20%, and 6% for phased 
ipilimumab, concurrent ipilimumab, and the control, respectively. Two patients (concurrent, 


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one patient; control, one patient) died from treatment-related toxicity. The study met its pri-
mary end point of improved irPFS for phased ipilimumab versus the control (hazard ratio 
[HR], 0.72; P = 0.05), but not for concurrent ipilimumab (HR, 0.81; P = 0.13). 
The results are in accordance with preclinical work, showing the best results for immune ther-
apy by adding this in patients where immunogenic cell death have been induced with massive 
release of tumour associated antigens by certain drugs and – very consistently over several 
tumour models – by radiotherapy. 
In patients with stage IV SCLC, 130 patients were enroled in the randomised phase II study 
comparing concurrent or phased ipilimumab plus paclitaxel and carboplatin [55]. Phased ipili-
mumab plus chemotherapy appeared to show improved efficacy as shown by an improvement 
in irPFS (6.4 vs. 5.3 months, p = 0.03), a numerically higher irBORR (best overall response 
rate by irRC) (71% vs. 53%) and a trend for improved overall survival (12.9 vs. 9.9 months, 
p = 0.13). The concurrent-ipilimumab regimen showed no such activity. 
Ipilimumab did not appear to exacerbate toxicities observed with chemotherapy alone and 
observed toxicities (see Table 1) were generally manageable using protocol-defined treatment 
guidelines. 
Table 1: AEs in a randomised placebo-controlled phase II trial in stage IV SCLC com-
paring chemotherapy to concurrent or sequential chemotherapy and ipilimumab 
 
Events 
Control: 
Placebo + chemo 
Concurrent Ipilimu-
mab + chemo 
Phased Ipilimumab  
+ chemo 
 
Any grade 
% 
G 3/4 % 
Any grade 
% 
G 3/4 % 
Any grade 
% 
G 3/4 % 
Fatigue 
25 
5 
31 
7 
29 
12 
Arthralgia 
32 
- 
24 
- 
45 
10 
Alopecia 
59 
n.a. 
57 
n.a. 
67 
n.a. 
Rash 
2 
- 
36 
5 
24 
- 
Pruritus 
5 
- 
24 
- 
19 
2 
Diarrhoea 
16 
5 
26 
4 
33 
10 
Nausea 
23 
2 
24 
- 
29 
- 
Decreased ap-
petite 
9 
- 
19 
2 
10 
- 
Peripheral 
neuropathy 
11 
- 
14 
- 
24 
- 
Peripheral 
neuropathy, 
sensory 
32 
- 
24 
- 
33 
- 
The results of this study were considered worth to support further investigation of the phased-
ipilimumab regimen in previously untreated stage IV SCLC in an ongoing phase III trial. 
 
4.6.2. 
Nivolumab 


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Nivolumab (BMS-936558; anti-PD-1) is a fully human monoclonal immunoglobulin G4 
(IgG4) antibody (HuMAb) that targets the cell surface membrane receptor PD-1. The co-in-
hibitory receptor PD-1, a member of the CD28 superfamily of molecules, has important T-cell 
regulatory functions. It is inducibly expressed on activated T-cells, B-cells, a subset of mye-
loid cells and a fraction of T-memory cells, and it has been shown to mediate inhibition of 
T-cell responses in peripheral tissues and tumours. Engagement of PD-1 by its natural ligands, 
PD-L1 and PD-L2, results in an inhibition of T-cell proliferation, survival and cytokine se-
cretion [56, 57]. Nivolumab abrogates this interaction between PD-1 and its ligands. 
Nivolumab monotherapy has been approved for the treatment of advanced melanoma (FDA, 
EMA, and Japan) and previously treated squamous NSCLC (FDA, positive CHMP opinion). 
Nivolumab and ipilimumab improved PFS compared to nivolumab or ipilimumab alone in a 
study in melanoma (CA209067). 
A phase I trial tested nivolumab in 296 patients with advanced solid cancers, including 129 
NSCLC patients [58, 59]. Nivolumab was administered intravenously once every 2 weeks at 
doses of 1, 3 or 10 mg/kg. Patients continued treatment for up to 96 weeks (12 cycles) or until 
unacceptable toxicity, confirmed complete response, confirmed disease progression, or with-
drawal of consent. In the absence of clinical deterioration, patients could continue treatment 
after initial disease progression to allow for patterns of response consistent with immune-
related response criteria. In the NSCLC cohort, with a long term median follow-up of 
27.5 months (range, 21 to 54 months), median overall survival (OS) across nivolumab doses 
was 9.9 months. One- and 2-year OS rates were 42% and 24%, respectively, across doses and 
56% and 45%, respectively, at the 3 mg/kg dose (n=37) being used for further clinical devel-
opment. Among 22 (17%) patients with objective responses, estimated median response du-
ration was 17.0 months. Response rates were similar in squamous and non-squamous NSCLC 
and in patients who received 3 or more prior therapies. Sixteen responding patients discontin-
ued nivolumab for reasons other than progressive disease and 6 (38%) had responses lasting 
>30 weeks after their last dose. Grade 3-4 treatment-related adverse events occurred in 14% 
of patients. Three treatment-related deaths (2% of patients) occurred, each associated with 
pneumonitis [58]. 
Recently, the first randomized trials using nivolumab in comparison to standard of care docet-
axel in the second line setting have been reported [60, 61]. 
The first one (checkmate 017) was focusing on squamous histology advanced NSCLC pa-
tients. 272 patients were assigned to receive nivolumab at a dose of 3 mg per kilogram of 
body weight every 2 weeks, or docetaxel at a dose of 75 mg per square meter of body-surface 
area every 3 weeks. The median overall survival was 9.2 months (95% confidence interval 
[CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The 
risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 
0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with 
nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with 
nivolumab versus 9% with docetaxel (P=0.008). The median PFS was 3.5 months with 
nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 
0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither 


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prognostic nor predictive of benefit. Treatment-related adverse events of Grade 3 or 4 were 
reported in 7% of the patients in the nivolumab group as compared with 55% of those in the 
docetaxel group [60]. 
The second trial, checkmate 057 used the same design in the non-squamous subgroup. Patients 
in the CheckMate 057 study had progressed after treatment with platinum-based doublet 
chemotherapy (and, if eligible, a tyrosine kinase inhibitor), a guideline-recommended first-
line therapy for nonsquamous NSCLC. They were randomly assigned to subsequent treatment 
with nivolumab (3 mg/kg every 2 weeks; 292 patients) or docetaxel (75 mg/m2 every 3 weeks; 
290 patients); both drugs were continued until progression or discontinuation due to toxicity. 
The primary efficacy endpoint of the study was overall survival (OS). Treatment with 
nivolumab significantly improved median OS, with a hazard ratio for death of 0.73 (95% CI: 
0.59, 0.89; P=0.00155) compared with docetaxel. One-year OS was 50.5% with nivolumab 
versus 39.0% with docetaxel. Other study endpoints included PFS, ORR, and nivolumab ef-
ficacy by PD-L1 expression. 
Significantly more patients had an objective response (19.2% vs. 12.4%; P=0.0235). At the 
time of the analysis, the median duration of response to nivolumab was 17.1 months, com-
pared with 5.6 months for docetaxel. No difference between nivolumab and docetaxel was 
observed in median PFS (2.3 months vs. 4.2 months; P=0.393). PD-L1 expression was asso-
ciated with improved efficacy for patients treated with nivolumab, an effect most dramatically 
seen in patients with PD-L1 expression 5% or higher and 10% or higher, but evident at PD-
L1 expression levels as low as 1% or higher. 
Also of note, subgroup analysis favoured nivolumab over docetaxel in all categories, except 
patients 75 years of age or older, never smokers, and those positive for EGFR mutations. 
Treatment-related adverse reactions of grade 3 to 5 severity occurred at a higher rate with 
docetaxel (53.7%) than with nivolumab (10.5%). 
Regarding toxicity, and as a summary, across all clinical trials perfomred to date using anti-
PD-1 drug monotherapy and in particular nivolumab, the observed incidence of severe pneu-
monitis is less than 5% with nivolumab monotherapy. Of note, after thoracic definitive radi-
otherapy (of 60-70 Gy) with or without chemotherapy, the incidence of severe pneumonitis is 
approximately 15%. It is unknown if nivolumab influences the incidence of pneumonitis after 
radiotherapy [61]. 
4.6.3. 
Dual blockade of CTLA-4 and PD-1 with ipilimumab and nivolumab  
The two monoclonal antibodies nivolumab and ipilimumab bind to different cell receptors in 
immune cells and target different pathways in the activation of anticancer immune response. 
CTLA-4 and PD-1/PD-L1 regulate distinct inhibitory pathways and have non-overlapping 
mechanisms of action. Anti-CTLA-4 therapies seem to drive T-cells into tumours, resulting 
in an increased number of T-cells and a concomitant increase in IFN-. This in turn can induce 
the expression of PD-L1 in the tumour microenvironment, with subsequent inhibition of 
anti-tumour T-cell responses, but may also increase the chance of benefit from anti-PD-1 and 
anti-PD-L1 therapies.  A combination treatment with anti-CTLA-4 (e.g. ipilimumab) plus 


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anti-PD-1 (e.g. nivolumab) or anti-PD-L1 antibodies should enable the creation of an immu-
nogenic tumour microenvironment with subsequent clinical benefit for patients [44, 62, 63]. 
Preclinical data suggest that combining PD-1 and CTLA-4 blockade may indeed improve 
antitumour activity over blocking either receptor alone [62, 64, 65]. 
In tumour models, dual blockade led to tumour rejection in two thirds of mice and was asso-
ciated with increased proliferation of effector CD8+ and CD4+ T-cells, increased cytokine 
release, inhibition of suppressive functions of Tregs, and upregulation of key signaling mol-
ecules critical for T-cell function, compared with single pathway blockade. 
Nivolumab plus ipilimumab in advanced melanoma has shown higher response rates than 
those seen with monotherapy, with early responses and an encouraging survival profile [63, 
65]. 
The safety and efficacy of the combined CTLA-4 and PD-1 blockage with nivolumab and 
ipilimumab has been tested in a phase I dose escalation study in patients with advanced mel-
anoma. In this study a high rate of objective response (including complete responses), a pro-
longed duration of response, and a favourable overall survival rate of 79% at 2 years were 
observed[63, 65, 66].  
In a second, randomised, double-blind trial comparing nivolumab in combination with ipili-
mumab with standard-of-care ipilimumab monotherapy as first-line treatment in patients with 
advanced melanoma, it was shown that the objective-response rate and the progression-free 
survival were significantly higher in the combination than with ipilimumab monotherapy. The 
incidence of Grade 3 or 4 adverse events was higher with combination therapy, but most of 
these toxicities were reversible and were generally manageable when established safety guide-
lines were used [66]. 
Collectively, the results of both studies suggest that nivolumab and ipilimumab can be admin-
istered concurrently with a manageable safety profile. Nevertheless, the risk–benefit profile 
of combined PD-1 and CTLA-4 blockade, as compared with monotherapy, will be further 
clarified by data from ongoing phase III double-blind, randomised trials, such as the Check-
Mate 067 study [66]. 
4.6.4. 
Immune check point inhibitors in SCLC 
In SCLC, a phase I/II trial evaluating nivolumab with or without ipilimumab in pretreated ED 
SCLC patients (CheckMate 032) has been recently presented [67]. 
In this open-label trial, SCLC patients with progressive disease and sensitive or refractory to 
platinum based chemotherapy were enroled, independent of the tumour PD-L1 status. Patients 
were randomised to either nivolumab monotherapy (3 mg/kg i.v. every 2 weeks) or to 
nivolumab plus ipilimumab combination therapy (1 mg/kg ipilimumab plus 1 mg/kg 
nivolumab vs 3 mg/kg ipilimumab plus 1 mg/kg nivolumab vs 1 mg/kg ipilimumab plus 
1 mg/kg nivolumab i.v. every 3 weeks for 4 cycles followed by nivolumab 2 mg/kg i.v. every 
2 weeks for 1 year). Primary objective was overall response. Other objectives were safety, 
PFS, OS and biomarker analysis. 


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At last database lock, the trial reported a response rate of 18% and SD in 20% with nivolumab 
monotherapy while the combination of ipilimumab and nivolumab yielded 33% response and 
22% stabilisation.  
Interestingly, activity was observed in platinum-sensitive and resistant/refractory patients. A 
preliminary analysis showed that clinical responses occurred in patients regardless of PD-L1 
expression. 
The safety profiles of nivolumab monotherapy and nivolumab and ipilimumab combination 
are consistent with other tumour types, mainly fatigue, diarrhoea, rash and nausea and were 
managed with established safety guidelines. One drug-related death in the nivolumab 1 mg/kg 
/ ipilimumab 3 mg/kg cohort occurred. This patient developed myasthenia gravis (reported as 
Grade 4) after treatment start and suffered from complications causing the patient’s death. 
Paraneoplastic syndromes (limbic encephalitis) and autoimmune diseases (myasthenia gravis) 
have been reported in clinical trials with nivolumab. Limbic encephalitis of Grade 2 occurred 
in 2 patients (nivolumab, n = 1; nivolumab 1 mg/kg + ipilimumab 3 mg/kg, n = 1) and re-
solved with immunosuppressive treatment. One patient on nivolumab had Grade 4 limbic en-
cephalitis that did not resolve with immunosuppressive treatment. 
Of note, early results from another early phase I trial using anti-PD-1 drug monotherapy (pem-
brolizumab)[68], confirmed a promising RR of 35% (SD of 5%) in 20 patients selected at 
enrolment for expression of PD-L1. The safety profile was manageable and in line with anti-
PD-1 usual toxicities with no pneumonitis or paraneoplastic syndrome reported. 
4.7. 
Overall risk/benefit assessment 
Ipilimumab is the first drug to demonstrate prolonged survival in patients with pre-treated 
advanced melanoma, based on a large, multinational, double-blind, pivotal, Phase III study 
supported by a comprehensive Phase II program.  
In the recent subsequent large, randomised, double-blind, phase II study involving patients 
with previously untreated advanced melanoma, treatment with nivolumab alone or with the 
combination of nivolumab and ipilimumab resulted in significantly longer PFS and higher 
ORR than did treatment with ipilimumab alone. In the two nivolumab-treated groups, as com-
pared with ipilimumab, these results were observed independently of PD-L1 tumour status, 
BRAF mutation status, or metastasis stage [65]. Early clinical trials data show promising re-
sults of anti-PD-1 nivolumab or pembrolizumab monotherapy and suggest improved activity 
by combining nivolumab and ipilimumab in this disease too. Refinement of treatment doses 
and schedules is currently ongoing and larger randomised extensive stage SCLC confirmatory 
trials recently started or are planned to be started soon.   
The unique immune-based mechanism of action is reflected in the clinical patterns of anti-
cancer activity in some patients. Nivolumab and ipilimumab impact tumour cells indirectly, 
and measurable clinical effects emerge after the immunological effects. Tumour infiltration 
with lymphocytes and the associated inflammation (documented by biopsy in some patients) 
is likely the cornerstone of the effect of ipilimumab and nivolumab and can manifest in vari-
ous patterns of clinical activity leading to tumour control. In some cases, inflammation may 


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not be noted by radiological examination and objective response is observed with the first 
tumour assessment in a manner seen in patients receiving other types of anti-cancer treat-
ments. In other cases, response may be preceded by an apparent increase in initial tumour 
volume and/or the appearance of new lesions due to lymphocyte infiltration and inflammation, 
which may be mistaken for tumour progression on radiological evaluations.  
In metastatic disease, stabilisation is more common than response, and in some instances is 
associated with slow, steady decline in tumour burden over many months, sometimes improv-
ing to partial and/or complete responses. The immune-based mechanism of action of ipili-
mumab may result in durable disease control, sometimes with novel patterns of response, 
which contribute to its improvement in OS. 
The immune-based mechanism of action is also reflected in the safety profile. The most com-
mon drug-related AEs are immune-related, consistent with the mechanism of action of the 
drugs and generally medically manageable with topical and/or systemic immunosuppressants. 
As previously discussed, the immune-related adverse reactions primarily involve the GI tract, 
skin, liver, endocrine glands, and nervous system. 
The early diagnosis of immune- related adverse reactions is important to initiate therapy and 
minimise complications. Immune- related adverse reactions are generally manageable using 
symptomatic or immunosuppressive therapy as recommended through detailed diagnosis and 
management guidelines, as described fully in the current IBs for nivolumab and ipilimumab. 
The management guidelines for general immune- related adverse reactions and ipilimumab- 
as well as nivolumab-related GI toxicities, hepatotoxicity, skin toxicity, endocrinopathy, and 
neuropathy are provided in the appendices of the current IBs and as supplementary material 
to this protocol.  
A safety concern in this trial is the possible enhancement of radiation pneumonitis due to the 
nivolumab and ipilimumab combination. Radiation pneumonitis may occur in 15-20% of pa-
tients being treated with concurrent chemo-radiotherapy for stage I-III SCLC, mostly 2-6 
months after radiation. Thereafter, irreversible lung fibrosis, which is mostly asymptomatic, 
will occur in lung areas that have received high radiation doses.  
Pre-clinical observations show that CD4+CD25+IL-17+ and CD4+CD25+Foxp3+ expressing 
cells are recruited to the lung tissue of irradiated mice [69]. Interestingly, RAG-2−/− mice, who 
fail to generate mature T- and B-lymphocytes due to a total inability to initiate V(D)J rear-
rangement, had an increased sensitivity for radiation-induced lung fibrosis compared to wild-
type mice. 
An important question of this trial will thus be the pulmonary toxicity, both acute (pneumon-
itis) and fibrosis (scored on CT-scans). In order to exclude an exacerbation by nivolumab and 
ipilimumab treatment, a safety evaluation will take place 12 weeks after the first 30 patients 
have been randomised to the experimental arm (total of 60 pts, 30 in the nivolumab plus ipili-
mumab combination and 30 in observation arm). This first safety evaluation will be submitted 
to the IDMC for advice.  
In summary, the combination of nivolumab and ipilimumab offers clinically meaningful and 
statistically significant survival benefit to patients with advanced melanoma and evidence of 


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clinical activity in early or randomised studies in other tumour types, including SCLC. These 
findings, together with evidence of a safety profile that is manageable with careful monitoring 
and appropriate intervention for treatment of immune-mediated toxicities, suggest a favoura-
ble benefit to risk ratio. 
4.8. 
Rationale for trial design 
As previously discussed, even in the best series, the 5-year survival rate of patients with stage 
I-III (“limited stage”) SCLC is only about 25%, with median survival rates of 2 years. Both 
distant metastases and local recurrences remain problematic even after concurrent chemo-
radiotherapy and PCI.  
CTLA-4 inhibition as a single agent immuno-oncology approach for the treatment of SCLC 
patients might not be potent enough to result in clinically meaningful results. Recently, results 
from study CA184-156 (A Randomized, Multicenter, Double-Blind, Phase III Trial Compar-
ing the Efficacy of Ipilimumab plus Etoposide/Platinum versus Etoposide/Platinum in Sub-
jects with Newly Diagnosed Extensive-Stage Disease Small Cell Lung Cancer (ED-SCLC) 
became available. This study did not achieve its primary objective and did not demonstrate a 
statistically significant improvement in overall survival in subjects with newly diagnosed ED 
SCLC receiving ipilimumab plus etoposide/platinum versus etoposide/platinum alone. The 
overall safety profile of ipilimumab plus etoposide/platinum, was consistent with expectations 
based on prior data, in terms of type, frequency and severity of reported events. No new safety 
concerns with ipilimumab in combination with etoposide/platinum treatment were identified. 
Although this study was conducted in SCLC patients with extensive disease stadium and with 
sequentially administered ipilimumab as a component of the platinum based induction treat-
ment, it appears questionable if an ipilimumab maintenance therapy alone in the limited dis-
ease setting will result in a clinically meaningful overall survival prolongation [70] and inter-
nal communication BMS. 
As described above, preliminary phase I/II data from study CA209-032 showed an encourag-
ing overall response rate of 33% for the combination of nivolumab with ipilimumab in heavily 
pretreated SCLC patients with extensive disease status. Objective responses were long lasting. 
Combining nivolumab and ipilimumab therefore represents a very promising treatment option 
worth exploring, to be evaluated prospectively in a consolidation/maintenance setting within 
the curative intent treatment strategy used for LD SCLC. The observation that nivolumab 
combined with ipilimumab shows activity in ED SCLC is consistent with pre-clinical data 
and support the use of these drugs after definitive treatment. Moreover, radiotherapy is not 
only part of standard therapy of stage I-III SCLC, but it consistently induces up-regulation of 
tumour antigens or of tumour-associated antigens irrespective of the histology of the tumour. 
Fractionated irradiation of the tumour in combination with CTLA-4-blockage was shown to 
induce regression of distant metastases.  
The combination of nivolumab and ipilimumab will be delivered as a consolidation treatment 
after a standard schedule consisting of chemo-radiotherapy and PCI. Importantly, in 
CA184042, the first study to evaluate ipilimumab monotherapy among patients with advanced 
stage IV melanoma and active brain metastases [71], the safety profile observed in the subset 


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of 31 patients having received prior radiation therapy for CNS metastases was not different 
from the one regarding the whole 72 patients study population. 
These observations support this open-label randomised phase II trial in patients with stage I-
III SCLC which aims at improving the treatment outcome by delivering the combination of 
nivolumab and ipilimumab after concurrent cis- or carboplatin-etoposide, chest radiotherapy 
and PCI. 
5. 
Objectives and endpoints 
5.1. 
Primary objective 
To evaluate whether patients treated with chemo-radiotherapy and prophylactic cranial irra-
diation followed by nivolumab plus ipilimumab consolidation treatment have a better out-
come in terms of progression-free survival (PFS) and overall survival (OS) compared to pa-
tients treated with chemo-radiotherapy and prophylactic cranial irradiation without consoli-
dation treatment. 
5.2. 
Secondary objectives 
5.2.1. 
To evaluate secondary measures of clinical efficacy including objective response rate 
(ORR), and time to treatment failure. 
5.2.2. 
To assess the safety and the tolerability of the treatment in both arms. 
5.3. 
Co-primary endpoints 
5.3.1. 
Progression-free survival (PFS) according to RECIST 1.1 
5.3.2. 
Overall survival (OS) 
For definition, see section 14.1 
5.4. 
Secondary endpoints 
5.4.1. 
Objective response determined by RECIST 1.1 
5.4.2. 
Time to treatment failure 
5.4.3. 
Adverse events graded according to CTCAE V4.0 
For definitions, see section 14. 
6. 
Trial design, duration and termination  
This is an open-label, randomised, two-arm, phase II international multi-centre clinical trial 
with early interim analysis for safety in patients with radically treated limited-stage SCLC 
following completion of thoracic radiotherapy concomitant to chemotherapy and PCI. 


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Patients randomised to the experimental arm will receive nivolumab 1 mg/kg plus ipilimumab 
3 mg/kg combination as induction, 4 cycles every 3 weeks, followed by maintenance with 
nivolumab 240 mg every 2 weeks for maximum 12 months from start of maintenance (see 
section 0 for rational to support “flat” dose of nivolumab).  
Patient accrual is expected to be completed within 3 years including a run-in-period of 
3 months. Treatment and follow-up is expected to extend the study duration to a total of 7.0 
– 7.5 years. Patients will be followed until death – thus follow-up is estimated to last up to 4.5 
years following the enrolment of the last patient. 
The trial will end with the preparation of the final report, scheduled for 7.5 years after the 
inclusion of the first patient. 
 
It is expected that after the chemo-radiotherapy phase, about 20% of treated patients will pre-
sent with progressive disease or will not have completed chemo-radiotherapy per protocol 
definition (4 cycles of chemotherapy, 85% of PTV of thoracic radiotherapy) and/or completed 
mandatory PCI and will therefore not be randomised. Thus, at least 325 patients will have to 
be enroled in order to randomise 260 patients under the amendment 1. Patients who are not 
randomised will be followed up for survival and documentation of type of further lines of 
therapy until death. Approximately 30 - 60 sites from several European countries will partic-
ipate. 
 
 
Chemo-Radiotherapy:
cis-/carboplatin + etoposide 
4 cycles
Biomaterial for translational research:
Consolidation vs observation:
induction
maintenance
max 1 year
combination
nivolumab
nivolumab/ipilimumab
observation
Screening:
LD SCLC
PCI
Tumour
evaluation:
PD
off
Voluntary re-biopsy: 
→ FFPE block
yes
no
R

3
6
9
3
6
9
18
12
after randomisation
RT (Thoracic Radiotherapy):
CT scans for tumour assessment
accelerated schedule preferred 
- up to 18 months: 
every 9 weeks
start: day 1 of chemo cycle 1 or
- up to 2 years: 
every 12 weeks 
day 1 of chemo cycle 2 
- years 3 & 4: 
every 6 months
- at 5 years
0
Week
Serum
At progression:
Whole blood
Whole blood
Whole blood
RT
RT
from start of chemotherapy
-2
CT
Serum
Serum
Serum
FDG-PET-CT
or CT 
Brain MRI 
or CT
Biopsy: 
FFPE block 
or slides
27 ∙∙∙
CT

14
16


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7. 
Patient selection 
Written Informed Consent (IC) must be signed and dated by the patient and the investigator 
prior to any trial-related intervention (with the exception of one cycle of chemotherapy given 
prior to enrolment) for trial treatment and biomaterial submission for central review and test-
ing.  
Patients should only be selected and consented for screening if they fulfil the criteria in the 
next section: 
7.1. 
Inclusion criteria for enrolment  
7.1.1. 
Histologically or cytologically confirmed small cell lung carcinoma 
7.1.2. 
Untreated limited stage disease (with the exception of one cycle of chemotherapy 
given prior to enrolment) as defined by stage I-IIIB based on 7th TNM classification 
(IASLC classification for SCLC proposal). M0 proven by  
 Whole body FDG-PET CT including a contrast-enhanced CT of thorax and up-
per abdomen (incl. liver, kidney, adrenals);  
OR contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, ad-
renals) and bone scan; 
AND 
 Brain MRI (or contrast enhanced CT of the brain).  
within 28 days before start of chemotherapy. 
7.1.3. 
Age ≥18 years 
7.1.4. 
ECOG performance status 0-1 
7.1.5. 
Adequate haematological function:  
- 
haemoglobin >9 g/dL 
- 
neutrophils count >1.5×109/L  
- 
platelet count >100 × 109/L  
7.1.6. 
Adequate liver function: 
- 
Total bilirubin <2.5 × ULN 
- 
ALT and/or AST <2.5 × ULN 
- 
alkaline phosphatase <5 × ULN. 
7.1.7. 
Adequate renal function: Calculated creatinine clearance ≥30 mL/min (Cockroft-
Gault). 
7.1.8. 
Pulmonary function FEV1 of 1.0L or >40% predicted value and DLCO >40% 
predicted value. 


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7.1.9. 
Patient capable of proper therapeutic compliance, and accessible for correct follow-
up. 
7.1.10. Women of childbearing potential, including women who had their last menstrual 
period in the last 2 years, must have a negative serum or urine pregnancy test within 
7 days before beginning of chemotherapy. The test has to be repeated within 7 days 
before randomisation and then every 6 weeks during consolidation treatment. 
Pregnancy tests should be repeated at approximately 30 days and approximately 70 
days after consolidation treatment stop. 
7.1.11. All sexually active men and women of childbearing potential must use an effective 
contraceptive method (two barrier methods or a barrier method plus a hormonal 
method) during the study treatment and for a period of at least 12 months following 
the last administration of trial drugs. 
7.1.12. Measurable or evaluable disease (according to RECIST 1.1 criteria). Not eligible: 
patients with only one measurable or evaluable tumour lesion which was resected or 
irradiated prior to enrolment. 
7.1.13. Written Informed Consent (IC) must be signed and dated by the patient and the 
investigator prior to any trial-related intervention for  
a) Chemo-radiotherapy treatment, PCI, and subsequent randomisation, including 
mandatory biological samples 
b) Optional biological material collection, long-term storage and future use of 
biological material for translational research 
7.2. 
Exclusion criteria for enrolment 
7.2.1. 
Patient with mixed small-cell and non-small-cell histologic features 
7.2.2. 
Patient with pleural or pericardial effusions proven to be malignant 
7.2.3. 
Patients who have had in the past 5 years any previous or concomitant malignancy 
EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ 
carcinoma of the cervix or bladder, in situ ductal carcinoma of the breast (if no RT 
was involved). 
7.2.4. 
Patients with other serious diseases or clinical conditions, including but not limited 
to uncontrolled active infection and any other serious underlying medical processes 
that could affect the patient’s capacity to participate in the study. 
7.2.5. 
Ongoing clinically serious infections requiring systemic antibiotic or antiviral, 
antimicrobial, or antifungal therapy. 
7.2.6. 
Known or suspected hypersensitivity to nivolumab or ipilimumab or any of their 
excipients. 
7.2.7. 
Substance abuse, medical, psychological or social conditions that may interfere with 
the patient’s participation in the study or evaluation of the study results. 
7.2.8. 
Documented history of severe autoimmune or immune mediated symptomatic 


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disease that required prolonged (more than 2 months) systemic immunosuppressive  
treatment (e.g. steroids), such as but not limited to ulcerative colitis and Crohn´s 
disease, rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic 
lupus erythematosus, or autoimmune vasculitis (e.g. Wegener’s granulomatosis). 
7.2.9. 
Subjects with an autoimmune paraneoplastic syndrome requiring concurrent 
immunosuppressive treatment. 
7.2.10. Interstitial lung disease or pulmonary fibrosis.  
7.2.11. Women who are pregnant or in the period of lactation.  
7.2.12. Sexually active men and women of childbearing potential who are not willing to use 
an effective contraceptive method during the study. 
7.2.13. Patients with any concurrent anticancer systemic therapy (except for chemotherapy 
cycle 1).  
7.2.14. HIV, active Hepatitis B or Hepatitis C infection 
7.2.15. Previous radiotherapy to the thorax (prior to inclusion), including RT for breast 
cancer 
7.2.16. Planned radiotherapy to lung of mean dose >20 Gy or V20 >35% 
7.2.17. Patients who received treatment with an investigational drug agent during the 3 
weeks before enrolment in the study. 
7.2.18.  Prior chemotherapy or radiotherapy for SCLC. Exception: one cycle of 
chemotherapy (as specified to section 10.2) may be administered prior to enrolment. 
7.3. 
Inclusion criteria for randomisation 
7.3.1. 
Chemo-radiotherapy completed per protocol: 4 cycles of chemotherapy, ≥85% of 
PTV of thoracic radiotherapy, as well as completed, mandatory PCI 
7.3.2. 
Non-PD after chemo-radiotherapy and PCI 
7.3.3. 
ECOG performance status 0-2 
7.3.4. 
Recovery of all adverse events to a Grade ≤1, except for fatigue, appetite, 
oesophagitis and renal impairment (where ≤2 is allowed) and alopecia (any grade) 
7.3.5. 
Women of childbearing potential, including women who had their last menstrual 
period in the last 2 years, must have a negative serum or urine pregnancy test within 
7 days before randomisation.  
7.4. 
Exclusion criteria for randomisation 
7.4.1. 
Less than 4 cycles of chemotherapy administered, less than 85% PTV of thoracic 
radiotherapy delivered, or PCI not completed 


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7.4.2. 
Progressive disease after chemo-radiotherapy and PCI 
8. 
Patient screening, enrolment and randomisation 
This trial will use a web-based registration and randomisation system. Each participating cen-
tre will access the system directly to enrol and later to randomise patients. Specific details for 
enrolment of patients are in the STIMULI Procedures Manual which will be available on the 
trial documentation download section of the ETOP website (www.etop-eu.org). 
8.1. 
Screening 
Complete the following steps to screen and enrol a patient on this trial. Please consult the 
STIMULI Procedures Manual for detailed instructions. 
Note that written informed consent has to be obtained from the patient prior to any trial-spe-
cific intervention. 
Verify eligibility and enrol the patient in the RDE facility ETOPdata according to the infor-
mation in the ETOPdata User Manual. The dates the Informed Consent Form and the consent 
to pathology material submission section of the Informed Consent Form were signed by the 
patient as well as the dates the investigator signed those forms are all required to complete the 
eligibility checklist. 
Patients should preferably be enroled before start of chemotherapy, and chemotherapy should 
start within 7 days after enrolment. If the start of chemotherapy cannot be delayed, a maxi-
mum of 1 chemotherapy cycle can be administered before enrolment (according to section 
10.2). Patients must be enroled prior to chemotherapy cycle 2 and prior to start of thoracic 
radiotherapy (section 10.4). 
8.2. 
Randomisation and stratification 
After completion of the 4 cycles of chemotherapy, thoracic radiotherapy and prophylactic 
cranial irradiation (see section 10.5) patients who have not progressed can be randomised to 
one of the 2 treatment arms. Patient eligibility needs to be checked before randomisation (see 
sections 7.3 and 7.4). Randomisation should take place within 5-6 weeks after day 1 of chem-
otherapy cycle 4 (between days 35 and 42 of cycle 4). Please complete and submit the Eligi-
bility Check and Randomisation eCRF (see sections 7.3 and 7.4). Then submit the Randomi-
sation eCRF in ETOPdata in order to randomise the patient. Nivolumab and ipilimumab com-
bination treatment has to start within 6-8 weeks (42-56 days) from start of chemotherapy cycle 
4, and not more than 2 weeks (14 days) after the date of randomisation. 
Block stratified randomisation balanced by institution will be performed, stratified by radio-
therapy schedule (twice-daily vs once-daily) and PET-CT done vs not done [72]. 
9. 
Investigational Medicinal Products 
Nivolumab and ipilimumab are the Investigational Medicinal Products (IMPs) used in this 
trial. BMS will provide both IMPs at no cost for this trial. 


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Complete details of the trial drug logistics, distribution, packaging, labeling, storage and han-
dling as well as accountability are described in the STIMULI drug supply manual, which is 
available on the trial documentation download section of the ETOP website (www.etop-
eu.org).  
9.1. 
Description of the Investigational Medicinal Products 
9.1.1. 
Ipilimumab  
Ipilimumab is a human immunoglobulin G (IgG1)κ anti-CTLA-4 monoclonal antibody 
(mAb). In vitro studies were performed with ipilimumab to demonstrate that it is specific for 
CTLA-4, actively inhibits CTLA-4 interactions with B7.1 and B7.2, does not show any cross-
reactivity with human B7.1, B7.2 negative cell lines, and stains the appropriate cells without 
non-specific cross-reactivity in normal human tissues, as demonstrated by immunohistochem-
istry. Ipilimumab does cross-react with CTLA-4 in non-human primates including cynomol-
gus monkeys. The clinical study product is a sterile solution for intravenous administration. 
9.1.2. 
Nivolumab 
Nivolumab (also referred to as BMS-936558 or MDX-1106) is a fully human monoclonal 
immunoglobulin G4 (IgG4-S228P) antibody (HuMAb) that targets PD-1, a transmembrane 
protein from the CD28 family of receptors. PD-1 is highly expressed on activated T-cells and 
B cells. Two ligands specific for PD-1 have been identified: PD-L1 and PD-L2. Both ligands 
have been shown to down-regulate T-cell activation upon binding to PD-1. Inhibition of the 
interaction between PD-1 and its ligands promotes immune responses and antigen-specific T-
cell responses to both foreign antigens as well as self antigens. The clinical study product is a 
sterile solution for intravenous administration.  
9.2. 
Packaging and labelling 
BMS will provide the IMPs (nivolumab and ipilimumab) at no cost for this study. Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.  
Ipilimumab is available at a concentration of 5 mg/mL(200 mg in 40 mL per vial). 
Nivolumab is available at a concentration of 10 mg/mL (100 mg in 10 mL per vial).  
The pharmaceutical form of both IMPs is a sterile solution for intravenous injection. The 
liquid is clear, colourless to pale yellow and may contain trace amounts of proteinaceous par-
ticles. 
9.3. 
Receipt of the drugs 
Both IMPs will be supplied by BMS directly to the sites. See the STIMULI drug supply 
manual for details. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by the 
study site should be recorded on the Drug Accountability Log. In the event that either of the 


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IMPs is destroyed at site a certification of destruction form should be generated and retained 
in the Investigator Site File. 
9.4. 
Storage and handling 
9.4.1. 
Storage  
Both IMPs must be stored in a secure area according to local regulations. The investigator 
must ensure that IMPs are stored refrigerated at 2-8⁰C, protected from light and freezing, see 
the STIMULI drug supply manual for details. 
9.4.2. 
Handling  
Both, nivolumab and ipilimumab are to be administered on the same day. Separate infusion 
bags and filters must be used for each infusion. Nivolumab infusion has to be administered 
over 30 min and ipilimumab infusion has to be administered over 90 min. Nivolumab is to be 
administered first. The nivolumab infusion must be promptly followed by a saline flush to 
clear the line of nivolumab before starting the ipilimumab infusion.  
The second infusion will always be ipilimumab, and will start no sooner than 30 minutes after 
completion of the nivolumab infusion. See respective IBs for ipilimumab and nivolumab and 
the STIMULI drug supply manual for details. 
9.5. 
Unused trial drug supplies 
If either of the IMPs is to be destroyed on site, it is the investigator’s responsibility to ensure 
that arrangements have been made for disposal and that procedures for proper disposal have 
been established according to applicable regulations, guidelines, and institutional procedures. 
Appropriate records of the disposal must be maintained. Provide a certificate of destruction 
to ETOP upon disposal. See the STIMULI drug supply manual for details. 
10. 
Trial treatments 
10.1. 
Overview of treatment sequence 
10.1.1. After enrolment, the patient will receive or, if included after the first chemotherapy 
cycle, continue receiving standard of care treatment for limited disease SCLC 
consisting of chemo-radiotherapy and PCI  
 Chemotherapy: will be started in the week following enrolment (alternatively, 
maximum 1 cycle of chemotherapy may be administered before enrolment), and 
consists of a total of 4 cycles of cisplatin (25 mg/m2 i.v. on days 1 – 3 or 75 mg/ 
m2 on day 1) or carboplatin (AUC 5-6, calculated according Calvert formula, i.v. 
on day 1), plus etoposide (100 mg/ m2 i.v. days 1 – 3), repeated every 3 weeks 
(+/- 3 days without cycle delay). 
 Concomitant Thoracic Radiotherapy: Accelerated twice-daily administration 
of 45 Gy in 30 twice-daily fractions of 1.5 Gy (6-8 hours apart), 5 days per week 
for 3 weeks, or an allowed, but not-recommended schedule of 56 Gy, given in 


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28 once-daily fractions of 2 Gy, 5 days per week for 6 weeks. Two options are 
allowed: Thoracic radiotherapy MUST start either from day 1 of cycle 1 or day 
1 of cycle 2. 
Radiotherapy start at day 1 of cycle 3 is allowed if patient is enroled after the 
first cycle only but should be exceptional. Optimally, radiotherapy should start 
at the latest on day 1 of cycle 2. 
 Prophylactic Cranial Irradiation (PCI): 25 Gy in 10 fractions starting between 
day 8 and day 15 of chemotherapy cycle 4 and finished not later than day 29 
from start of cycle 4. 
10.1.2. After randomisation, which should take place within 5-6 weeks after day 1 of cycle 
4 (between days 35 and 42 of cycle 4) 
Experimental arm: 
 Induction phase (to start within 6-8 weeks (42-56 days) from start of chemo-
therapy cycle 4, and not more than 2 weeks (14 days) after the date of randomi-
sation: 
- Nivolumab at a dose of 1 mg/kg i.v. over a period of 30 minutes 
 followed (on the same day) by  
- Ipilimumab at a dose of 3 mg/kg i.v. over a period of 90 minutes 
 once every 3 weeks (+/- 3 days, without dose delays), 4 cycles 
 Maintenance phase:  
Nivolumab 240 mg i.v. over a period of 30 minutes, once every 2 weeks (+/- 
2 days, without dose delays), for a maximum of 12 months from start of mainte-
nance. The first dose of maintenance nivolumab will be administered 3 weeks 
(21 days) after the last IMP doses of induction phase. 
Observation arm: no further treatment 
10.2. 
Chemotherapy dosage, administration and schedule  
Patients should preferably be enroled before start of chemotherapy, and chemotherapy should 
start within 7 days after enrolment. If the start of chemotherapy cannot be delayed, a maxi-
mum of 1 chemotherapy cycle can be administered before enrolment. Patients must be enroled 
prior to start of thoracic radiotherapy. Maximum 1 chemotherapy cycle may be given prior to 
radiotherapy start (exception for patients enroled after chemotherapy start is described in sec-
tion 8.1). 
Chemotherapy consists of the standard combination of platinum compound (cis- or car-
boplatin) and etoposide and is given for 4 cycles. The cisplatin and etoposide doses should be 
based on the patient’s calculated pre-treatment body surface area (BSA) using actual body 
weight. Carboplatin doses must be calculated according to the Calvert formula: 
Dose (in mg) = Target AUC × (GFR+ 25) 
AUC : Area under curve ; GFR: Creatinine Clearance must be calculated according to the 
formula of Cockroft-Gault. 


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There will be no dose capping. A detailed plan for administering a cycle of chemotherapy is 
given below. Centres can opt for one of the 3 chemotherapy regimens. Cycles are given at 3 
week intervals:  
 Option 1: cisplatin 75 mg/ m2 i.v. day 1 and etoposide 100 mg/m2 i.v. days 1-3 (see 
Table 2) 
OR 
 Option 2: cisplatin 25 mg/ m2 i.v. days 1-3 and etoposide 100 mg/m2 i.v. days 1-3 
(see Table 3) 
OR 
 Option 3: carboplatin AUC 5-6 (calculated according Calvert formula)  i.v. day 1 
and etoposide 100 mg/m2 i.v. days 1-3 (see Table 4) 
 
Centres have the choice to give cisplatin (at a dose of 75 mg/m2 on day 1 at a dose of 25 mg/ 
m2 on days 1-3 every 21 days) or carboplatin (at a dose of AUC 5-6, calculated according 
Calvert formula, on day 1 every 21 days).  
Etoposide will be administered as 100 mg/m2 on days 1-3, daily administered as an intrave-
nous infusion over 1 hour every 3 weeks.  
Cisplatin will be administered as 75 mg/m2 on day 1 or as 25 mg/m2 on days 1-3, as an intra-
venous infusion over 1-2 hours every 3 weeks. 
Carboplatin will be administered at a dose of AUC 5-6 on day 1, as an intravenous infusion 
over 2 hours every 3 weeks.  
Cis- or carboplatin and etoposide will be administered as per local guidelines and schedule, 
including local anti-emetics, prophylactic antibiotics and G-CSF co-medications as well as 
hydration standards. Patients should be encouraged to take a high oral fluid intake on the day 
prior to cis- or carboplatin chemotherapy. Below are suggested schemes of administration of 
chemotherapy cycles. 
 
Table 2: Chemotherapy administration using option 1 schedule (cisplatin day 1 only) 
Day 1 
 
 
Administer anti-emetics according to local guidelines 
Time 
Drug 
Fluid 
0.00 
Pre – cisplatin 
hydration 
1 L i.v. 0.9% NaCl over 2 hours with 20 mmol KCl 
When urine output ≥100mL per hour  
2.00 
Cisplatin 
75 mg/m2 
1  L 0.9% NaCl with 1 g MgCl 20 mmol over 1-
2 hours 
3.00 - 4.00 
Etoposide 
100 mg/m2 
1 L i.v. 0.9% NaCl over 1 hour 
4.30 - 5.30 
Post – cisplatin 
hydration 
1 L i.v. 0.9% NaCl with 20 mmol KCl  and 10 mmol 
MgSO4 sulphate over 2 hours 


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Maintain oral intake of 1-2 litres of fluid for 6 hours after iv fluids discontinued 
Days 2 and 3 
 
 
Administer anti-emetics according to local guidelines 
0.00 
Etoposide 
100 mg/m2 
1 L i.v. 0.9% NaCl over 1 hour 
Table 3: Chemotherapy administration using option 2 schedule (cisplatin days 1-3) 
Days 1-3 
 
 
Administer anti-emetics according to local guidelines 
Time 
Drug 
Fluid 
0.00 
Cisplatin 
25 mg/m2 dL-3 
500mL i.v. 0.9% NaCl over 1 hour 
1.00 
Etoposide 
100 mg/m2 dL-3 
500mL i.v. 0.9% NaCl over 1 hour 
Patients to have an oral intake of 2 litres of fluid days 1 to 3 
 
Table 4: Chemotherapy administration using option 3 schedule (carboplatin day 1 
only) 
Day 1 
 
 
Administer anti-emetics and hydration according to local guidelines 
Time 
Drug 
Fluid 
0.00 
Carboplatin 
AUC 5-6  
1 L i.v. 0.9% NaCl 1 g MgCl 20 mmol over 1-2 hours, 
according to local standards 
1.00 - 2.00 
Etoposide 
100 mg/m2 
1 L i.v. 0.9% NaCl over 1 hour 
Days 2 and 3 
 
 
Administer anti-emetics according to local guidelines 
0.00 
Etoposide 
100 mg/m2 
1 L i.v. 0.9% NaCl over 1 hour 
Prophylactic antibiotics with fluoroquinolones (choice left to local investigator) are recom-
mended to start on day 8 of cycle 1 chemotherapy and to continue for 7 days to minimise the 
risk of neutropenic sepsis and respiratory infection. Consideration should be given to contin-
uing prophylactic antibiotics after subsequent cycles if bronchial obstruction is present.  
Anti-emetics will be routinely used using a combination of a steroid, aprepitant, and a 5-HT3 
antagonist.  
 The use of G-CSF is optional: 
- 
G-CSF will be prescribed, if clinically indicated, as per ASCO 2006 guide-
lines or in line with local policy / guidelines for treatment of febrile or pro-
longed neutropenia. 
- 
Secondary prophylaxis with G-CSF is recommended.  
- 
GM-CSF is not allowed.  
 The use of erythropoietin for the treatment of anaemia is prohibited. If Hb<10, 
blood transfusions will be required. 


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10.3. 
Chemotherapy delay and dose modification for toxicity 
In case of toxicity, symptomatic treatment and dose interruptions should be used according to 
the following sections. Repeated dose delays are allowed as required, but the sum of all delays 
should not exceed 6 weeks.  
The policy should be to delay and give at full dose, rather than reduced dose. The dose mod-
ification schedule should be followed, but clinical judgment and local standards should be 
used in individual cases. Common side effects are listed in sections 11.2 − 11.7.  
10.3.1. Haematological toxicity  
Table 5: Dose modifications of cisplatin/etoposide for haematological toxicity 
Dose modifications are based on pre-chemotherapy blood count. 
ANC x 109/ L 
 
Platelets x 109/L 
Cisplatin /Etoposide 
>1.5 at day 1 
of cycle 
and  
>100  
Full dose  
≤1.5 at day 1 
of cycle 
or  
≤100  
Delay until recovery ANC >1.5 and 
Platelets >100 
Febrile neutro-
penia episode 
or treatment 
delay for 
Grade 4 neu-
tropenia >7 
days 
 
 
First event: full dose and G-CSF sup-
port is recommended. 
Second event or if G-CSF support 
was already delivered: 20% dose re-
duction and continuing G-CSF sup-
port.  
Third event despite 20% dose reduc-
tion and G-CSFsupport: 35% dose 
reduction  
Subsequent event: off trial  
 
 
Grade 4 thrombocyto-
penia requiring medical  
intervention or 
≥ Grade 2 bleeding 
with thrombocytopenia 
First event: 20% dose reduction  
Second event: 35% dose reduction  
Subsequent event: off trial 
 
Table 6: Dose modifications of carboplatin/etoposide for haematological toxicity 
Dose modifications are based on pre-chemotherapy blood count. 
ANC x 109/ L 
 
Platelets x 109/L 
Carboplatin /Etoposide 
 1.5 at day 1 of cycle 
and  
100  
Full dose  
<1.5 at day 1 of cycle 
or  
<100  
Delay until recovery ANC  
1.5 and Platelets >100 


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ANC x 109/ L 
 
Platelets x 109/L 
Carboplatin /Etoposide 
Febrile neutropenia 
episode or treatment 
delay for Grade 4 neu-
tropenia >7 days 
 
 
First event: full dose and G-
CSF support is recommended. 
Second event or if G-CSF 
support was already delivered: 
20% dose reduction and con-
tinuing G-CSF support.  
Third event despite 20% dose 
reduction and G-CSFsupport: 
35% dose reduction  
Subsequent event: off trial  
 
 
Grade 4 thrombocyto-
penia requiring medical  
intervention or 
≥ Grade 2 bleeding 
with thrombocytopenia 
First event: 20% dose reduc-
tion  
Second event: 35% dose re-
duction  
Subsequent event: off trial 
If chemotherapy cannot be administered after a 3-week delay because of haematological tox-
icity, chemotherapy should be discontinued. If Hb<10, blood transfusions will be required. 
10.3.2. Hepatic toxicity 
Table 7: Dose modifications of cisplatin/etoposide for hepatic toxicity 
Dose modifications are based on pre-chemotherapy laboratory values 
AST 
 
Bilirubin 
Cisplatin 
Etoposide 
2-5 x ULN at day 1 
of cycle 
And 
≤ 1.5 x ULN 
Full dose 
Full dose 
>5 x ULN at day 1 
of cycle 
Or 
>1.5 x ULN 
Delay 1 week then reassess using the 
same criteria;  
A delay up to 3 weeks is allowed 
 
Table 8: Dose modifications of carboplatin/etoposide for hepatic toxicity 
Dose modifications are based on pre-chemotherapy laboratory values 
AST 
 
Bilirubin 
Carboplatin 
Etoposide 
2-5 x ULN at day 1 
of cycle 
And 
≤ 1.5 x ULN 
Full dose 
Full dose 
>5 x ULN at day 1 
of cycle 
Or 
>1.5 x ULN 
Delay 1 week then reassess using the 
same criteria;  
A delay up to 3 weeks is allowed 
 
10.3.3. Renal toxicity 
Request calculated creatinine clearance (according to Cockroft-Gault) before each course of 
chemotherapy. 


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Table 9: Dose modifications of cisplatin/etoposide for renal toxicity 
Dose modifications are based on pre-chemotherapy laboratory values 
 Calculated creatinine clear-
ance at day 1 of cycle 
Cisplatin 
Etoposide 
>50 mL/min 
Full dose 
Full dose 
30-50 mL/min 
Switch to carboplatin  
20% dose reduction 
<30 mL/min 
Off trial treatment 
Off trial treatment 
 
Table 10: Dose modifications of carboplatin/etoposide for renal toxicity 
Dose modifications are based on pre-chemotherapy laboratory values 
 Calculated creatinine clear-
ance at day 1 of cycle 
Carboplatin 
Etoposide 
>50 mL/min 
Full dose 
Full dose 
30-50 mL/min 
Full dose 
20% dose reduction 
<30 mL/min 
Off trial treatment 
Off trial treatment 
 
10.4. 
Thoracic radiation 
Thoracic radiation will be administered concurrently to chemotherapy and should preferen-
tially start  at the same time as the first chemotherapy cycle  (e.g. day 1 of cycle 1), see also 
ref. [73], if the patient can be enroled before the first chemotherapy cycle. Otherwise, radio-
therapy should optimally start at day 1 of cycle 2, i.e. in treatment week 4. As a latest start of 
radiotherapy day 1 of cycle 3 is allowed, but should be exceptional.  
10.4.1. Doses and fractionation 
Two different radiation doses are allowed: the recommended schedule is 45 Gy in 30 twice-
daily fractions of 1.5 Gy (6-8 hours apart), in 30 treatments on 5 days per week over 3 weeks 
(preferred). The alternative, but not-recommended schedule is 56 Gy, given in 28 once-daily 
fractions of 2 Gy, 5 days per week over 6 weeks. In case the twice-daily fractionation is used, 
the treatment times (a.m./p.m.) must be documented in the daily record. 
Treatment is administered 5 days/week. A minimum of 3 days concurrent chemotherapy with 
chest radiotherapy is required. 
In case of interruptions of radiotherapy, 4 treatment days per week are allowed, as long as the 
foreseen overall treatment time is not exceeded by more than 4 days. 
10.4.2. Treatment techniques  
Normalisation of the treatment plan will cover 95% of the planning target volume (PTV) with 
the prescription dose. The minimum PTV dose must not fall below 90% of the prescription 
dose, the maximal dose must not exceed 115% PTV. All radiation doses will be calculated 
with inhomogeneity corrections that take into account the density differences within the irra-
diated volume (i.e., air in the lung and bone).  The maximum, mean and minimum point doses 
(within the PTV) will be reported. 


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10.4.3. Variations of dose prescription: 
No deviation: 
≥99% of the PTV receives ≥90% of the prescribed dose, and a contiguous 
volume of no more than 2cc inside PTV exceeds 20% of the prescribed 
dose. 
Minor deviation: 
Deviations of this magnitude are not desirable, but are acceptable. Cov-
erage that is equal to 90% of the prescribed dose and falls between 99% 
and 95% of the PTV, or a contiguous volume of no more than 2cc inside 
the PTV exceeds 20-25% of the prescribed dose. 
Major deviation: 
Doses in this region are not acceptable. More than 1 cm3 of tissue outside 
the PTV receives ≥120% of the prescribed dose, or 90% of the prescribed 
dose falls below 90% of the PTV, or a contiguous volume of no more 
than 2cc inside the PTV exceeds 25% of the prescribed dose.  
10.4.4. Heterogeneous dose calculations 
In order to calculate the radiation dose to the PTV and the organs at risk, advanced dose 
calculation algorithms that take into account the secondary electron range, should preferen-
tially be used. Examples include a superposition/ convolution and an AAA algorithm. Simple, 
so-called “type A dose calculation algorithms” such as Clarkson or pencil beam are thus al-
lowed, when no Intensity Modulated RadioTherapy (IMRT) or Volumetric Arc Therapy 
(VMAT) is used.   
10.4.5. Technical factors 
Beam Energy: 6 - 18 MV are to be used. 
3D-conformal techniques, as well as Intensity Modulated RadioTherapy (IMRT) and Arc 
treatments are all accepted, provided the PTV dose criteria and the constraints for the Organs 
at Risk (OAR) are met.  
10.4.6. Localisation, simulation, and immobilisation 
A volumetric treatment planning CT study will be required to define gross tumour volume 
(GTV), clinical target volume (CTV), and planning target volume (PTV). Each patient will 
be positioned in an immobilisation device in the treatment position on a flat table. 
Contiguous CT slices, having at maximum 3 mm thickness starting from the level of the cri-
coid cartilage and extending inferiorly through the entire liver volume will be obtained. The 
GTV, CTV, and PTV and normal organs will be outlined on all appropriate CT slices. 
Intravenous (i.v.) contrast during the planning CT is optional provided a diagnostic chest CT 
was done with contrast to delineate the major blood vessels. If not, i.v. contrast should be 
given during the planning CT. If contrast is used, the densities can be over-ridden or the con-
trast scan must be registered to a non-contrast scan for planning purposes. 
Optimal immobilisation is critical for this protocol. Immobilisation to assure reproducibility 
of the setup is necessary. 


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The use of 4-dimensional radiation treatment planning is highly encouraged. Acceptable 
methods of accounting for tumour motion include: design of the PTV to cover the excursion 
of the lung primary cancer and nodes during breathing such as an ITV approach, a maximum 
intensity projection (MIP) approach, automatic breath-hold (e.g. Elekta ABC device) or a 
gating approach (e.g. Varian RPM system). 
10.4.7. Target Volumes 
The definitions of target volumes will be in accordance with ICRU Reports 50, 62 and 83 
Definition of the GTV [74]. 
The primary tumour and clinically positive lymph nodes seen either on the planning CT 
(>1 cm short axis diameter) or pre-treatment PET scan (SUV >3) will constitute the GTV. 
This volume(s) may be disjointed. In the event of a collapsed lobe or lung segment, the use 
of PET to distinguish tumour from fluid/atelectasis is encouraged. The ITV includes the en-
velope that encompasses the tumour motion for a complete respiratory cycle. 
10.4.7.1. Definition of the CTV 
The CTV is defined to be the GTV plus a 0.5 cm margin as appropriate to account for micro-
scopic tumour extension. CTV expansion can be edited to exclude anatomic structures such 
as vertebrae. Elective treatment of the mediastinum and supraclavicular fossae will not be 
done. 
10.4.7.2. Definition of the PTV 
The CTV-PTV margins should be determined according to international guidelines and may 
thus differ according to the techniques used. 
For institutions not using 4DCT, the use of fluoroscopy to determine the margin for motion 
in the inferior superior direction is encouraged.  
For institutions with gating technology, the use of respiratory gating is encouraged. 
10.4.7.3. Normal anatomy to be identified 
The normal anatomy to be outlined on each CT image will include the lungs (right and left 
done separately), heart, skin, oesophagus and spinal cord. The heart should be contoured from 
its base to apex, beginning at the CT slice where the ascending aorta originates. The oesoph-
agus should be contoured from the bottom of the cricoid to the gastroesophageal junction. The 
skin and spinal cord should be contoured on each CT slice. The spinal cord should be con-
toured based on the bony limits of the spinal canal. 
10.4.8. Treatment Planning 
10.4.8.1. 3D Conformal Therapy 
The PTV is to be treated with any combination of coplanar or Non-coplanar 3D conformal 
fields shaped to deliver the specified dose while restricting the dose to the normal tissues. 
Field arrangements will be determined by 3D planning to produce the optimal conformal plan 
in accordance with volume definitions. The treatment plan used for each patient will be based 


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on an analysis of the volumetric dose including DVH analyses of the PTV and critical normal 
structures. Each field is to be treated daily. 
10.4.8.2. Intensity Modulated Radiation Therapy (IMRT) or Arc treatments 
IMRT or Arc techniques are allowed as long as the participating institution is credentialed by 
an official organisation, such as the EORTC, the RTOG, or in some countries local or national 
accreditation bodies.  
10.4.8.3. Organs at risk (OAR) 
Normal tissue constraints shall be prioritised in the following order for treatment planning: 
1=spinal cord, 2=lungs, 3=oesophagus, 4=brachial plexus, and 5=heart. 
1. Spinal Cord: The spinal cord dose limitation is the highest priority dose constraint and 
thus must be met irrespective of other constraints. Total “direct” plus “scatter” dose 
to the spinal cord must not exceed 50.5 Gy. 
2. Lungs: The dose-volume constraint to the lungs is the second highest priority and must 
be met, except if it conflicts with the cord dose constraints. The volume of both lungs 
that receive more than 20 Gy (the V20) should not exceed 35% of the total. Alterna-
tively, the mean lung dose should optimally be ≤ 20 Gy. (By total lung volume we 
mean the total lung minus the GTV both for V20 and MLD). 
When using Arc techniques, on top of these pulmonary constraints, the V5 of the con-
tralateral lung should be less than 60% and the V5 of both lungs together less than 
75%. 
3. Brachial Plexus: Brachial plexus doses should be kept ≤ 70 Gy. In this trial, because 
of the low PTV doses, this constraint will not be reached.  
4. Oesophagus: The mean dose to the oesophagus is optimally kept below 34 Gy. This 
is not an absolute requirement, but is strongly recommended unless other, more critical 
constraints force the situation.  
5. Heart: The mean dose should not exceed 46 Gy. 
10.4.9. Documentation requirements 
 Portal image of each field of 3D radiotherapy or orthogonal images that localise the 
isocentre placement of IMRT must be obtained on the first day of therapy but should 
not be submitted. 
 Weekly verification or orthogonal images are required to be taken, but not submitted. 
This verification information also can be gathered with cone-beam CT or other CT 
devices that are present in the treatment room. 
 DVHs of GTV, CTVs, and critical normal structures for IMRT. 


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10.5. 
Prophylactic cranial irradiation (PCI)  
Patients without clinical evidence of disease progression and after completion of concurrent 
chemo-radiotherapy per protocol (4 cycles of chemotherapy, 85% of PTV of thoracic radio-
therapy), and with an ECOG performance status of 0-2 should be offered PCI. 
All patients will receive PCI in 10 daily fractions of 2.5 Gy, 5 days per week, to a total dose 
of 25 Gy. Treatment will be delivered with right and left lateral equally weighted fields with 
the dose calculated on the central ray at mid-separation of the beams. 
All efforts should be made to initiate PCI between day 8 and no later than day 15 of cycle 4. 
PCI should be completed no later than day 29 from the start of cycle 4. 
10.5.1. Technical factors 
Beam Energy: 4-6 MV beam energy is to be used for PCI 
10.5.2. Localisation, simulation, and immobilisation 
Simulation must be done prior to the start of PCI. Patients will be supine with radio-opaque 
markers placed at the lateral orbital canthi to assist in blocking the lenses in case no CT-
simulation is used. Aquaplast or similar immobilisation per institution standard must be used. 
10.5.3. Treatment planning/target volumes 
The target volume is the entire intracranial contents. There should be at least a 1 cm margin 
around the bony skull superiorly, inferiorly, anteriorly and posteriorly. The inferior border at 
the cervical vertebral bodies should be at the C1-C2 interspace.  
Individual shaped ports with tailor-made blocks or multileaf collimator must define the irra-
diation target volume. 
IMRT techniques are also allowed. 
10.6. 
Nivolumab and ipilimumab combination treatment 
The IMPs (ipilimumab and nivolumab) will be administered according to the following sched-
ule: 
Induction phase (to start within 6-8 weeks (42-56 days) after the start of chemotherapy cy-
cle 4, and not more than 2 weeks (14 days) after the date of randomisation): 
 Nivolumab at a dose of 1 mg/kg i.v. over a period of 30 minutes 
followed (on the same day) by 
 Ipilimumab at a dose of 3 mg/kg i.v. over a period of 90 minutes 
once every 3 weeks (+/- 3 days, without dosing delay), for 4 cycles 
Nivolumab is to be administered as a 30 minute i.v. infusion and ipilimumab is to be admin-
istered as a 90 minute i.v. infusion. It is not to be administered as an i.v. push or bolus injec-
tion. Nivolumab is to be administered first. The nivolumab infusion must be promptly fol-
lowed by a flush of normal saline to clear the line of nivolumab before starting the ipilimumab 


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infusion. The second infusion will always be ipilimumab, and will start no sooner than 
30 minutes after completion of the nivolumab infusion. At the end of the infusion, flush the 
line with a sufficient quantity of normal saline.  
Maintenance phase (to start 3 weeks (21days) after the last IMP doses of induction phase): 
 Nivolumab at a dose of 240 mg i.v. over a period of 30 minutes, once every 
2 weeks (+/- 2 days, without dosing delay), for a maximum of 12 months  from 
start of maintenance . Patients should not be dosed less than 12 days from the pre-
vious dose of nivolumab. 
10.7. 
Nivolumab and ipilimumab delay and discontinuation for toxicity during 
consolidation phase 
Dose delay criteria apply for all drug-related adverse events attributed to nivolumab, ipili-
mumab, or both. Nivolumab and ipilimumab must both be delayed until treatment can 
resume.  
Note: There will be no nivolumab and ipilimumab dose modifications allowed for the man-
agement of toxicities of individual patients. Doses for both, nivolumab and ipilimumab may 
be delayed or “withheld” for a specific time. 
Please refer to the management algorithms for pulmonary toxicity, GI toxicity, hepato-
toxicity, endocrinopathy, skin toxicity, neurological toxicity, and nephrotoxicity in the 
appendices of the respective IBs for nivolumab and ipilimumab. 
10.7.1. Dose delay criteria due to toxicities likely attributable to either nivolumab or 
ipilimumab 
Nivolumab and ipilimumab administration should be delayed for the following reasons: 
 Any Grade 2 non-skin, drug-related adverse event, with the following exceptions: 
o Grade 2 drug-related fatigue or laboratory abnormalities do not require a 
treatment delay 
 Any Grade 3 skin drug-related adverse event 
 Any Grade 3 drug-related laboratory abnormality, with the following exceptions 
for asymptomatic amylase or lipase, AST, ALT, or total bilirubin: 
o Grade 3 amylase or lipase abnormalities that are not associated with symp-
toms or clinical manifestations, or radiographic signs of pancreatitis do not 
require a dose delay. It is recommended to consult with the ETOP Medical 
Reviewer for Grade 3 amylase or lipase abnormalities. 
o If a patient has a baseline AST, ALT, or total bilirubin that is within normal 
limits, delay dosing for drug-related Grade 2 toxicity 
o If a patient has baseline Grade 1 AST, ALT, or total bilirubin elevation, de-
lay dosing for drug-related Grade 3 toxicity 


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 Any adverse event, laboratory abnormality, or concurrent illness which, in the 
judgment of the investigator, warrants delaying the dose of study medication. 
Because of the potential for nivolumab- or ipilimumab-related AEs requiring early recogni-
tion and prompt intervention, management algorithms have been developed for suspected pul-
monary toxicity, GI toxicity, hepatotoxicity, endocrinopathy, skin toxicity, neurological tox-
icity, and nephrotoxicity. Adverse event treatment management algorithms included in the 
appendices of the IBs for nivolumab or ipilimumab should be considered for individual cases. 
10.7.2. Dose modification 
Nivolumab and/or ipilimumab dose reductions for the management of toxicities of individual 
patients or dose escalations are not permitted. 
10.7.3. Criteria to resume treatment 
Patients may resume treatment with study drugs when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions: 
 Patients may resume treatment in the presence of Grade 2 fatigue. 
 Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose delays 
for reasons other than a 2-Grade shift in AST/ALT or total bilirubin may resume 
treatment in the presence of Grade 2 AST/ALT OR total bilirubin. Patients with 
combined Grade 2 AST/ALT AND total bilirubin values meeting discontinuation 
criteria (section 10.7.4) should have treatment permanently discontinued. 
 Drug-related pulmonary toxicity, diarrhoea, or colitis must have resolved to base-
line before treatment is resumed. 
 Drug-related endocrinopathies adequately controlled with only physiologic hor-
mone replacement or glucose controlling agents may resume treatment. 
If the criteria to resume treatment are met, the patients should restart treatment at the next 
scheduled timepoint per protocol. However, if the treatment is delayed past the scheduled 
timepoint per protocol, the next scheduled timepoint will be delayed, but not skipped, until 
dosing resumes. In particular, this is to ensure that patients in the experimental arm will re-
ceive 4 administrations of combined nivolumab and ipilimumab treatment if toxicity allows. 
If dose delay is necessary for patients in the experimental arm during week 1-12, both 
nivolumab and ipilimumab must be delayed until treatment can resume. However, if a 
nivolumab-related infusion reaction prevents subsequent infusion of ipilimumab on the same 
day, the dose of ipilimumab should be replaced as soon as possible. In such instances, at least 
19 days must elapse between the replacement dose of ipilimumab and the administration of 
the next dose of nivolumab combined with ipilimumab. 
If treatment is delayed >6 weeks, the patients must be permanently discontinued from study 
therapy, except as specified in section 10.7.4.4. 
 


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10.7.4. Discontinuation criteria 
Discontinuation criteria apply for all drug-related adverse events attributed to either 
nivolumab or ipilimumab. 
Treatment should be permanently discontinued for the following: 
10.7.4.1. Any Grade 2 drug-related uveitis, eye pain, or blurred vision that 
- does not respond to topical therapy and does not improve to Grade 1 severity 
within the maximum allowed treatment delay of 6 week  
- requires systemic treatment 
10.7.4.2. Any Grade 3 non-skin, drug-related adverse event lasting >7 days, with 
the following exceptions for drug-related laboratory abnormalities, 
uveitis, pneumonitis, bronchospasm, diarrhoea, colitis, neurologic 
toxicity, hypersensitivity reactions, and infusion reactions: 
- Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhoea, colitis, neu-
rologic toxicity, hypersensitivity reaction, or infusion reaction of any duration 
requires discontinuation 
- Grade 3 drug-related laboratory abnormalities do not require treatment discontin-
uation except: 
o Grade 3 drug-related thrombocytopenia >7 days or associated with bleeding 
requires discontinuation 
o Any drug-related liver function test (LFT) abnormality that meets the fol-
lowing criteria require discontinuation: 
 AST or ALT >8 x ULN 
 Total bilirubin >5 x ULN 
 Concurrent AST or ALT >3 x ULN and total bilirubin >2 x ULN 
10.7.4.3. Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
- Grade 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations, or radiographic signs of pancreatitis. It is recom-
mended to consult with the ETOP Medical Reviewer for Grade 4 amylase or 
lipase abnormalities. 
- Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate man-
agement within 72 hours of their onset. 
- For Grade 4 endocrinopathy adverse events such as adrenal insufficiency, 
ACTH deficiency, hyper- or hypothyroidosis, or glucose intolerance, which re-


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solve or are adequately controlled with physiologic hormone replacement (ster-
oids, thyroid hormones) or glucose controlling agents, respectively, retreatment 
can be considered after discussion with the ETOP Medical Reviewer. 
10.7.4.4. Any dosing interruption lasting >6 weeks with the following exceptions: 
- Dosing interruptions to allow for prolonged steroid tapers to manage drug re-
lated adverse events are allowed. Prior to re-initiating treatment in a patient with 
a dosing interruption lasting >6 weeks, the ETOP Medical Reviewer 
(STIMULI@etop-eu.org) must be consulted. Tumour assessments should con-
tinue as per protocol even if dosing is interrupted. 
- Dosing interruptions >6 weeks that occur for non-drug-related reasons may be 
allowed if approved by ETOP (STIMULI@etop-eu.org). Prior to re-initiating 
treatment in a patient with a dosing interruption lasting >6 weeks, ETOP 
(STIMULI@etop-eu.org) must be consulted. Tumour assessments should con-
tinue as per protocol even if dosing is interrupted. 
10.7.4.5. Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, warrants discontinuation of study medication. 
If a patient in the experimental arm meets criteria for discontinuation of nivolumab, the patient 
should discontinue both nivolumab and ipilimumab and be taken off the treatment phase of 
the trial entirely. However, if the investigator assesses the drug-related AE to be related to 
ipilimumab only and not related to nivolumab, ipilimumab dosing alone may be discontinued 
while nivolumab dosing is delayed until the patient meets criteria to resume nivolumab treat-
ment (specified section 10.7.3). Nivolumab would be continued at 240 mg with 2 week dosing 
interval. The relationship to ipilimumab and nivolumab should be well documented in the 
source documents and the eCRFs. The ETOP Medical Reviewer needs to be contacted prior 
to continuation with nivolumab therapy. 
10.8. 
Immune-related Adverse Events (irAEs): definition, monitoring and 
treatment 
Blocking the function of immune checkpoint receptors may permit the emergence of auto-
reactive T-cells and resultant clinical autoimmunity. Rash/vitiligo, diarrhoea/colitis, uvei-
tis/episcleritis, hepatitis, and hypopituitarism were drug-related, presumptive autoimmune 
events, now termed immune-mediated adverse reactions, noted in previous nivolumab and 
ipilimumab studies. 
For the purposes of this study, an immune-related adverse reaction (irAE) is defined as an 
adverse reaction of unknown etiology associated with drug exposure and consistent with an 
immune phenomenon. Efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an event an immune-related adverse reaction. 
Serologic, immunologic, and histologic (biopsy) data should be used to support the diagnosis 
of an immune-related toxicity. Suspected immune-related adverse reactions must be docu-
mented on an AE and/or SAE form, see section 12. 


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Patients should be informed of and carefully monitored for evidence of clinically significant 
systemic immune-related adverse reactions (e.g., systemic lupus erythematosus-like diseases) 
or organ-specific immune-related adverse reaction (e.g., rash, colitis, uveitis, hepatitis or thy-
roid disease). If an immune-related adverse reaction is noted, appropriate work-up (including 
biopsy if possible) should be performed, and steroid therapy may be considered if clinically 
necessary. 
It is unknown if systemic corticosteroid therapy has an attenuating effect on nivolumab or 
ipilimumab activity. However, clinical anti-tumour responses have been maintained in pa-
tients treated with corticosteroids and discontinued from nivolumab and ipilimumab. If uti-
lised, corticosteroid therapy should be individualised for each patient. Prior experience sug-
gests that colitis manifested as ≥ Grade 3 diarrhoea requires corticosteroid treatment. 
Specific management algorithms for immune-related gastro-intestinal, hepatic, skin, endo-
crine and neurological adverse events are included as appendices in the IB and in separate 
guidelines for management algorithms for gastro-intestinal, hepatic, skin, endocrine and neu-
rological toxicities. 
10.8.1. Treatment of nivolumab- or ipilimumab-related infusion reactions 
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, 
each is unlikely to be immunogenic and induce an infusion or hypersensitivity reaction. How-
ever, if such a reaction were to occur, it might manifest with fever, chills, rigours, headache, 
rash, pruritis, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All 
Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE (Version 4.0) guidelines. 
Treatment recommendations are provided below and may be modified based on local treat-
ment standards and guidelines as appropriate:  
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
Remain at bedside and monitor patient until recovery from symptoms. The following prophy-
lactic premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before 
additional nivolumab or ipilimumab administrations. 
For Grade 2 symptoms (moderate reaction requires therapy or infusion interruption but re-
sponds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti inflamma-
tory drugs, narcotics, corticosteroids, bronchodilators, i.v. fluids]; prophylactic medications 
indicated for ≤24 hours): 
Stop the nivolumab or ipilimumab infusion, begin an i.v. infusion of normal saline, and treat 
the patient with diphenhydramine 50 mg i.v. (or equivalent) and/or paracetamol 325 to 
1000 mg (acetaminophen); remain at bedside and monitor patient until resolution of symp-
toms. Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, restart the infusion at 50% of the original infusion rate when symptoms 


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resolve; if no further complications ensue after 30 minutes, the rate may be increased to 100% 
of the original infusion rate. Monitor patient closely. If symptoms recur then no further 
nivolumab or ipilimumab will be administered at that visit. Administer diphenhydramine 
50 mg i.v., and remain at bedside and monitor the patient until resolution of symptoms. The 
amount of IMP infused must be recorded on the electronic case report form (eCRF). The 
following prophylactic premedications are recommended for future infusions: diphenhydra-
mine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) should be 
administered at least 30 minutes before additional nivolumab or ipilimumab administrations. 
If necessary, corticosteroids (recommended dose: up to 25 mg of i.v. hydrocortisone or equiv-
alent) may be used. 
For Grade 3 or Grade 4 symptoms (severe reaction, Grade 3: prolonged [ie, not rapidly re-
sponsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalisation indicated for other clinical sequelae 
[e.g. renal impairment, pulmonary infiltrates]; Grade 4: (life threatening; pressor or ventila-
tory support indicated): 
Immediately discontinue infusion of nivolumab or ipilimumab. Begin an i.v. infusion of nor-
mal saline, and treat the patient as follows. Recommend bronchodilators, epinephrine 0.2 to 
1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for i.v. administration, and/or diphenhydramine 50 mg i.v. with 
methylprednisolone 100 mg i.v. (or equivalent), as needed. Patient should be monitored until 
the investigator is comfortable that the symptoms will not recur. Nivolumab or ipilimumab 
will be permanently discontinued. Investigators should follow their institutional guidelines 
for the treatment of anaphylaxis. Remain at bedside and monitor patient until recovery from 
symptoms. In the case of late-occurring hypersensitivity symptoms (e.g. appearance of a lo-
calised or generalised pruritis within 1 week after treatment), symptomatic treatment may be 
given (e.g. oral antihistamine, or corticosteroids). 
Specific management algorithms for immune-related gastro-intestinal, renal, pulmonary, he-
patic, skin, endocrine and neurological adverse events are included as appendices in the re-
spective IBs of the IMPs and in separate guidelines for management algorithms which can be 
accessed on the trial documentation download section of the ETOP website (www.etop-
eu.org).  
10.8.2. Treatment of ipilimumab-related isolated drug fever 
In the event of isolated drug fever, the investigator must use clinical judgment to determine if 
the fever is related to ipilimumab or to an infectious etiology. If a patient experiences isolated 
drug fever, for the next dose, pre-treatment with anti-pyretic or non-steroidal anti-inflamma-
tory agent (investigator discretion) should be instituted and a repeated antipyretic dose at 6 
and 12 hours after ipilimumab infusion, should be administered. The infusion rate will remain 
unchanged for future doses. If a patient experiences recurrent isolated drug fever following 
premedication and post dosing with an appropriate antipyretic, the infusion rate for subse-


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quent dosing should be decreased to 50% of the previous rate. If fever recurs following infu-
sion rate reduction, the investigator should assess the patient’s level of discomfort with the 
event and use clinical judgment to determine if the patient should receive further ipilimumab. 
10.8.3. Liver function test (LFT) assessments required before administration of nivolumab 
and ipilimumab 
Liver function tests (AST, ALT, total bilirubin) will be evaluated for every patient within 3 
days prior to administration of nivolumab or ipilimumab. Results must be reviewed by the 
principal investigator (or designee) to meet dosing criteria specifications: ≤2.5 x ULN for 
AST, and/or ALT, ≤2.5 x ULN for alkaline phosphatase, and ≤1.5 x ULN for total bilirubin. 
If, during the course of treatment abnormal LFT values are detected, the patient must be man-
aged using the hepatotoxicity algorithm section of the separate guidelines for toxicity man-
agement algorithms. 
10.9. 
Prohibited and restricted therapies during trial treatment 
10.9.1. Accepted and prohibited treatment during chemo-radiotherapy treatment  
The following treatments are allowed during the treatment phase of the trial: 
 G-CSF is allowed according to local standards  
 Use of corticosteroids is allowed if used as premedication for chemotherapy/radio-
therapy or on study management of an AE. 
 Safe alternative medicine if potential interactions with trial drugs can be excluded.  
The following treatments are NOT allowed: 
 Chronic use of immune suppressive drugs.  
 Systemic treatment with either corticosteroids (>10 mg daily prednisone equiva-
lents) or other immunosuppressive medications within 14 days of IMP administra-
tion.  
 Any non-trial cytotoxic or immunotherapy anti-cancer treatment  
 Treatment with inhibitor or agonist of T-cell costimulation. 
 GM-CSF 
 Erythropoietin (for the treatment of anaemia) 
10.9.2. Prohibited Therapies during treatment with IMP 
Concomitant systemic or local anti-cancer medications or treatments are prohibited in this 
study while receiving nivolumab and/or ipilimumab treatments. Patients may not use any of 
the following therapies during the study: 
 Any non-study anti-cancer agent (investigational or non-investigational) 
 Any other investigational agents 


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 Anti-PD-1 / PD-L1immune check-point blockers (except for nivolumab) 
 Immunosuppressive agents 
 Chronic systemic corticosteroids (more than prednisone 10 mg/day continuous or 
equivalent) 
10.10. Pregnancy prevention 
Female patients who are not of childbearing potential due to being postmenopausal (1 year 
without menstruations without an alternative medical cause or at least 2 years without men-
struation following chemotherapy) or surgically sterilised (oophorectomy, hysterectomy 
and/or tubal ligation) do not need to use contraception to be eligible for the trial. All other 
patients are considered to be of childbearing potential. 
Women of childbearing potential and sexually active men must use highly effective contra-
ception during treatment with nivolumab and ipilimumab and until 12 months thereafter. The 
following contraception methods are considered highly effective: 
- 
Hormonal (estrogen and progesterone) contraception (oral, intravaginal, transdermal) 
associated with inhibition of ovulation 
- 
Progesteron-only hormonal contraception (oral, injectable, implantable) associated 
with inhibition of ovulation 
- 
Intrauterine deviced (IUD) or intrauterine hormone releasing systems (IUS) 
- 
Bilateral tubal occlusion 
- 
Vasectomised partner 
Women who become pregnant while participating in the trial must discontinue trial medica-
tion immediately. The pregnancy must be reported following procedures detailed in section 
12.9. Also any pregnancy that occurs in a female partner of a male study participant must be 
reported. 
10.11. Treatment duration 
Patients remain on treatment until one of the following events, whichever occurs first: 
 Documented progression according to RECIST v1.1 in chemo-radiotherapy phase 
 Documented progression according to RECIST v1.1 in randomised consolidation 
phase 
 Secondary malignancy resulting in need of systemic treatment 
 Unacceptable toxicity 
 Medical condition that prevents further treatment 
 Patient withdraws consent 
 Patient becomes pregnant 


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 One year of maintenance treatment has been completed 
Nivolumab and ipilimumab are expected to trigger immune-mediated responses, which re-
quire activation of the immune system prior to the observation of clinical responses. Such 
immune activation may take weeks to months to be evident. Some patients may have objective 
volume increase of SCLC tumour lesions within 9 weeks following the start of nivolumab 
and ipilimumab dosing. In some patients, tumour volume or other disease parameter increases 
may represent infiltration of lymphocytes into the original tumour or blood. In conventional 
studies, such tumour volume or relevant laboratory parameter increases during the first 9 
weeks of the study would constitute PD and lead to discontinuation of imaging to detect re-
sponse, thus disregarding the potential for subsequent immune-mediated clinical response.  
Therefore, patients with tumour volume increase detected up to week 9 of IMP treatment but 
without appearance of new lesions or rapid clinical deterioration should continue to be treated 
with IMPs and be clinically observed with a stringent imaging schedule 4 weeks later to allow 
detection of a subsequent tumour response. This will improve the overall assessment of the 
clinical activity of IMPs and more likely capture its true potential to induce clinical responses. 
This must follow the definitions below: 
10.11.1. Treatment beyond disease progression 
Accumulating evidence indicates a minority of patients treated with immunotherapy may de-
rive clinical benefit despite initial evidence of PD. 
The assessment of clinical benefit should take into account whether the patient is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. 
Patients should discontinue study therapy upon evidence of further progression, defined as an 
additional 10% or greater increase in tumour burden volume from time of initial progression 
(including all target lesions and new measurable lesions). 
New lesions are considered measurable at the time of initial progression if the longest diam-
eter is at least 10 mm (except for pathological lymph nodes, which must have a short axis of 
at least 15 mm). Any new lesion considered non-measurable at the time of initial progression 
may become measurable and therefore included in the tumour burden measurement if the 
longest diameter increases to at least 10 mm (except for pathological lymph nodes, which 
must have an increase in short axis to at least 15 mm). 
Patients treated with IMPs will be permitted to continue treatment beyond initial RECIST 1.1 
defined PD – at 9 weeks CT scan assessment – if they meet all of the following criteria: 
1. Investigator-assessed clinical benefit, and do not have rapid disease progression 
2. Continue to meet all other study protocol eligibility criteria 
3. Tolerance of study drug 
4. Stable performance status 
5. Only local progressive disease of known LD SCLC (absence of new lesion) 


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After the 9 week scan, a radiographic assessment / scan should be performed at least 4 weeks 
after the original PD scan to determine whether there has been a decrease in the tumour size 
or disease stabilisation, or alternatively continued PD which would terminate the trial treat-
ment. 
If the IMPs have been stopped for any reason, the patient enters the follow-up phase of the 
trial. Patients who discontinue trial treatment should be assessed by the investigator who must 
document the case on the appropriate eCRF.  
11. 
Safety of Investigational Medicinal Products 
Please note that both nivolumab and ipilimumab are considered as Investigational Medicinal 
Product (IMP). Cisplatin, carboplatin and etoposide constitute the required chemotherapy, but 
are not investigational. 
11.1. 
Ipilimumab 
11.1.1. Safety profile of ipilimumab 
The safety profile of ipilimumab at a dose of 10 mg/kg was characterised in a total of 325 pa-
tients who received multiple doses of 10 mg/kg ipilimumab as monotherapy in the 4 com-
pleted melanoma studies (CA184004, -007, -008, and -022). Overall, the incidence of 
Grade 3/4 AEs attributable to study drug was 31%. The target organ system, the incidence 
and the severity of the most commonly observed irAEs are displayed in Table 11. 
Table 11: Summary of irAE safety data for 10 mg/kg ipilimumab in melanoma 
 
 
Total (%) 
Low-grade 
(Grade 1 - 2) (%) 
High-grade 
(Grade 3 - 4) (%) 
Median Time to 
Resolution of 
Grade 2 - 4 irAEs 
(weeks) 
All irAEs 
72.3 
46.2 
25.2 
- 
Skin (eg, rash, pruritus) 
52.0 
49.2 
2.8 
6.14 
GI (eg, colitis, diarrhoea) 
37.2 
24.9 
12.3 
2.29 
Liver (eg, LFT elevations) 
8.0 
0.9 
6.8 
4.0 
Endocrine (eg, hypophysitis, 
hypothyroid) 
6.2 
3.7 
2.5 
20.1 
Overall, the 10 mg/kg had an acceptable safety regimen, while being the most active dose. 
The study drug-related deaths across the program are in section 5 of the IB. 
Across clinical studies that utilised ipilimumab doses ranging from 0.3 to 10 mg/kg, the fol-
lowing adverse reactions were also reported (incidence less than 1% unless otherwise noted): 
urticaria (2%), large intestinal ulcer, oesophagitis, acute respiratory distress syndrome, renal 
failure, and infusion reaction. 


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Based on the experience in the entire clinical program for melanoma, the incidence and se-
verity of enterocolitis and hepatitis appear to be dose dependent. 
11.1.2. Immunogenicity 
In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies 
against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has sub-
stantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. In-
fusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis 
were not reported in these 11 patients nor were neutralising antibodies against ipilimumab 
detected. 
Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis 
was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 
evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibod-
ies against ipilimumab. 
Immunogenicity assay results are highly dependent on several factors including assay sensi-
tivity and specificity, assay methodology, sample handling, timing of sample collection, con-
comitant medications, and underlying disease. For these reasons, comparison of incidence of 
antibodies to ipilimumab with the incidences of antibodies to other products may be mislead-
ing. 
11.1.3. Pregnancy outcomes 
The use of ipilimumab during human pregnancy has not been formally studied in clinical 
trials.  
As of Jan 2013, 20 healthcare professional confirmed reports of exposure to ipilimumab dur-
ing pregnancy. Of these, 17 were clinical trial cases and 2 were spontaneous cases. Thirteen 
of the 20 cases were paternal exposure to blinded therapy (8) or open-label ipilimumab (4) 
from clinical trials or spontaneously reported (1). The outcome of these 13 cases was normal 
infant (7), spontaneous abortion (1), full term baby with “small ureters” that was expected by 
the paediatrician to disappear as baby grows (1), unknown (4). In the remaining 7 maternal 
exposure cases (2 on blinded study), outcome was elective abortion (4), unknown (2), prem-
ature baby (1) at 36 gestational weeks with respiratory distress that resolved by birth week 16 
11.1.4. Immune-related adverse reactions with ipilimumab  
Ipilimumab can result in severe and fatal immune-related reactions due to T-cell activation 
and proliferation. 
11.1.4.1. Immune-related gastrointestinal events 
As of 24-Jan-2013, 78 patients (<1%) reported a bowel wall perforations deemed as related 
to ipilimumab in open-label and completed clinical trials. Of the 78 patients with bowel wall 


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perforations, 61 had surgical intervention (colectomy). Twenty-four of the 78 patients died of 
complications associated with the bowel wall perforations. 
GI perforation in association with narcotic use: 
A review of the ipilimumab safety data showed that intestinal perforation in association with 
narcotic use reported in isolated cases is a potential safety concern. While the diarrhoea and 
colitis management algorithm has been effectively used for minimising the risk of complica-
tions such as immune-related events, the use of narcotics may potentially mask the GI symp-
toms or delay detection of their relevant complications, such as bowel perforation. Therefore, 
it is recommended that: 
 In general, use of narcotics during the treatment with ipilimumab should be ap-
proached with caution. Extra caution should be exercised for those patients on nar-
cotics with respect to any GI signs or symptoms. Even minor diarrhoea may indi-
cate a more severe colitis requiring immediate attention. 
 For patients already experiencing diarrhoea or abdominal pain while on ipilimumab 
therapy, narcotic use should be avoided. In rare cases where the use of narcotics is 
medically required, the patients should be closely monitored for potential intestinal 
perforation. 
11.1.4.2. Immune-related hepatotoxicity 
Hepatic immune-related AEs were mostly clinically silent and manifested as transaminase or 
bilirubin laboratory abnormalities. Fatal hepatic failure has been reported in clinical trials of 
ipilimumab. Serum transaminase and bilirubin levels must be evaluated before each dose of 
ipilimumab as early laboratory changes may be indicative of emerging immune-related hep-
atitis. Elevations in liver function tests (LFTs) may develop in the absence of clinical symp-
toms. Increase in LFT or total bilirubin should be evaluated to exclude other causes of hepatic 
injury, including infections, disease progression, or medications, and monitored until resolu-
tion. Liver biopsies from patients who had immune-related hepatotoxicity showed evidence 
of acute inflammation (neutrophils, lymphocytes, and macrophages). 
11.1.4.3. Immune-related skin toxicity 
Skin immune-related AEs presented mostly as a rash and/or pruritus. Some patients reported 
vitiligo associated with ipilimumab administration. Severe reaction such as Stevens Johnson 
syndrome and toxic epidermal necrolysis are rarely seen. Fatal toxic epidermal necrolysis has 
been reported in clinical trials of ipilimumab.  
11.1.4.4. Immune-related endocrinopathy 
Ipilimumab can cause inflammation of the endocrine system organs, specifically hypophy-
sitis, hypopituitarism, and adrenal insufficiency and patients may present with nonspecific 
symptoms, which may resemble other causes such as brain metastasis or underlying disease. 


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Close monitoring of symptoms and laboratory values before each administration are im-
portant. The most common clinical presentation includes headache and fatigue. Symptoms 
may also include visual field defects, behavioural changes, electrolyte disturbances, and hy-
potension. Adrenal crisis as a cause of the patient’s symptoms should be excluded. Based on 
the available data with known outcome, most of the patients symptomatically improved with 
hormone replacement therapy. It is possible that long-term hormone replacement therapy will 
be required for patients developing hypophysitis/hypopituitarism after treatment with ipili-
mumab. 
11.1.4.5. Immune-related neurological events 
Such events have been reported in up to 0.3% with ipilimumab monotherapy, mostly with low 
grade. Neurological manifestations included muscle weakness and sensory neuropathy. Fatal 
Guillain-Barré syndrome has been reported in clinical trials of ipilimumab. Patients may pre-
sent with unilateral or bilateral muscle weakness, sensory alterations and paresthesias. Unex-
plained motor neuropathy, muscle weakness, or sensory neuropathy lasting more than 4 days 
should be evaluated and non-inflammatory causes such as disease progression, infections, 
metabolic syndromes, and medications should be excluded. 
11.1.4.6. Other immune-related AEs 
Ocular inflammation, manifested as Grade 2 or Grade 3 episcleritis or uveitis, was associated 
with concomitant diarrhoea in a few patients (<1%) and occasionally occurred in the absence 
of clinically apparent GI symptoms. Other presumed immune-related AEs reported include, 
but were not limited to, arthritis/arthralgias, pneumonitis, pancreatitis, autoimmune (aseptic) 
meningitis, autoimmune nephritis, pure red cell aplasia, noninfective myocarditis, polymyo-
sitis, and myasthenia gravis, which were individually reported for <1% of patients.  
Overall, immune-related AEs commonly started within 3 to 10 weeks from first dose, were 
successfully managed in most instances by omitting doses, discontinuing dosing, and/or 
through administering symptomatic or immunosuppressive therapy, including corticosteroids, 
as mentioned above and detailed in section 10.8. Immune-related AEs generally resolved 
within days to weeks in the majority of patients.  
11.1.5. Contraindications  
Hypersensitivity to the active substance or to any of the excipients. 
11.2. 
Nivolumab 
In a Phase I/II study of nivolumab and nivolumab combined with ipilimumab for treatment of 
recurrent SCLC (CA209032), patients who were platinum sensitive or refractory, and had 
progressive disease were enroled regardless of tumour PD-L1 status or number of prior chem-
otherapy regimens. This open-label study randomised patients to nivolumab 3 mg/kg i.v. 
every 2 weeks or nivolumab + ipilimumab (1 + 1 mg/kg, 1 + 3 mg/kg or 3 + 1 mg/kg) i.v. 


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every 3 weeks for 4 cycles followed by nivolumab 3 mg/kg every 2 weeks. The primary ob-
jective was objective response rate. Other objectives were safety, PFS, OS and biomarker 
analysis. The CA209032 data shown here are based on an interim database lock date of 16-
Feb-2015 and focus on the treatments groups nivolumab monotherapy (3 mg/kg: N = 40) and 
nivolumab / ipilimumab combination (nivolumab 1 mg/kg plus ipilimumab 1 mg/kg: N = 3; 
nivolumab 1 mg/kg plus ipilimumab 3 mg/kg: N = 47) which represent the groups with the 
longest follow up. 
11.2.1. Demographics and Baseline Characteristics 
All patients had prior platinum-based first-line treatment and progression after the most recent 
treatment regimen. Baseline characteristics were typical for a SCLC population in respect to 
age, smoking history and gender. 35% of patients (nivolumab monotherapy) and 56% 
(nivolumab/ipilimumab combination) had one prior chemotherapy treatment regimen. 35% 
of patients (nivolumab monotherapy) and 34% (nivolumab/ipilimumab combination) had 
platinum-resistant or refractory disease. 
11.2.2. Exposure and Disposition 
As of the 16-Feb-2015 database lock, 20% of patients (nivolumab monotherapy), 33% 
(nivolumab 1 mg/kg plus ipilimumab 1 mg/kg), and 43% (nivolumab 1 mg/kg plus ipili-
mumab 3 mg/kg) were continuing study treatment. Patients in the different cohorts were in 
part sequentially enroled with patients in the combination cohorts in general at later 
timepoints, resulting in a shorter follow up for patients in the nivolumab 1 mg/kg plus ipili-
mumab 3 mg/kg group. 7.5% of patients (nivolumab monotherapy) and 11% (nivolumab 
1 mg/kg plus ipilimumab 3 mg/kg) permanently discontinued treatment because of treatment 
related AEs. 
11.2.3. Safety 
Nivolumab monotherapy in patients with SCLC was well tolerated. 52.5% of the patients had 
drug-related AEs of any grade, 15.0% with Grade 3-4 events (Table 12). There were no drug 
related adverse AEs leading to death. The most frequent (10%, any grade) drug-related AEs 
were fatigue, diarrhoea, nausea, and decreased appetite (Table 12). A total of 7.5% of patients 
permanently discontinued treatment because of treatment related AEs (N = 3, limbic enceph-
alitis, hyperglycemia, and stomatitis). 
Nivolumab plus ipilimumab combination therapy showed a manageable safety profile. While 
the incidence of drug-related AEs (nivolumab 1 mg kg plus ipilimumab 3 mg/kg: 76.6% any 
grade, 34% Grade 3-4) was higher than in the nivolumab monotherapy group (Table 12), the 
treatment discontinuation rate for treatment related AEs was 11% (nivolumab 1 mg/kg plus 
ipilimumab 3 mg/kg): N = 5, diarrhoea, myasthenia gravis [subsequently developing compli-
cations with fatal outcome], pneumonitis, cardiomyopathy, one patient with hypothyroidism, 
hyperglycemia and increased ALT). The most frequent (10%, any grade) drug-related AEs 


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were diarrhoea, fatigue, rash, pruritus, hypothyroidism, rash maculo-papular, nausea, hyper-
thyroidism, and lipase increased (Table 12).  
One treatment-related death in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort oc-
curred. This patient developed myasthenia gravis (reported as Grade 4) after treatment start 
and suffered from complications causing the patient’s death. 
Limbic encephalitis was reported in 3 patients and resolved with immunosuppressive treat-
ment in 2 cases. Another patient had a minor response to immunosuppressive treatment and 
eventually died due to the underlying tumour disease. 
Table 12: Drug-related AEs ≥5% (any grade) and all Grade 3-5 AEs – SCLC patients 
treated with nivolumab monotherapy or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg 
combination therapy 
 
System organ class (%) 
Nivolumab 
(N = 40) 
Nivolumab 1 mg/kg + ipilimumab 3 mg/kg 
(N = 47) 
Any grade 
Grade 3-4 
Grade 5 
Any grade 
Grade 3-4 
Grade 5 
Total patients with an event 
21 (52.5) 
6 (15.0) 
0 
36 (76.6) 
16 (34.0) 
0 
Gastrointestinal disorder 
10 (25.0) 
1 (2.5) 
0 
19 (40.4) 
6 (12.8) 
0 
Skin and subcutaneous tissue 
disorder 
6 (15.0) 
0 
0 
21 (44.7) 
4 (8.5) 
0 
General disorders and admin-
istration site conditions 
7 (17.5) 
1 (2.5) 
0 
11 (23.4) 
0 
0 
Endocrine disorders 
2 (5.0) 
0 
0 
10 (21.3) 
0 
0 
Metabolism and nutrition disor-
der 
6 (15.0) 
1 (2.5) 
0 
7 (14.9) 
1 (2.1) 
0 
Nervous system disorder 
3 (7.5) 
0 
0 
6 (12.8) 
1 (2.1) 
0 
Respiratory, thoracic and medi-
astinal disorders 
3 (7.5) 
0 
0 
4 (8.5) 
2 (4.3) 
0 
Musculoskeletal and connective 
tissue disorders 
4 (10.0) 
0 
0 
2 (4.3) 
0 
0 
Cardiac disorders 
0 
0 
0 
3 (6.4) 
1 (2.1) 
0 
Infections and infestations 
3 (7.5) 
1 (2.5) 
0 
2 (4.3) 
0 
0 
Hepatobiliary disorders 
0 
0 
0 
1 (2.1) 
1 (2.1) 
0 
Injury, poisoning and procedural 
complications 
2 (5.0) 
0 
0 
1 (2.1) 
0 
0 
 


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11.2.4. Rationale to support nivolumab monotherapy “flat” dose of 240 mg 
Nivolumab monotherapy has been extensively studied in NSCLC patient population and other 
solid tumour indications with body weight normalized dosing (mg/kg). Nivolumab pharma-
cokinetics (PK) and exposures of patients in these studies have been characterized by popu-
lation pharmacokinetic (PPK) analysis of data collected in these studies, together with PK 
data from several Phase I, II and III clinical studies of nivolumab monotherapy in solid tu-
mours. Nivolumab PK was determined to be linear, with dose proportional exposures over a 
dose range of 0.1 to 10 mg/kg. Nivolumab clearance and volume of distribution was found to 
increase with increasing body weight, but the increase was less than proportional, indicating 
that an mg/kg dose represents an over-adjustment for the effect of body weight on nivolumab 
PK. Conversely, given the relationship between nivolumab PK and body weight, a flat dose 
is expected to lead to lower exposures in heavier patients, relative to the exposures in lighter 
patients. Table 13 presents summary statistics of the estimated nivolumab steady state trough, 
peak and time-averaged concentration (Cminss, Cmaxss, and Cavgss, respectively) in NSCLC pa-
tients receiving 3 mg/kg, together with corresponding statistics of exposures predicted for a 
“flat” nivolumab dose of 240 mg. It should be noted that a dose of 240 mg nivolumab is iden-
tical to a dose of 3 mg/kg for patients weighing 80 kg, which is the approximate median body 
weight of NSCLC patients in the 3 Phase II and III clinical studies of nivolumab monotherapy 
in NSCLC patients (CA209017, CA209057, and CA209063). As evident from the data pre-
sented in Table 13, the geometric mean values of Cminss, Cmaxss, and Cavgss with flat dosing are 
slightly (<15%) higher than that produced by a 3 mg/kg dose, and the coefficient of variation 
(cv %) in these measures of exposure are only slightly (<10%) greater than that of 3 mg/kg 
dosing. 
Table 13: Summary statistics of nivolumab steady-state exposure 
 
Nivolumab Dose 
Cminss Geo. Mean 
[g/mL] (cv %) 
Cmaxss Geo. Mean 
[g/mL] (cv %) 
Cavgss Geo Mean 
[g/mL] (cv %) 
3 mg/kg 
54.7 (41.9) 
118.9 (31.8) 
73.3 (35.6) 
240 mg 
61.5 (44.6) 
133.7 (35.0) 
84.2 (38.2) 
Nivolumab has been shown to be safe and well tolerated up to a dose level of 10 mg/kg, and 
the relationship between nivolumab exposure produced by 3 mg/kg and efficacy has been 
found to be relatively flat. Taken together, the PK, safety, and efficacy data indicate that the 
safety and efficacy profile of 240 mg nivolumab will be similar to that of 3 mg/kg nivolumab. 
 


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11.3. 
Safety profile of nivolumab and ipilimumab combination therapy 
The CA209067 study was conducted to evaluate the safety and efficacy of nivolumab alone 
or nivolumab combined with ipilimumab in comparison with ipilimumab alone in patients 
with previously untreated metastatic melanoma [65]. Eligible patients had histologically con-
firmed stage III (unresectable) or stage IV melanoma and had received no prior systemic 
treatment for advanced disease. In this double-blind, phase III study, enroled patients were 
randomly assigned in a 1:1:1 ratio to receive one of the following regimens: 3 mg of 
nivolumab per kilogram of body weight every 2 weeks (plus ipilimumab-matched placebo); 
1 mg of nivolumab per kilogram every 3 weeks plus 3 mg of ipilimumab per kilogram every 
3 weeks for 4 doses, followed by 3 mg of nivolumab per kilogram every 2 weeks for cycle 3 
and beyond; or 3 mg of ipilimumab per kilogram every 3 weeks for 4 doses (plus nivolumab-
matched placebo). Overall, 945 patients were enroled (nivolumab: n = 316; ipilimumab: 
n = 315; nivolumab plus ipilimumab n = 314). 
Treatment-related adverse events of any grade occurred in 82.1% of the patients in the 
nivolumab group, 95.5% of those in the nivolumab-plus-ipilimumab group, and 86.2% of 
those in the ipilimumab group. The most common adverse events in the nivolumab-plus-ipili-
mumab group were diarrhoea (in 44.1% of patients), fatigue (in 35.1%), and pruritus (in 
33.2%). The incidence of treatment-related adverse events of Grade 3 or 4 was also higher in 
the nivolumab plus-ipilimumab group (55.0%) than in the nivolumab group (16.3%) or the 
ipilimumab group (27.3%). 
Treatment-related adverse events of any grade that led to discontinuation of the study drug 
occurred in 7.7% of the patients in the nivolumab group, 36.4% of those in the nivolumab-
plus-ipilimumab group, and 14.8% of those in the ipilimumab group, with the most common 
events being diarrhoea (in 1.9%, 8.3%, and 4.5%, respectively) and colitis (in 0.6%, 8.3%, 
and 7.7%, respectively). One death due to toxic effects of the study drug was reported in the 
nivolumab group (neutropenia) and one in the ipilimumab group (cardiac arrest); none were 
reported in the nivolumab-plus-ipilimumab group. 
Immune modulatory agents, including topical agents, to manage adverse events were used in 
47.0% of the patients in the nivolumab group, 83.4% of those in the nivolumab-plus-ipili-
mumab group, and 55.9% of those in the ipilimumab group, with secondary immunosuppres-
sive agents (e.g., infliximab) used in 0.6%, 6.1%, and 5.1% of the patients, respectively. Res-
olution rates for select adverse events of Grade 3 or 4 were between 85 and 100% in the 
nivolumab-plus-ipilimumab group for most organ categories. As in prior studies, most endo-
crine events did not resolve and patients continued on physiological hormone substitution. 
In general, the safety profile of the combination therapy was consistent with previous experi-
ence with nivolumab or ipilimumab alone. No new safety signals were identified, and there 
were no drug-related deaths in the combination group. Adverse events were manageable with 
established treatment guidelines, and most select adverse events resolved with the use of im-
mune-modulatory agents. 


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11.4. 
Early analysis for treatment related pneumonitis 
Pneumonitis related to radiation has been observed in 15-20% of patients treated with chemo-
radiotherapy. In order to exclude an exacerbation by nivolumab and ipilimumab treatment, a 
safety evaluation will take place 12 weeks after the first 30 patients have been randomised to 
the experimental arm (total of 60 pts, 30 in the nivolumab plus ipilimumab combination and 
30 in observation arm). This first safety evaluation will be submitted to the IDMC for advice 
(see also sections 4.7 and 18.5).  
11.5. 
Cisplatin 
The most frequently reported adverse events (>10%) of cisplatin were haematological (leu-
kopenia, thrombocytopenia and anaemia), gastrointestinal (anorexia, nausea, vomiting and 
diarrhoea), ear disorders (hearing impairment), renal disorders (renal failure, nephrotoxicity, 
hyperuricaemia) and fever.  
Serious toxic effects on the kidneys, bone marrow and ears have been reported in up to about 
one third of patients given a single dose of cisplatin; the effects are generally dose-related and 
cumulative.  
Nephrotoxicity: Renal toxicity has been noted in about one third of patients given a single 
dose of cisplatin when prior hydration has not been employed. It is first noted during the 
second week after a dose and is manifested by elevations in plasma urea and serum creatinine, 
serum uric acid and/or decrease in creatinine clearance.  
Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal 
function must return to acceptable levels before another dose of cisplatin can be given.  
Renal function impairment has been associated with renal tubular damage. The administration 
of cisplatin using a 6-8 hour infusion with intravenous hydration and mannitol has been used 
to reduce nephrotoxicity. However renal toxicity still can occur after utilisation of these pro-
cedures.  
Gastrointestinal toxicity: Nausea and vomiting occur in the majority of patients, usually 
starting within 1 hour of treatment and lasting up to 24 hours. Anorexia, nausea and occasional 
vomiting may persist for up to a week. 
Ocular toxicity: There have been reports of optic neuritis, papilloedema and cerebral blind-
ness following treatment with cisplatin. Improvement and/or total recovery usually occurs 
following immediate discontinuation. Blurred vision and altered colour perception have been 
reported after the use of regimens with higher doses of cisplatin or greater dose frequencies 
than those recommended. 


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Ototoxicity: Ototoxicity has occurred in up to 31% of patients treated with a single dose of 
cisplatin 50 mg/m2. Ototoxicity may be more severe in children and more frequent and severe 
with repeated doses. 
Careful monitoring should be performed prior to initiation of therapy and prior to subsequent 
doses of cisplatin. 
Unilateral or bilateral tinnitus, which is usually reversible, and/or hearing loss in the high 
frequency range may occur. 
The overall incidence of audiogram abnormalities is 24%, but large variations exist. These 
abnormalities usually appear within 4 days after drug administration and consist of at least a 
15 decibel loss in pure tone threshold. The damage seems to be cumulative and is not reversi-
ble. The audiogram abnormalities are most common in the 4000-8000 Hz frequencies.  
Haemotoxicity: Myelosuppression is observed in about 30% of patients treated with cisplatin. 
Leucopenia and thrombocytopenia are more pronounced at higher doses. The nadirs in circu-
lating platelets and leucocytes generally occur between days 18-23 (range 7.3 to 45) with most 
patients recovering by day 39 (range 13 to 62). Leucopenia and thrombocytopenia are more 
pronounced at doses greater than 50 mg/m2. Anaemia (decreases of greater than 2 g% hae-
moglobin) occurs at approximately the same frequency, but generally with a later onset than 
leucopenia and thrombocytopenia. Subsequent courses of cisplatin should not be instituted 
until platelets are present at levels greater than 100,000/mm2 and white cells greater than 
4,000/mm2. A high incidence of severe anaemia requiring transfusion of packed red cells has 
been observed in patients receiving combination chemotherapy including cisplatin.  
Anaphylaxis: Reactions possibly secondary to cisplatin therapy have been occasionally re-
ported in patients who were previously exposed to cisplatin. Patients who are particularly at 
risk are those with a prior history or family history of atopy. Facial oedema, wheezing, tach-
ycardia, hypotension and skin rashes of urticarial non-specific maculopapular type can occur 
within a few minutes of administration. Serious reactions seem to be controlled by i.v. adren-
aline, corticosteroids or antihistamines.  
Serum electrolyte disturbances: Hypomagnesaemia, hypocalcaemia, hyponatraemia, 
hypokalaemia and hypophosphataemia have been reported to occur in patients treated with 
cisplatin and are probably related to renal tubular damage. Hypomagnesaemia and hy-
pocalcaemia may result in tetany. Generally, normal serum electrolyte levels are restored by 
administering supplemental electrolytes and discontinuing cisplatin. Inappropriate antidiu-
retic hormone syndrome has also been reported.  
Neurotoxicity: Usually characterised by peripheral neuropathies and paresthesia in both up-
per and lower extremities. Peripheral neuropathy, while reversible, may take a year or more 
to recover. Loss of taste and seizures have also been reported. Neuropathies resulting from 
cisplatin treatment may occur after prolonged therapy; however, neurological symptoms have 


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been reported to occur after a single dose. The neuropathy may progress after stopping treat-
ment.  
Hyperuricaemia: Hyperuricaemia occurring with cisplatin is more pronounced with doses 
greater than 50 mg/m2. Allopurinol effectively reduces uric acid levels.  
Other toxicities: Vascular toxicities coincident with the use of cisplatin in combination with 
other antineoplastic agents have been reported rarely. These events may include myocardial 
infarction, cerebrovascular accident, thrombotic microangiopathy (haemolytic uraemic syn-
drome) or cerebral arteritis. There are also reports of Raynaud's phenomenon occurring in 
patients treated with the combination of bleomycin, vinblastine with or without cisplatin. It 
has been suggested that hypomagnesaemia developing coincident with the use of cisplatin 
may be an added, although not essential factor, associated with this event. However the cause 
of this Raynaud's phenomenon is currently unknown.  
Other toxicities reported to occur infrequently are cardiac abnormalities including tachycardia 
and arrhythmia.  
Local soft tissue toxicity has been reported rarely following extravasation of cisplatin. Infil-
tration of solutions of cisplatin may result in tissue cellulitis, fibrosis and necrosis. 
11.6. 
Carboplatin 
The following adverse reactions have been reported:  
Frequency definition:  
Very common (≥1/10)  
Common (≥1/100, <1/10)  
Uncommon (≥1/1,000, <1/100)  
Rare (≥1/10,000, <1/1,000)  
Very rare (<1/10,000), not known (cannot be estimated from the available data)  
Cardiac and vascular disorders 
Very rare: Cardiovascular events (cardiac failure, embolism) as well as cerebrovascular 
events (apoplexy) have been reported in single cases (causal relationship with carboplatin not 
established). Single cases of hypertension have been reported.  
Blood and lymphatic system disorders  
Very common: Myelosuppression is the dose-limiting toxicity of carboplatin. Myelosuppres-
sion may be more severe and prolonged in patients with impaired renal function, extensive 
prior treatment, poor performance status and age above 65. Myelosuppression is also wors-
ened by therapy combining carboplatin with other compounds that are myelosuppressive. 


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Myelosuppression is usually reversible and not cumulative when carboplatin is used as a sin-
gle agent and at the recommended dosages and frequencies of administration.  
At maximum tolerated dosages of carboplatin administered as a single agent, thrombocyto-
penia, with nadir platelet counts of less than 50 x 109/L, occurs in about a third of the patients. 
The nadir usually occurs between days 14 and 21, with recovery within 35 days from the start 
of therapy.  
Leucopenia has also occurred in approximately 20% of patients but its recovery from the day 
of nadir (day 14-28) may be slower and usually occurs within 42 days from the start of ther-
apy. Neutropenia with granulocyte counts below 1 x 109/L occurs in approximately 1/5 of 
patients. Haemoglobin values below 9.5 mg/100 mL have been observed in 48% of patients 
with normal base-line values. Anaemia occurs frequently and may be cumulative. 
Common: Haemorrhagic complications, usually minor, have also been reported. 
Uncommon: Infectious complications have occasionally been reported. 
Rare: Cases of febrile neutropenia have been reported. Single cases of life-threatening infec-
tions and bleeding have occurred. 
Respiratory, thoracic and mediastinal disorders  
Very rare: Pulmonary fibrosis manifested by tightness of the chest and dyspnoea. This should 
be considered if a pulmonary hypersensitivity state is excluded (see General disorders below). 
Interstitial pneumonitis under high dose therapy. 
Nervous system disorders 
Common: The incidence of peripheral neuropathies after treatment with carboplatin is 6%. In 
the majority of the patients neurotoxicity is limited to paraesthesia and decreased deep tendon 
reflexes. The frequency and intensity of this side effect increases in elderly patients and those 
previously treated with cisplatin. Paraesthesia present before commencing carboplatin ther-
apy, particularly if related to prior cisplatin treatment, may persist or worsen during treatment 
with carboplatin.  
Uncommon: Central nervous symptoms have been reported, however, they seem to be fre-
quently attributed to concomitant antiemetic therapy.  
On prolonged therapy with carboplatin: convulsions, peripheral neuropathies have been re-
ported. 
Eye disorders 
Rare: Transient visual disturbances, sometimes including transient sight loss, have been re-
ported rarely with platinum therapy. This is usually associated with high dose therapy in re-
nally impaired patients. Optic neuritis has been reported in post marketing surveillance.  
Ear and labyrinth disorders  


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Very common: Subclinical decrease in hearing acuity, consisting of high-frequency (4000-
8000 Hz) hearing loss determined by audiogram, has been reported in 15% of the patients 
treated with carboplatin.  
Common: Clinical ototoxicity (clinical hearing deficits). Only 1% of patients present with 
clinical symptoms, manifested in the majority of cases by tinnitus. In patients who have been 
previously treated with cisplatin and have developed hearing loss related to such treatment, 
the hearing impairment may persist or worsen.  
At higher than recommended doses in combination with other ototoxic agents, clinically sig-
nificant hearing loss has been reported to occur in paediatric patients when carboplatin was 
administered.  
Gastrointestinal disorders 
Very common: Nausea without vomiting occurs in about a quarter of patients receiving car-
boplatin vomiting has been reported in over half of the patients and about 1/3 of these suffer 
severe emesis. Nausea and vomiting are generally delayed until 6 to 12 hours after admin-
istration of carboplatin, usually disappear within 24 hours after treatment and are usually re-
sponsive to (and may be prevented by) anti-emetic medication. A quarter of patients experi-
ence no nausea or vomiting. Vomiting that could not be controlled by drugs was observed in 
only 1% of patients. Vomiting seems to occur more frequently in previously treated patients, 
particularly in patients pre-treated with cisplatin.  
Painful gastrointestinal disorders occurred in 17% of patients.  
Common: Diarrhoea (6%), constipation (4%), mucositis.  
Rare: Taste alteration. Cases of anorexia have been reported. Haemorrhagic colitis under high 
dose therapy. 
Renal and urinary disorders  
Very common: Renal toxicity is usually not dose-limiting in patients receiving carboplatin, 
nor does it require preventive measures such as high volume fluid hydration or forced diuresis. 
Nevertheless, increasing uric acid and blood urea nitrogen levels or serum creatinine levels 
can occur.  
Common: Renal function impairment, as defined by a decrease in the creatinine clearance 
below 60 mL/min, may also be observed. The incidence and severity of nephrotoxicity may 
increase in patients who have impaired kidney function before carboplatin treatment. Impair-
ment of renal function is more likely in patients who have previously experienced nephrotox-
icity as a result of cisplatin therapy. 
It is not clear whether an appropriate hydration programme might overcome such an effect, 
but dosage reduction or discontinuation of therapy is required in the presence of moderate 
alteration of renal function (creatinine clearance 41-59 mL/min) or severe renal impairment 


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(creatinine clearance 21-40 mL/min). Carboplatin is contra-indicated in patients with a creat-
inine clearance at or below 20 mL/min.  
Skin and subcutaneous tissue disorders 
Common: Alopecia, rash, skin irritation. 
Metabolism and nutrition disorders 
Very common: Decreases in serum electrolytes (sodium, magnesium, potassium and calcium) 
have been reported after treatment with carboplatin but have not been reported to be severe 
enough to cause the appearance of clinical signs or symptoms.  
Rare: Cases of hyponatraemia have been reported.  
Neoplasms benign, malignant and unspecified (including cysts and polyps) 
Uncommon: Secondary malignancies (including promyelocytic leukaemia which occurred 
6 years after monotherapy with carboplatin and preceding irradiation) have been reported fol-
lowing administration of carboplatin as a single agent or in combination therapy (causal rela-
tionship not established).  
General disorders and administration site conditions 
Very common: Hyperuricaemia is observed in about 1/4 of patients. Serum levels of uric acid 
can be decreased by allopurinol. Asthenia.  
Common: Malaise, urticaria, flu-like syndrome, erythematous rash, pruritis,  
Uncommon: Fever and chills without evidence of infection; injection site reactions such as 
pain, erythema, swelling, urticaria and necrosis  
Rare: Haemolytic uraemic syndrome.  
Immune system disorders 
Common: Allergic reactions to carboplatin have been reported in less than 2% of patients, 
e.g., skin rash, urticaria, erythematous rash, and fever with no apparent cause or pruritus. 
These reactions are similar to those observed after administration of other platinum containing 
compounds and should be managed with appropriate supportive therapy.  
Rare: Anaphylaxis, anaphylactic shock, angio-oedema and anaphylactoid reactions, including 
bronchospasm, urticaria, facial oedema and facial flushing, dyspnoea, hypotension, dizziness, 
wheezing, and tachycardia have occurred. These were reactions similar to those seen after 
cisplatin therapy, but in a few cases no cross-reactivity was present.  
Hepatobiliary disorders  
Very common: Abnormalities of liver function tests (usually mild to moderate) have been 
reported with carboplatin in about 1/3 of the patients with normal baseline values. The alkaline 


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phosphatase level is increased more frequently than SGOT, SGPT or total bilirubin. The ma-
jority of these abnormalities regress spontaneously during the course of treatment.  
Rare: Severe hepatic dysfunction (including acute liver necrosis) has been reported after ad-
ministration of higher than recommended carboplatin dosages. 
11.7. 
Etoposide 
The following adverse reactions have been reported:  
Table 14: Summary of AE safety data for etoposide 
 
System Or-
gan Class 
Very com-
mon 
(>1/10) 
Common 
(>1/100, 
<1/10) 
Uncommon 
(>1/1,000, 
<1/100) 
Rare 
(>1/10,000, 
<1/1,000) 
Very rare 
(<1/10,000) 
Not known 
Infections 
and infesta-
tions 
 
 
 
 
 
Infections 
have been 
reported in 
patients with 
bone mar-
row depres-
sion 
Neoplasms 
benign and 
malignant 
 
Leukaemia 
secondary to 
oncology 
chemother-
apy* 
 
 
 
Acute pro-
myelocytic 
leukemia 
Blood and 
lymphatic 
systems dis-
orders 
Myelosup-
pression**, 
leucopenia, 
thrombocy-
topenia, 
anaemia 
 
 
 
 
 
Immune sys-
tem disor-
ders 
 
Anaphylac-
tic-like reac-
tions*** 
 
 
 
 
Metabolism 
and nutrition 
disorders 
Anorexia 
 
 
Hyperuricae-
mia 
 
 
Nervous sys-
tem disor-
ders 
Central 
nervous sys-
tem disor-
ders (fa-
tigue, 
drowsiness) 
 
Peripheral 
neuropathies 
Insults, par-
aesthesiae, 
optic neuri-
tis, taste dis-
turbance 
 
 
Eye disor-
ders 
 
 
 
Reversible 
loss of vi-
sion, transi-
ent 
 
 
Cardiac dis-
orders 
 
 
Arrhythmia, 
myocardial 
infarction, 
cyanosis 
 
 
 


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System Or-
gan Class 
Very com-
mon 
(>1/10) 
Common 
(>1/100, 
<1/10) 
Uncommon 
(>1/1,000, 
<1/100) 
Rare 
(>1/10,000, 
<1/1,000) 
Very rare 
(<1/10,000) 
Not known 
Vascular 
disorders 
 
Hypoten-
sion%, haem-
orrhage (in 
patients with 
severe mye-
losuppres-
sion) 
 
Phlebitis 
 
 
Respiratory, 
thoracic and 
mediastinal 
disorder 
 
 
Bron-
chospasm, 
coughing, 
laryn-
gospasm 
Apnoea, in-
terstitial 
pneumonitis 
or pulmo-
nary fibrosis 
 
 
Gastrointes-
tinal disor-
der 
Nausea, 
vomiting 
Abdominal 
pain, diar-
rhoea, sto-
matitis 
Mucositis, 
oesophagitis 
Constipa-
tion, swal-
lowing dis-
orders (dys-
phagia 
 
 
Hepatobili-
ary disorders 
 
Hepatic dys-
function 
 
 
 
 
Skin and 
subcutane-
ous tissue 
disorders 
Reversible 
alopecia 
(sometimes 
progressing 
to total bald-
ness) 
 
Rash, urti-
caria, pig-
mentation 
and pruritus 
 
Toxic epi-
dermal 
necrolysis, 
radiation 
“recall” der-
matitis, 
hand-foot 
syndrome 
 
Renal and 
urinary dis-
orders 
Etoposide 
has been 
shown to 
reach high 
concentra-
tions in the 
liver and 
kidney, thus 
presenting a 
potential for 
accumula-
tion in cases 
of functional 
impairment 
 
 
 
 
 
General dis-
orders and 
administra-
tion site con-
ditions 
 
Fatigue 
 
Asthenia; af-
ter extra-va-
sation, irrita-
tion of soft 
tissue and 
inflam-
mation occur 
occasionally 
 
 
Investiga-
tions 
 
Bilirubin in-
creased, 
SGOT in-
creased, al-
kaline phos-
phatase in-
creased 
 
 
 
 


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* 
The risk of secondary leukaemia among patients with germ-cell tumours after treatment with 
etoposide is about 1%. This leukaemia is characterised with a relatively short latency period 
(mean 35 months), monocytic or myelomonocytic FAB subtype, chromosomal abnormalities at 
11q23 in about 50% and a good response to chemotherapy. A total cumulative dose (etoposide 
>2 g/m²) is associated with increased risk.  
Etoposide is also associated with development of acute promyelocytic leukaemia (APL). High 
doses of etoposide (>4,000 mg/m2) appear to increase the risk of APL.  
** Myelosuppression is dose limiting, with granulocyte nadirs occurring 5 to 15 days after drug 
administration and platelet nadirs occurring 9 to 16 days after drug administration. Bone marrow 
recovery is usually complete by day 21, and no cumulative toxicity has been reported.  
Fatal cases of myelosuppression have been reported.  
Infections have been reported in patients with bone marrow depression.  
*** Anaphylactic-like reactions characterised by fever, flushing, tachycardia, bronchospasm, and hy-
potension have been reported (incidence 0.7-2%), also apnoea followed by spontaneous recur-
rence of breathing after withdrawal of etoposide infusion, increase in blood pressure. The reac-
tions can be managed by cessation of the infusion and administration of pressor agents, cortico-
steroids, antihistamines and/ or volume expanders as appropriate.  
Anaphylactoid-like reactions may occur after the first intravenous administration of etoposide.  
Erythema, facial and tongue oedema, coughing, sweating, cyanosis, convulsions, laryngospasm 
and hypertension have also been observed. The blood pressure usually returns to normal within 
few hours following cessation of therapy.  
% 
Transient hypotension following rapid intravenous administration has been reported in 1% to 2% 
of patients. It has not been associated with cardiac toxicity or electrocardiographic changes. To 
prevent this rare occurrence, it is recommended that etoposide be administered by slow intrave-
nous infusion over a 30- to 60-minute period. If hypotension occurs, it usually responds to sup-
portive therapy after cessation of the administration. When restarting the infusion, a slower ad-
ministration rate should be used.  
+ 
Phlebitis has been observed following bolus injection of etoposide. This adverse reaction can be 
avoided by i.v. infusion over 30 to 60 minutes.  
Etoposide has been shown to reach high concentrations in the liver and kidney, thus presenting a 
potential for accumulation in cases of functional impairment. 
12. 
Adverse events and reporting 
12.1. 
Adverse event reporting 
The main criterion for tolerability is the occurrence of toxicities and adverse events.  The 
severity and causality will be classified according to the NCI CTCAE Version 4. The CTCAE 
is 
available 
for 
downloading 
on 
the 
internet, 
see 
appendix 3 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
An adverse event is defined as any untoward medical occurrence that occurs from the day of 
enrolment in the RDE until 100 days after the final dose of IMP, regardless of whether it is 
considered related to the trial treatment. The relationship of the adverse event with the admin-
istered trial treatment has to be indicated (unrelated – unlikely – possible – probable – defi-
nite). 


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In addition, any known untoward event that occurs subsequent to the adverse event reporting 
period that the investigator assesses as possibly related to the protocol treatment should be 
considered an adverse event. 
Symptoms of the targeted cancer (if applicable) should not be reported as adverse events. 
The adverse event severity grade provides a qualitative assessment of the extent or intensity 
of an adverse event, as determined by the investigator or as reported by the patients.  The 
severity grade does not reflect the clinical seriousness of the event, only the degree or extent 
of the affliction or occurrence (e.g. severe nausea, mild seizure), and does not reflect the re-
lationship to study drug. 
Severity grade for other adverse events not covered in the toxicity grading scale: 
1 = Grade 1 
Mild 
2 = Grade 2 
Moderate 
3 = Grade 3 
Severe 
4 = Grade 4 
Life-threatening 
5 = Grade 5 
Fatal 
Note: 
 Baseline symptoms will be recorded on the eCRF and changes in grade as well as 
resolution of an AE during treatment have to be reported 
 Laboratory abnormalities for non-safety parameters will be documented on the AE 
eCRF from Grade ≥3 only 
 AEs should not be reported in a narrative description. 
12.2. 
Targeted Adverse Events for chemo-radiotherapy 
The following adverse events must be documented if observed during the chemo-radiotherapy 
phase of trial treatment: 
CTCAE Version 4.0 system organ class / preferred terms: 
Blood and lymphatic system disorders 
Anaemia 
Febrile neutropenia 
Ear and labyrinth disorder 
Tinnitus 
Infections and infestations 
Infections and infestations - Other, specify 
Investigations: 
Platelet count decreased 
Neutrophil count decreased 


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Renal and urinary disorders 
Acute kidney injury 
Respiratory, thoracic and mediastinal disorders 
Pneumonitis 
12.3. 
Definition of immune-related Adverse Events (irAE) 
The following adverse events are of special interest and must be documented after randomi-
sation in both treatment arms: 
CTCAE Version 4.0 system organ class / preferred terms: 
Nervous system disorders 
Peripheral motor neuropathy 
Peripheral sensory neuropathy 
Meningismus 
Limbic Encephalitis 
Nervous system disorders - Other, specify (Guillain-Barré, myasthenia gravis, aseptic 
or non-infectious meningitis) 
Skin and subcutaneous tissue disorders: 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
Bullous dermatitis 
Rash acneiform 
Rash maculo-papular 
Pruritus 
Skin and subcutaneous tissue disorders - Other, specify 
Gastrointestinal disorders 
Colitis 
Diarrhoea 
Colonic perforation 
Small intestinal perforation 
Gastric perforation 
Gastrointestinal disorders - Other, specify 
Hepatobiliary disorders 
Hepatic failure 


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Hepatitis viral 
Drug-induced liver injury (DILI) (see section 12.4) 
Investigations: 
Alanine aminotransferase increased 
Aspartate aminotransferase increased 
Blood bilirubin increased 
Endocrine 
Adrenal insufficiency 
Hypothyroidism 
Endocrine disorders - Other, specify (hypopituitarism, hypophysitis) 
Respiratory, thoracic and mediastinal disorders 
Pneumonitis  
Renal and urinary disorders 
Renal and urinary disorders - Other, specify (nephritis) 
Eye disorders 
Uveitis 
Eye disorders - Other, specify (iritis) 
Blood and lymphatic system disorders 
Blood and lymphatic system disorders- Other, specify (haemolytic anaemia) 
Cardiac disorders 
Myocarditis 
12.4. 
Drug-induced liver injury (DILI): 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event. All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs. Potential DILI is defined as: 
1) ALT or AST elevation >3 times upper limit of normal (ULN)  
AND 
2) Total bilirubin >2 times ULN, without initial findings of cholestasis (elevated se-
rum alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AST/ALT elevation and hyper-
bilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 


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A hepatic AE management algorithm has been established (appendix 2 to the nivolumab IB) 
for appropriate management of DILI cases. 
12.5. 
Definition of Serious Adverse Event (SAE) 
12.5.1. SAEs during trial treatment 
An SAE is defined in general as any undesirable medical occurrence/adverse drug experience 
that occurs during or within 100 days after stopping study treatment that, at any dose, results 
in any of the following:  
 is fatal (any cause) 
 life-threatening, 
 requires or prolongs inpatient hospitalisation, 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly or birth defect 
 is a secondary malignancy 
 is a  medically important event 
 overdose (although this event is not always serious by regulatory definition, over-
dose must be handled as SAE) 
 pregnancy (see section 12.9) 
Second (non-SCLC) malignancies are always considered SAEs, no matter when they are di-
agnosed. These events should be reported on the Serious Adverse Event Forms. 
Other significant/important medical events which may jeopardise the patient are also consid-
ered SAEs. An overdose is defined as the accidental or intentional administration of any dose 
of a product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE. 
Serious also includes any other event that the investigator or the ETOP Safety Office judges 
to be serious or which is defined as serious by the regulatory agency in the country in which 
the event occurred. 
An unexpected adverse event is one that is not listed as a known toxicity of the investigational 
drug in the summary of product characteristics. 
A related adverse event is one for which the investigator assesses that there is a reasonable 
possibility that the event is related to the investigational drug. All adverse events judged as 
having a reasonable suspected causal relationship to the trial medication qualify as adverse 
reactions. 
Events not considered to be SAEs are hospitalisations occurring under the following circum-
stances:  
 elective surgery;  


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 occur on an outpatient basis and do not result in admission (hospitalisation <24 h);  
 are part of the normal treatment or monitoring of the studied treatment; 
 progression of disease (by convention, clinical events related to the primary cancer 
being studied or to the primary cancer progression are not to be reported as SAEs, 
even if they meet any of the seriousness criteria from the standard SAE definition, 
unless the event is more severe than expected and therefore the investigator consid-
ers that their clinical significance deserves reporting). 
12.5.2. SAEs after end of trial treatment 
During the follow-up phase (starting 100 days after end of trial treatment), the following 
events have to be reported as SAE: 
 fatal, life-threatening and other medically significant events possibly, probably or 
definitely related to late effects of trial treatment 
 disabling events 
 second primary cancer 
 congenital anomaly 
 pregnancy (see section 12.9) 
12.6. 
Definition of Serious Adverse Drug Reaction (SADR) 
SADRs are all SAEs considered to be related (possibly, probably, definitely) to the trial treat-
ment. 
12.7. 
Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A SUSAR is a serious adverse reaction that is assessed as unexpected on the basis of the 
applicable Swiss product information, the European summary of product characteristics, and 
the relevant IBs. 
12.8. 
Reporting SAEs and protocol-specified significant events 
Following the patient’s written consent to participate in the study, all SAEs, whether related 
or not to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur within 100 days of the last ad-
ministered study medication or within 100 days after the last visit in the observation arm. 
Any SAE must be reported by submitting the completed SAE Initial Report eCRF in the RDE 
system within 24 hours of awareness. 
DILI are to be reported by submitting the completed SAE Initial Report eCRF in the RDE 
system, even if they do not meet any of the seriousness criteria. Please submit the completed 
SAE Report eCRF (initial and follow-up) in the RDE system within 24 hours if the event is 
serious, or within 5 days, if the event is non serious, after awareness of the event. Indiate in 
“Description” section if “non-serious adverse event of special interest” yes or no 


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Submission of SAE is done via the electronic data capture system, or in case of unavailability, 
by sending the SAE form by fax to the ETOP Safety Office: 
+41 31 389 92 29 
Once the RDE system is available again, the SAE eCRF has to be completed and submitted 
by the site. 
The SAE outcome must be reported within 14 days after initial reporting by online submitting 
the SAE Follow-up Report eCRF. 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 ETOP Safety Office will forward each SAE to the trial chairs and notify principal inves-
tigators of any SADR meeting the criteria for expedited reporting (SUSAR) within the time-
lines specified in GCP. 
The local Ethics Committee must be informed by the principal investigator about local SAEs 
(if applicable by local law). 
The ETOP Safety Office will inform Bristol-Myers Squibb (by e-mail to world-
wide.safety@bms.com) of all SAEs – regardless of relatedness – and other appropriate per-
sons (per either investigator or ETOP Safety Office review) within 24 hours of receipt. 
The ETOP Safety Office will record the SAE and prepare a summary report of all SAEs re-
ceived. Listings of SAEs will be prepared as required. 
12.9. 
Pregnancy 
Patients who are not of childbearing potential due to being postmenopausal (2 years without 
menstruation) or surgical sterilisation (oophorectomy, hysterectomy and/or tubal ligation) do 
not need to use contraception to be eligible for the trial. All other patients are considered to 
be of childbearing potential. 
Women of childbearing potential and sexually active men must use highly effective contra-
ception during treatment with nivolumab and ipilimumab and until 12 months thereafter. 
Please refer to section 10.10 for highly effective contraception methods. 
In the case of pregnancy occurring during the course of the trial or within 12 month after 
treatment discontinuation, the investigator shall immediately (within 24 hours after awareness 
of pregnancy) notify ETOP by completing the pregnancy form in ETOPdata in accordance 
with the SAE reporting procedures. Follow-up information regarding the course of the preg-
nancy, including perinatal and neonatal outcome and, where applicable, offspring information 
must be reported (within 14 days) on the Pregnancy Form in ETOPdata. 
Any pregnancy that occurs in a female partner of a male study participant should be reported 
to ETOP. Information on this pregnancy will be collected on the Pregnancy Form. 


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13. 
Response evaluation 
13.1. 
RECIST 1.1 criteria 
The patient’s response to chemo-radiotherapy treatment and to nivolumab plus ipilimumab 
consolidation treatment will be assessed by RECIST 1.1 criteria (see appendix 2). Only pa-
tients with stable or responding disease will be eligible for randomisation. The response as-
sessment according to RECIST 1.1 should be done by the local radiologist and reported on 
the eCRF.  
For exploratory purposes, the response in the randomised nivolumab plus ipilimumab consol-
idation phase of the trial will also be assessed post-hoc centrally by immune-related response 
criteria based on RECIST 1.1.  
13.2. 
CT Schedule for tumour assessment 
Before randomisation: 
At baseline: brain MRI (or contrast enhanced CT of the brain), and whole body FDG-PET CT 
including a contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals). 
If FDG-PET CT is not available, contrast enhanced CT of the thorax and upper abdomen (incl. 
liver, kidney, adrenals) and bone scan is required for tumour assessment at baseline. 
Within 14 days prior to randomisation: contrast-enhanced CT of thorax and upper abdomen 
(incl. liver, kidney, adrenals) 
After randomisation: 
For both treatment arms, post randomisation CT scans of thorax and upper abdomen will be 
repeated according to the schedule indicated below, until tumour progression: 
- up to 18 months: every 9 weeks 
9, 18, 27, 36, 45, 54, 63, 72, 81 (+/- 1 week) 
- up to 2 years: 
every 12 weeks 
93, 105 (+/- 1 week) 
- years 3 and 4: 
every 6 months (26 weeks) 131, 157, 183, 209 (+/- 1 week) 
- at 5 years: 
 
260 (+/- 1 week) 
13.3. 
Determination of time point response 
Table 15: Determination of time point response 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR / non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 


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Target lesions 
Non-target lesions 
New lesions 
Overall response 
Not all evaluated 
Non-PD 
No 
NE 
unless the sum of diam. 
of evaluated lesions in-
dicates PD 1) 
PD 
Any  
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes  
PD 
1) From ref. 1 in appendix 2, p.234: When no imaging/measurement is done at all at a particular time 
point, the patient is not evaluable (NE) at that time point. If only a subset of lesion measurements are 
made at an assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change the 
assigned time point response. This would be most likely to happen in the case of PD. For example, if a 
patient had a baseline sum of 50 mm with 3 measured lesions and at follow-up only 2 lesions were 
assessed, but those gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 
13.4. 
Determination of best overall response 
Best overall response is defined as best response across all time points. Confirmation of partial 
or complete response by an additional scan is not requested in this trial.  
13.5. 
Storage of imaging 
All CT, FDG-PET-CT scans and MRI images must be stored locally in electronic format for 
later central review, please consult the STIMULI procedures manual for detail. 
14. 
Endpoints definition 
14.1. 
Progression-free survival  
It is defined as the time from the date of randomisation until documented progression or death, 
if progression is not documented. Censoring will occur at the last tumour assessment only if 
patient is lost to follow-up. 
14.2. 
Overall survival  
Defined as time from the date of randomisation until death from any cause. Censoring will 
occur at the last follow-up date. 


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14.3. 
Objective response 
Objective response is defined as best overall response (CR or PR) across all assessment time-
points during the period from randomisation to termination of trial treatment. Objective re-
sponse to chemo-radiotherapy will be determined by tumour assessment around week 15 (see 
trial schedule in section 2). 
Objective response to IMP treatment will be determined using RECIST 1.1 criteria (see sec-
tion 13). 
14.4. 
Time to treatment failure 
Defined as time from the date of randomisation to discontinuation of treatment for any reason 
(including progression of disease, treatment toxicity, refusal and death). Censoring will occur 
at the last follow-up date. 
14.5. 
Toxicity 
Adverse events classified according to NCI CTCAE Version 4.  
15. 
Biological material and translational research 
 
15.1. 
Mandatory evaluations 
Serum levels of TNF α/β and IL6, and circulating antibodies will be determined centrally in 
every patient from samples taken prior to or at enrolment, at the time of randomisation, 9 and 
18 weeks (+/- 3 days) after randomisation and at the time of progression. 
Chemo-Radiotherapy:
cis-/carboplatin + etoposide 
4 cycles
Biomaterial for translational research:
Consolidation vs observation:
induction
maintenance
max 1 year
combination
nivolumab
nivolumab/ipilimumab
observation
Screening:
LD SCLC
PCI
Tumour
evaluation:
PD
off
Voluntary re-biopsy: 
→ FFPE block
yes
no
R

3
6
9
3
6
9
18
12
after randomisation
RT (Thoracic Radiotherapy):
CT scans for tumour assessment
accelerated schedule preferred 
- up to 18 months: 
every 9 weeks
start: day 1 of chemo cycle 1 or
- up to 2 years: 
every 12 weeks 
day 1 of chemo cycle 2 
- years 3 & 4: 
every 6 months
- at 5 years
0
Week
Serum
At progression:
Whole blood
Whole blood
Whole blood
RT
RT
from start of chemotherapy
-2
CT
Serum
Serum
Serum
FDG-PET-CT
or CT 
Brain MRI 
or CT
Biopsy: 
FFPE block 
or slides
27 ∙∙∙
CT

14
16


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15.2. 
FDG-PET CT 
A pre-chemo-radiotherapy whole body FDG-PET-CT will be taken before enrolment to as-
sess background FDG avidity in the tumour, the hilar and mediastinal lymph nodes (if in-
volved at staging), and the lungs. If FDG-PET CT is not available, contrast enhanced CT of 
the thorax and upper abdomen (incl. liver, kidney, adrenals) and bone scan is required for 
tumour assessment at baseline. 
FDG-PET CT images must be stored locally in electronic format for later central review, 
please consult the STIMULI procedures manual for detail. 
15.3. 
Optional evaluations 
A biobank will be created with centralised samples for translational research. Tumour blocks, 
PBMCs (selected centres only), whole blood and mandatory serum sample will be centrally 
collected and biobanked at the Ludwig Institute for Cancer Research at University of Lau-
sanne, Switzerland. 
15.3.1. Blood sample 
Whole blood samples will be taken at baseline, at randomisation and 9 and 18 weeks (+/- 
3 days) after randomisation, as follows: 
 2.5 mL in PAXgene tubes for RNA profiling; 
 At selected sites: 50 mL in lithium heparin tubes for immunomonitoring with blood 
cell subtyping and quantification, including FACS analysis. 
 
For details on blood collection and processing of samples, please consult the 
STIMULI procedures manual. 
15.3.2. FFPE material 
A diagnostic tumour FFPE block, or a cell block if the diagnosis is done by cytology, will be 
collected from all consenting patients. If requested, these blocks can be returned to the sub-
mitting site after the slides for the analyses have been cut. If no blocks can be submitted, 5-
10 sections with a minimum thickness of 15-20μm from the tumour block or cell blockcan be 
submitted instead. If further slides can be be provided, 5 sections at 4-5 μm thickness should 
also be submitted for immunohistochemistry characterization. All slides should be freshly cut. 
Progressing patients will be asked for a voluntary re-biopsy, if possible not in an irradiated 
area to avoid fibrotic tissue. 
15.3.3. Translational research 
The following projects will be considered, at least, and subsequently adapted according to the 
growing knowledge about immunological modification observed and potential biomarkers of 
nivolumab plus ipilimumab immunotherapy:  


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 Presence of infiltrating lymphocytes in tumour (TILs) will be evaluated. Study and 
characterisation of TILs in detail will be performed using flow cytometry and func-
tional in vitro assays. 
 Tregs and T effectors quantitative analyses by FACS 
 Immune modulation on respective lymphocyte subtypes by FACS 
 Measurement and characterisation of T-cell infiltration, T-cell subsets and activa-
tion, and immune activation using multispectral immunohistochemistry (IHC) to 
quantify immune cell subsets. Immunohistochemistry on tumour micro-environ-
ment for immune cell infiltration description. 
 Gene expression profile (targeting selected panel of immune-related genes) will be 
analysed by deep sequencing, using Next Generation Sequencing technology in-
cluding TCR sequencing to capture clonal expansion of TILs. 
 Multiple tumour, inflammatory- and immune-related genes will be analysed by 
multiplex Nanostring technology.  
 PD-L1 expression 
15.4. 
Submission of material 
The tissue and blood samples collected during the conduct of the trial must be marked with 
the patient identifier issued by the RDE system and shipped to the central reference laboratory 
(Ludwig Institute for Cancer Research, University of Lausanne, Switzerland) and will be 
stored there for an unlimited time. This precious material will be used for central quality as-
surance and made available for translational research projects. 
15.4.1. Submission of FFPE material 
The following items should be submitted for all patients: 
1. Pathology Report from diagnostic biopsy (all information allowing identification of 
the patient, e.g. patient name, day and month of birth, must be removed) 
2. Tumour block or cell block from diagnostic biopsy, or alternatively 5-10 sections of 
at least 15-20 μm from the tumour block or cell block, and, when feasible, also 
5 freshly cut sections at 4-5 μm thickness.  
Recommended, but not required:  
3. Pathology report from re-biopsy at progression (all information allowing identifica-
tion of the patient, e.g. patient name, day and month of birth, must be removed) 
4. Tumour or cell block from re-biopsy at progression, or alternatively 5-10 sections of 
at least 15-20 μm from the tumour block or cell block, and, when feasible, also 5 
freshly cut sections at 4-5 μm thickness. 
Paraffin-embedded cell blocks are a valuable alternative to tumour blocks. Cytology smears 
alone are not accepted in this trial. Tumour material should be submitted as soon as obtained, 
and documented in the Biological Material Tracking eCRF in the database. If requested, these 
blocks can be returned to the submitting site after the slides for the analyses have been cut. 


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Alternatively, 5-10 sections of at least 15-20μm will be acceptable if the tumour block is not 
available for banking. If further slides can be provided, 5 freshly cut sections at 4-5 μm thick-
ness should also be submitted. 
All reports, slides, and blocks must be marked with the patient identification number issued 
by the RDE system. The pathology number, and any other identification should be removed 
or blackened. 
Please ensure that the blocks and/or slides are carefully packaged as otherwise they could 
easily get damaged during transport. 
Samples have to be sent to: 
Ludwig Center for Cancer Research 
Hôpital Orthopédique HO 05/1552 
Av. P-Decker 4 
CH-1011 Lausanne, Switzerland 
 
Anonymised pathology reports should be uploaded via the RDE system. Please consult the 
STIMULI procedures manual for specific instructions. 
15.4.2. Submission of blood and serum samples 
Blood collection and serum preparation (see STIMULI procedures manual): 
 2.5 mL whole blood will be put into PAXgene tubes (Qiagen; for gene profiling) 
and stored locally at -80°C. 
 Serum samples taken from 5mL blood should be immediately frozen at -80ºC  
 50 mL blood will be collected to isolate PBMCs (in selected centers only) 
Samples will be kept at the participating site until shipment. Shipments will be arranged cen-
trally. Samples have to be sent to the same address as indicated above (section 15.4.1). 
15.5. 
Banking of biological material 
ETOP has established a central repository for tissue blocks/slides, PBMCs, whole blood and 
serum samples from every patient enroled in this trial. The required pathological material 
(described in the previous section) is submitted to, catalogued, and maintained at the Ludwig 
Institute for Cancer Research, University of Lausanne, Switzerland, and will be made availa-
ble for translational research, following completion of the primary trial translational research 
objectives.  
16. 
Trial procedures 
This section gives an overview of procedures, clinical and laboratory evaluations and follow-
up investigations. 


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16.1. 
Trial phases 
The trial consists of the following phases:  
16.1.1. Screening: Baseline evaluations must be done within 28 days prior to enrolment (if 
the first chemotherapy cycle has been administered before enrolment, baseline 
evaluations must have been done within 35 days before start of first chemotherapy 
cycle). Please consult the STIMULI procedures manual for details. 
16.1.2. Chemotherapy-radiotherapy: 
Chemotherapy: will be started in the week following enrolment (alternatively, 
maximum 1 cycle of chemotherapy may be administered before enrolment) and 
consists of 4 cycles of cisplatin (25 mg/m2 i.v. on days 1 - 3 or 75 mg/ m2 on day 1) 
or carboplatin (AUC 5-6, calculated according Calvert formula, i.v. on day 1), plus 
etoposide (100 mg/ m2 i.v. on days 1 – 3), repeated every 3 weeks (+/- 3 days without 
cycle delay). 
 
Thoracic radiotherapy: Two different radiation doses are allowed: the recom-
mended schedule is 45 Gy in 30 twice-daily fractions of 1.5 Gy (6-8 hours apart), 
in 30 treatments on 5 days per week over 3 weeks (preferred). The alternative, but 
not-recommended schedule is 56 Gy, given in 28 once-daily fractions of 2 Gy, 5 
days per week over 6 weeks. Radiotherapy should start on day 1 of chemotherapy 
cycle 1 or on day 1 of chemotherapy cycle 2. Radiotherapy start on day 1 of cycle 3 
is allowed as an exception if patient is enroled after the first cycle only. 
 
Prophylactic cranial irradiation (PCI): 25 Gy in 10 fractions starting between 
day 8 and day 15 of first day of chemotherapy cycle 4 and finished not later than 
day 29 from start of cycle 4. 
16.1.3. Consolidation phase: Nivolumab plus ipilimumab combination therapy (induction) 
is to start within 6-8 weeks (42-56 days) from start of chemotherapy cycle 4, and not 
more than 2 weeks (14 days) after the date of randomisation. 
a) Induction: 
- Nivolumab at a dose of 1 mg/kg i.v. over a period of 30 minutes 
 followed (on the same day) by  
- Ipilimumab at a dose of 3 mg/kg i.v. over a period of 90 minutes 
once every 3 weeks (+/- 3 days, without dosing delay), for 4 cycles 
 
b) Maintenance: 
Nivolumab at a dose of 240 mg i.v. over a period of 30 minutes, once every 
2 weeks (+/- 2 days, without dosing delay) for maximum 12 months from start 
of maintenance phase. The first dose of maintenance nivolumab will be admin-
istered 3 weeks after the last IMP doses of induction phase 
 
Upon disease progression or completion of trial treatment, further therapy will be at 
the discretion of the treating physician. 
 


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16.1.4. End of treatment: an end of treatment visit will occur within 30  days following the 
last administered dose of trial treatment. For patients in the observation arm the end 
of treatment visit is to be scheduled within 30 days following PD or 15 months after 
randomisation. For patients who have not been randomised the end of treatment visit 
is to be scheduled within 30 days following PD or within 30 days following the last 
chemotherapy cycle. 
16.1.5. Follow-up period 
16.1.5.1. Before tumour progression: In the first 18 months after randomisation 
follow-up visits will occur together with the CT scans according to the 
schedule indicated in section 13.2, then every 12 (+/- 1) weeks until PD 
for a maximum of 4.5 years after the enrolment of the last patient. 
16.1.5.2. After tumour progression: follow-up visits will occur every 12 weeks in 
the first year after randomisation starting from date of progression, then 
every 6 months up to 4.5 years after the enrolment of the last patient. This 
applies also to patients who have been enroled but not randomised (see 
section 18.4). 
16.2. 
Baseline evaluations 
To be done within 28 days prior to enrolment. If the first chemotherapy cycle has been ad-
ministered before enrolment, baseline evaluations must have been done within 35 days before 
start of first chemotherapy cycle. 
16.2.1. Obtain written informed consent prior to any trial-specific evaluations or 
interventions 
16.2.2. Medical history including symptoms, smoking history, medications, comorbidities 
and allergies 
16.2.3. Physical examination including blood pressure [mmHg], ECOG performance status 
(see definition in STIMULI procedures manual), and body weight [kg], height [cm] 
16.2.4. Haematology: haemoglobin, platelets, complete white blood cell count (leukocytes, 
neutrophils, eosinophils, basophils (or total granulocytes), lymphocytes and 
monocytes) 
16.2.5. HIV, hepatitis B and C status 
16.2.6. Renal function: serum creatinine and creatinine clearance calculated according to 
Cockroft-Gault 
16.2.7. Hepatic function: ALT, AST, AP, bilirubin 
16.2.8. Pulmonary function: relative FEV1 and DLCO (%) 
16.2.9. Pregnancy test for women with childbearing potential within 7 days before 
chemotherapy start. 
 


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16.2.10. Whole body FDG-PET-CT (with max SUV measurements) including a contrast-
enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals), see 
procedure manual and STIMULI CRF completion guidelines for details;  
OR  
contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals) 
and bone scan; 
16.2.11. TNM categories 
16.2.12. Brain MRI (or contrast enhanced CT of the brain) 
16.2.13. FFPE block from diagnosis available for biobanking (subject to additional consent). 
If no blocks can be submitted, 5-10 sections with a minimum thickness of 15-20μm 
from the tumour block or cell block can be submitted instead. Submission of 
additional 5 freshly cut sections at 4-5 m thickness is desired. 
16.2.14. Mandatory serum sample, whole blood sample (subject to additional consent). 
16.3. 
During chemo-radiotherapy 
To be done within 24 hours of each chemotherapy administration 
16.3.1. Physical exam: blood pressure, performance status and body weight 
16.3.2. Haematology: haemoglobin, platelets neutrophils 
16.3.3. Hepatic function: AST, bilirubin 
16.3.4. Renal function: serum creatinine and creatinine clearance (calculated according to 
Cockroft-Gault) 
Recording symptoms, adverse events, concomitant medications. 
16.4. 
Before randomisation 
Contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals) should take 
place within 14 days before randomisation. 
All other examinations, listed below, should take place within 7 days before randomisation: 
16.4.1. Physical examination including blood pressure, performance status, and body weight 
16.4.2. Haematology: haemoglobin, platelets, complete white blood cell count (leukocytes, 
neutrophils, eosinophils, basophils (or total granulocytes), lymphocytes and 
monocytes) 
16.4.3. Hepatic function: AST, ALT, AP, bilirubin 
16.4.4. Renal function: serum creatinine plus creatinine clearance (calculated according to 


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Cockroft-Gault) 
16.4.5. Recording of symptoms, adverse events and concomitant medications 
16.4.6. Pregnancy test 
16.5. 
Before start of consolidation phase 
16.5.1. Serum sample; whole blood sample (subject to additional consent);  
16.6. 
During consolidation phase (induction and maintenance) 
Within 3 days before the administration of the next dose, the following evaluations will be 
done. 
In the observation arm, these evaluations should be done 9 and 18 weeks (+/- 3 days) after 
randomisation and thereafter every 18 weeks (+/- 1 week), according to local standard of 
follow-up, until PD or for maximum 15 months after randomisation. Beyond these 15 months 
or upon PD patients will enter the follow-up phase.. 
16.6.1. Recording of symptoms, adverse events and concomitant medications. 
16.6.2. Physical examination including blood pressure, performance status, and body weight 
16.6.3. Haematology: haemoglobin, platelets, complete white blood cell count (leukocytes, 
neutrophils, eosinophils, basophils (or total granulocytes), lymphocytes and 
monocytes) 
16.6.4. Renal function: serum creatinine and creatinine clearance (calculated according to 
Cockroft-Gault) 
16.6.5. Hepatic function: ALT, AST, AP, Bilirubin 
16.6.6. Na, K 
16.6.7. Serum sample; whole blood (subject to additional consent) at 9 and 18 weeks 
(+/- 3 days) after randomisation. 
16.6.8. A serum or urine pregnancy testing is required every 6 weeks during consolidation 
treatment (only in experimental arm). 
16.6.9. Ca, LDH, Glucose, amylase, lipase (only in experimental arm). To be done before 
each administration of nivolumab and ipilimumab during induction phase and then 
before every 3rd administration of nivolumab during maintenance phase. 
16.6.10. TSH (only in the experimental arm). To be done before the 1st and the 3rd 
administration of nivolumab and ipilimumab during induction phase and before the 
1st and then every 3rd administration of nivolumab in the maintenance phase (always 
within 3 days prior to next IMP dose). In case of abnormal TSH, also free T3 / T4 
have to be mearured. In case a value is abnormal then free T3/T4 needs to be repeated 
before the next administration. 
Note: For both treatment arms, post randomisation CT scans of thorax and upper abdomen 


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(incl. liver, kidney, adrenals) have to be repeated as indicated below, until tumour progression: 
 
- up to 18 months: every 9 weeks 
9, 18, 27, 36, 45, 54, 63, 72, 81 (+/- 1 week) 
- up to 2 years: 
every 12 weeks 
93, 105 (+/- 1 week) 
- years 3 and 4: 
every 6 months (26 weeks) 131, 157, 183, 209 (+/- 1 week) 
- at 5 years: 
 
260 (+/- 1 week) 
In case of early local tumour progression documented by CT scan 9 weeks after randomisa-
tion, a radiographic assessment / scan should be performed at least 4 weeks after the original 
PD scan to determine whether there has been a decrease in the tumour size or disease stabili-
sation, or alternatively continued PD which would terminate the trial treatment. Please consult 
the STIMULI procedures manual for a detailed schedule. 
16.7. 
Evaluations at progression 
At progression, the following assessments are required: 
16.7.1. CT thorax and upper abdomen, document progression on the respective eCRF 
16.7.2. Serum sample 
16.7.3. Tumour re-biopsy is strongly encouraged  
16.8. 
End of treatment visit 
At the end of the trial treatment and irrespective of the reason for stopping treatment, a 
post treatment visit at the centre is to be scheduled within 30 days following the last dose of 
treatment.  For patients in the observation arm the end of treatment visit is to be scheduled 
within 30 days following PD or 15 months after randomisation. For patients who have not 
been randomised the end of treatment visit is to be scheduled 30 days following PD or 30 
days following the last chemotherapy cycle. The following procedures should be performed: 
16.8.1. Recording of symptoms / adverse events / concomitant medications 
16.8.2. Physical examination including blood pressure, performance status and body weight 
16.8.3. Haematology: haemoglobin, platelets, complete white blood cell count [leukocytes, 
neutrophils, eosinophils, basophils (or total granulocytes), lymphocytes and 
monocytes] 
16.8.4. Hepatic function: ALT, AST, AP, bilirubin 
16.8.5. Renal function: serum creatinine and calculated creatinine clearance (according to 
Cockroft-Gault) 
16.8.6. Pregnancy tests should be repeated at approximately 30 days and approximately 70 
days after consolidation treatment stop. 


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16.8.7. CT thorax and upper abdomen, if not done within the last 6 weeks, and thereafter 
adhere to the schedule described in section 16.9, if reason for treatment 
discontinuation is oher than PD. 
16.9. 
Evaluations in the follow-up phase before progression 
Patients who completed consolidation treatment (this corresponds to 15 months after random-
isation in the observation arm) or discontinue IMP treatment before progression should have 
a regular physical examination (blood pressure, performance status and weight). In the first 
18 months after randomisation this has to be done together with the CT scans according to the 
schedule below, then every 12 (+/- 1) weeks until PD or up to 4.5 years after the enrolment 
of the last patient. 
For both treatment arms, post randomisation CT scans of thorax and upper abdomen will be 
repeated according to the schedule indicated below, until tumour progression: 
- up to 18 months: every 9 weeks 
9, 18, 27, 36, 45, 54, 63, 72, 81 (+/- 1 week) 
- up to 2 years: 
every 12 weeks 
93, 105 (+/- 1 week) 
- years 3 and 4: 
every 6 months (26 weeks) 131, 157, 183, 209 (+/- 1 week) 
- at 5 years: 
 
260 (+/- 1 week) 
16.10. Evaluations after progression / in follow-up 
Patients with progression will end trial treatment and should have documented  
 survival and  
 further lines of treatment  
every 12 weeks (+/-1 week) starting from date of progression during the first year after ran-
domisation, then every 6 months (+/- 4 weeks) up to 4.5 years after the enrolment of the last 
patient. 
17. 
Case report forms and documentation 
17.1. 
Case report forms schedule 
eCRFs will only be available on-line at the Remote Data Entry (RDE) facility ETOPdata. No 
paper forms will be used, with the exception of a paper SAE form and pregnancy form in case 
of system unavailability. 
Table 16: Case report forms 
 


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CRF in ETOPdata 
To be completed 
Eligibility for Enrolment 
Within 28 days after start of baseline assessments. 
Prior to start of 2nd cycle of chemotherapy and thoracic radi-
otherapy if the patient could not be enroled before the 1st cy-
cle of chemotherapy. 
Baseline for Chemotherapy 
Within 14 days after enrolment 
Tumour Assessment  
Before randomisation 
Baseline before enrolment: within 14 days after enrolment; 
Baseline before randomisation: between 3-6 weeks after 
day 1 of chemotherapy cycle 4; 
After randomisation: within 14 days of date of CT scans, 
which take place as follows until tumour progression: 
- up to 18 months: 
every 9 (+/- 1) weeks 
- up to 2 years: 
every 12 (+/- 1) weeks 
- years 3 and 4: 
every 26 (+/- 1) weeks 
- at 5 years: 
week 260 (+/- 1) 
Concomitant Medication 
Continuously from date of enrolment to 30 days after end of 
trial treatment (100 days if applied for the treatment of AEs 
and/or SAEs). 
Chemotherapy Cycles 
Within 14 days after the last administration  of chemother-
apy in each cycle. 
For patients that have been enroled after the first chemother-
apy cycle, an eCRF providing information about the 1st 
chemotherapy cycle has to be submitted within 14 days after 
enrolment. 
Thoracic Radiotherapy and 
PCI 
Within 14 days of last day of each radiotherapy 
Adverse Events Chemo-ra-
diotherapy 
At baseline: within 14 days after enrolment (to record symp-
toms present at baseline); 
Within 14 days of end of each cycle of chemo-radiotherapy; 
Within 14 days after randomisation; 
Within 14 days of end-of-treatment visit if patient does not 
proceed to randomisation. 


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CRF in ETOPdata 
To be completed 
Biological Material Track-
ing  
This eCRF is to be completed incrementally.  
Entries are to be made: 
- 
immediately after local storage of  blood/serum samples 
(on same day). 
- 
immediately after submission of material (FFPE and 
blood/serum) for central biobanking (on same day).  
Baseline before Randomisa-
tion 
Within 14 days after randomisation 
Eligibility Check and Ran-
domisation 
After end of chemo-radiotherapy, for randomisation 
Experimental Arm / Obser-
vation Arm  
Experimental arm: within 7 days of the end of each consoli-
dation cycle (every 3 weeks during 4 induction cycles and 
every 2 weeks during maintenance) 
Observation Arm: within 7 days of each visit, which takes 
place at weeks 9 and 18 (+/- 3 days) after randomisation, and 
thereafter every 18 weeks (+/- 1 week) for 15 months after 
randomisation. 
Adverse Events after Ran-
domisation 
After randomisation: within 14 days after randomisation (to 
record ongoing events present at randomisation); 
Experimental arm: within 7 days of end of each cycle of IMP 
treatment; 
Observation arm: to be completed within 7 days of weeks 9 
and 18 and every 18 weeks  thereafter; 
End of treatment: within 7 days after end-of-treatment visit 
100 days period after last treatment / last visit in observation 
arm: within 14 days after follow-up visits 
End of Treatment  
Within 7 days after end of treatment visit (which is to take 
place as soon as possible after decision to end treatment/ob-
servation, but at the latest 30 days after the last dose of treat-
ment/progression of disease) 


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CRF in ETOPdata 
To be completed 
Follow-up  
Follow-up before progression: 
Within 14 days of clinical follow-up visits. In the first 
18 months after randomisation these visits take place to-
gether with the CT scans (see above) and then at 3-monthly 
intervals until PD, for a maximum of 4.5 years after the en-
rolment of the last patient  
Follow-up after progression: 
<12 months post randomisation:  
within 14 days of clinical follow-up visits (which take place 
at 3-monthly intervals from date of progression); 
>12 months post randomisation:  
within 14 days of clinical follow-up visits (which take place 
at 6-monthly intervals from date of progression) until death, 
for a maximum of 4.5 years after the enrolment of the last 
patient. 
Follow-up on death: 
To be completed within 14 days upon awareness of death. 
Serious Adverse Event Ini-
tial Report 
Within 24h of awareness of SAE; 
Must be submitted via ETOPDdata, submission via fax to 
ETOP safety office only in case of inavailability of 
ETOPdata. 
Serious Adverse Event Fol-
low-up Report 
Within 14 days of completion of initial report. 
If event was not resolved after 14 days, submit an additional 
report again within 7 days of resolution of event.  
Pregnancy  
Within 24h of first documentation of pregnancy; 
Within 14 days of end of pregnancy. 
WC/LFU 
Within 14 days of awareness of withdrawal of consent or loss 
to follow-up 
 
Consult the STIMULI CRF completion guideline for detailed instructions on how to com-
plete, save and submit the eCRFs. 


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18. 
Statistical considerations 
18.1. 
Primary objective 
To evaluate whether patients treated with chemo-radiotherapy and prophylactic cranial irra-
diation followed by nivolumab plus ipilimumab consolidation treatment have a better out-
come as measured by the co-primary endpoints of overall survival and progression-free sur-
vival, compared to patients without nivolumab plus ipilimumab consolidation treatment. OS 
and PFS (measured from randomisation) are compared between treatment arms only for ran-
domised patients. 
Patients randomised to ipilimumab monotherapy before the protocol amendment 1 will be 
excluded from the efficacy analyses, and will be evaluated separately. 
18.2. 
Sample size determination 
Hyperfractionated accelerated radiotherapy has been shown to be more efficacious than radi-
otherapy given in a long overall treatment time. By giving twice-daily fractionation (BID), 
late reacting normal tissues are spared compared to the tumour, with as a consequence more 
temporarily acute esophagitis. 
The value of twice daily (BID) radiotherapy given early and concurrently to chemotherapy 
was examined in a landmark trial [24] and confirmed in two meta-analyses [25, 29], which 
will be our benchmark data. 
After a median FU of over 8 years, 2-year OS for respectively BID and QD radiotherapy was 
47% and 41%, and 5-year OS was 26 % and 16 %, respectively. Median PFS was approxi-
mately 13-14 months. 
18.3. 
Co-primary endpoint: OS and PFS  
OS and PFS will be measured from randomisation and compared between treatment arms 
only in the cohort randomised under amendment 1. 
The 2-year survival rate for the observation arm is estimated to be approximately 44% (47% 
for BID and 41% for QD radiotherapy, assuming half of included patients will receive BID 
and QD respectively). Median PFS and OS are expected to be 13.1 and 20.7 months. 
For the experimental arm, medians as measured from randomisation are assumed to be 29.7 
and 22.8 months for OS and PFS respectively (OS HR=0.70; PFS HR=0.57), taking into ac-
count that the patients randomised are of better prognosis than the total patients enrolled. 
The overall one-sided significance level of 0.05 is split to 0.04 for OS and 0.01 for PFS. A 
total of 325 patients are expected to be enroled in 36 months of accrual time, leading to 260 
patients randomised to two arms based on a 20% attrition rate due mainly to early progression 
events during the first 4 months after enrolment. An additional 3% loss to follow-up is as-
sumed during the trial after randomisation.  
A trial duration of 87 months is necessary for the required 212 deaths to be observed, while 
on the main analysis of PFS will be performed when 148 PFS events have occurred, which is 


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expected at approximately 45 months. Using the log-rank test, the achieved power is 78% for 
OS at the end of the trial, and 80% for PFS at the 45-months evaluation. 
Total trial duration: 7.5 years 
The trial will end when either the total number of 212 deaths has been observed or at a maxi-
mum of 7.5 years from the first patient enrolment date. 
Alternative scenarios for the co-primary endpoint of PFS and OS were run each in 10,000 
simulations. The overall one-sided alpha level of 0.05 was split to 0.04 for OS and 0.01 for 
PFS. The alternative hypothesis of treatment benefit corresponds to an HR for PFS equal to 
0.55, 0.60 and 0.65 and an OS HR of 0.7. A piecewise exponential survival distribution was 
assumed based on the above assumptions, omitting the lower end of the distribution time, i.e., 
events occurring before randomisation. The follow-up after randomisation was simulated ac-
cording to the alternative of interest. 
Power of 78% for testing OS from randomisation to end of trial and of 80% for testing PFS 
were generally aimed and achieved for the different scenarios. The probability of rejecting 
the null hypothesis regarding OS given that the null hypothesis regarding PFS was rejected 
was of the order of 85%-87%, while at least one rejection was achieved (power for co-pri-
mary) from 88% to 91% of the time, with 67-68% observed joint rejection. 
Calculations are performed using the EAST package and simulations were run in the R sta-
tistical package. 
18.4. 
Evaluation of primary and secondary objectives 
The total study duration will be approximately 7.5 years including the 36 months recruitment 
period. The primary analyses on PFS and OS will be performed overall and stratified by ra-
diotherapy schedule. An intent to treat primary efficacy analysis will be performed, including 
all eligible patients randomised (= efficacy cohort).  
PFS and OS will be estimated by the Kaplan Meier method and compared between the two 
treatment arms by a stratified logrank test. In addition, stratified (by the randomisation strati-
fication factors) and multivariate Cox models will be used for exploring the association of 
PFS and OS with treatment in the presence of prognostic factors. 
The two treatment groups will also be compared with respect to secondary efficacy and toler-
ability endpoints. No multiplicity adjustment will be performed for these analyses. 
Time to treatment failure (TTF) will be estimated by the Kaplan Meier method and compared 
between the two treatment arms based on the logrank test stratified by the randomisation strat-
ification factors. Cox proportional hazards regression adjusting for prognostic factors will also 
be performed for this secondary endpoint. 
All time-to-event endpoints will be presented and evaluated from date of randomisation, with 
secondary presentation from date of enrolment. 
Clinical efficacy will be further described by objective response rate (ORR, defined as per-
centage of patients reaching a complete or partial response) based on RECIST 1.1 response 


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criteria. The determination of ORR will be restricted to patients who have not attained a CR 
during chemo-radiotherapy. 
Assessment of response by immune-related response criteria based on RECIST 1.1 will be 
explored post-hoc, centrally, in the randomised consolidation phase of the trial. 
Safety and the tolerability of the nivolumab plus ipilimumab consolidation therapy will be 
described by tabulation of the CTCAE Version 4 grade. The safety cohort will encompass all 
patients who have received at least 1 dose of IMP treatment plus all patients randomised to 
observation. 
The correlation of biological markers with OS and PFS will be evaluated by univariate and 
multivariate Cox proportional hazards regression. 
OS analysis will also be performed for the full cohort of 325 patients for descriptive purposes. 
The survival time for the full cohort will be defined as the time from enrolment into the trial 
until death. 
Statistical analysis for the primary, secondary endpoints and translational research will be 
described in detail in the Statistical Analysis Plan (SAP) document. 
18.5. 
Early safety evaluation 
Pneumonitis related to radiation has been observed in 15-20% of patients treated with chemo-
radiotherapy. In order to exclude an exacerbation by IMP treatment, a safety evaluation will 
take place 12 weeks after the first 30 patients have been randomised to the experimental arm 
(total of 60 pts, 30 in the nivolumab plus ipilimumab combination and 30 in observation arm). 
This first safety evaluation will be submitted to the IDMC for advice. The trial will continue 
while safety is evaluated. 
Safety evaluations will be performed 4 times a year and submitted to the IDMC at their regular 
meeting. 
19. 
Criteria for termination of the trial 
19.1. 
General criteria for termination of the trial 
The trial may be discontinued early in parts or completely if the information on the product 
leads to doubt as to the benefit/risk ratio, by decision of ETOP or Trial Steering Committee, 
or at the suggestion of the IDMC based on the interim safety evaluations. 
The trial can be terminated at any time if the authorisation and approval to conduct the Study 
is withdrawn by ethics committee or regulatory authority decision, insufficient accrual, 
emerging new data impacting the scientific value of the trial or on ethical grounds. 
19.2. 
Discontinuation of protocol treatment for individual patients  
Protocol treatment should be stopped in the following situations: 
 
Disease progression. 


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 
Occurrence of unacceptable toxicities. Stopping protocol treatment is determined 
by medical judgment of the treating physician. 
 
Inter-current severe illnesses which would in the judgment of the investigator affect 
assessments of the clinical status to a significant degree and require discontinuation 
of protocol therapy. Note: Diagnosis of another neoplastic disease (second malig-
nant tumour) does not mandate a stop of trial therapy, patients may continue to re-
ceive protocol treatment after appearance of a second primary tumour, stopping 
protocol treatment is determined by the medical judgment of the treating physician. 
 
Request by the patient. Patients have the right to refuse further trial treatment at 
any time during the trial. Such patients will remain in the trial and will be trans-
ferred to the follow-up phase. 
 
If a patient refuses to have follow-up examinations and tests needed to determine 
whether the treatment is safe and effective. 
The decision for discontinuation of protocol treatment of individual patients is taken by the 
treating physician based on his medical evaluation and taking into account the patient’s indi-
vidual situation. 
The patient will be followed for survival irrespective of whether treatment is discontinued 
(required provisions outlined in section 19.3). 
19.3. 
Withdrawal of consent 
Patients have the right to withdraw consent for further trial participation at any time without 
having to specify the reason. The data recorded up to the timepoint of withdrawal will con-
tinue to be evaluated in the trial. The investigator should ask the patient for consent to continue 
to collect information on her/his disease and survival status. 
It should be documented in both the medical records and in the eCRF, according to the in-
structions in the STIMULI CRF completion guidelines, if the patient accepts to be contacted 
for survival status despite withdrawing the trial consent. For the patient’s safety, an end of 
treatment visit should be performed and documented in the eCRF.  
20. 
Ethics aspects, regulatory approval, and Patient Informed Consent 
The Investigator will ensure that this study is conducted in full conformance with the princi-
ples of the “Declaration of Helsinki” or with the laws and regulations of the country in which 
the research is conducted, whichever affords the greater protection to the individual. The study 
must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” ICH 
Tripartite Guideline (January 1997) or with local law if it affords greater protection to the 
patient. For studies conducted in the EU/EEA countries, the Investigator will ensure compli-
ance with the EU Clinical Trial Directive (2001/20/EC). 


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20.1. 
Ethical Review Board/Ethics Committee 
All protocols and the patient informed consent forms must have the approval of a properly 
constituted committee or committees responsible for approving clinical trials. The ERB/IRB 
decision must contain approval of the designated investigator, the protocol (identifying pro-
tocol title and version number), and of the patient informed consent. 
The ERB/IRB written, signed approval letter/form must contain approval of the designated 
investigator, the protocol (identifying protocol title and version number), and of the patient 
informed consent. Documentation of Ethics Committee approval must be sent to the ETOP 
Coordinating Office prior to enrolment of the first patient. 
Any modifications made to the protocol must be submitted to the appropriate ERB/IRB for 
information or approval in accordance with local procedures and regulatory requirements and 
to Health Authorities if required.  
Once approved or acknowledged by the appropriate ERB/IRB and by the Health Authorities 
(if required), the investigator shall implement the protocol modifications. Protocol modifica-
tions for urgent safety matters may be directly implemented following the instructions of 
ETOP. 
20.2. 
Regulatory approval procedures 
If applicable, in addition to the approval of the Ethics Committee according to national legis-
lation, the protocol, other protocol related documents including patient information and in-
formed consent and other documents as required locally must be submitted to and be approved 
by the health authority. Documentation of health authority approval must be sent to the ETOP 
Coordinating Office prior to Participating Centre activation.  
20.3. 
Informed consent  
Informed consent for each patient will be obtained prior to initiating any trial procedures in 
accordance with the “Patient Information and Informed Consent" (See appendix 1). One 
signed and dated copy of the informed consent must be given to each patient and the original 
copy must be retained in the investigator’s trial records.  The informed consent form must be 
available in the case of data audits. Verification of signed informed consent and the date 
signed are required for enrolment to this trial.   
The “Declaration of Helsinki” recommends that consent be obtained from each potential pa-
tient in biomedical research trials after the aims, methods, anticipated benefits, and potential 
hazards of the trial, and discomfort it may entail, are explained to the individual by the phy-
sician.  The potential patient should also be informed of her/his right to not participate or to 
withdraw from the trial at any time.  The patient should be told that material from her/his 
tumour and blood and serum samples will be stored and potentially used for additional studies 
not described in this protocol.  
If the patient is in a dependent relationship to the physician or gives consent under duress, the 
informed consent should be obtained by an independent physician.  If the patient is legally 
incompetent (i.e., a minor, or mentally incompetent), informed consent must be obtained from 


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the parent, legal guardian, or legal representative in accordance with the law of the country in 
which the trial is to take place.  By signing this protocol, the investigator agrees to conduct 
the trial in accordance with Good Clinical Practice and the "Declaration of Helsinki".  
ETOP recognises that each institution has its own local, national, and international guidelines 
to follow with regard to informed consent.  Therefore, we provide a template information 
sheet and informed consent form (appendix 1), which can be edited to incorporate information 
specific to your institution. The template Patient Information Sheet and Informed Consent has 
been written according to ICH guidelines which state the Informed Consent should adhere to 
GCP and to the ethical principles that have origin in the “Declaration of Helsinki”. The final 
version should receive the Institutional Review Board/ Local Ethics Committee approval in 
advance of its use. Centres should send their locally modified PIS/IC to ETOP for review and 
approval before submitting to their Ethics Committee.  
21. 
Governance and administrative issues 
21.1. 
Final report 
A final clinical trial report will be written and distributed to Health Authorities as required by 
applicable regulatory requirements 
21.2. 
Steering Committee 
A Steering Committee will be constituted for this trial. The Steering Committee is responsible 
for maintaining the scientific integrity of the trial, for example, by recommending changes to 
the protocol in light of emerging clinical or scientific data from other trials. Membership will 
include the trial chair and co-chair, trial coordinators, trial statisticians, ETOP officials, rep-
resentatives from some participating institutions and groups, and a representative from Bris-
tol-Myers Squibb. 
21.3. 
Independent Data Monitoring Committee 
The trial will be presented for review to the ETOP IDMC at each of their meetings which take 
place 4 times a year. Accrual and safety will be monitored. 
21.4. 
Publication 
The results of the trial will be published according to the ETOP publication policy (appen-
dix 3). 
21.5. 
Clinical trial insurance 
ETOP will contract the appropriate liability insurance for this trial. Patients who suffer inju-
ries due to the trial should report them immediately to their physician. The local group/insti-
tution should report all alleged claims immediately to the ETOP Coordinating Office. 


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21.6. 
Quality assurance 
ETOP conducts trials according to the ICH Good Clinical Practice (GCP) guidelines.  The 
Trial Data Manager reviews each eCRF as it is received. In addition, the ETOP Medical Re-
viewer reviews each case at specific timepoints.  ETOP conducts periodic audit visits to en-
sure proper trial conduct, verify compliance with GCP, and perform source data verification. 
The Investigator should ensure that source documents are made available to appropriately 
qualified personnel from ETOP or its designees, or to ethics committee and health authority 
inspectors after appropriate notification. 
At regular intervals during the clinical trial, the Centre will be contacted, through monitoring 
visits, letters or telephone calls, by a representative of the Monitoring Team to review study 
progress, investigator and patient compliance with clinical trial protocol requirements and any 
emergent problems. These monitoring visits will include but not be limited to review of the 
following aspects: patient informed consent, patient recruitment and follow-up, SAE docu-
mentation and reporting, AEs with pre-specified monitoring documentation and reporting, AE 
documentation, dispensing IMP, compliance with protocol, drug accountability, concomitant 
therapy use, quality of data and storage of blood and serum samples. 
21.7. 
Protocol adherence 
Investigators ascertain that they will apply due diligence to avoid protocol deviations. Under 
no circumstances should the investigator contact ETOP or personnel monitoring the trial to 
request approval of a protocol deviation, as no deviations are permitted. The investigator 
should document and explain any deviations from the approved protocol. The investigator 
should promptly report any deviations to the Sponsor and to the EC concerned in accordance 
with the applicable EC policies and procedures. If the investigator feels a protocol deviation 
would improve the conduct of the trial this must be considered a protocol amendment, and 
unless such an amendment is developed and activated by the sponsor and approved by the 
IRB/IEC/ERB it cannot be implemented. All protocol deviations will be recorded. 
21.8. 
Data protection 
The samples and data collected will be coded to protect patient confidentiality. Each patient 
will have a unique identifier assigned by the RDE facility ETOPdata. Sites are responsible to 
keep a patient log locally in order to be able to link the unique identifier to the record of the 
patient.  
Biological material will be assigned the same unique identifier. No identifiable / personal data 
will be stored in the trial database or the tissue repositories in the central labs. 
Biological material will be transferred outside the treating institution for central screening and 
review. Results of the assays will be coded only by the patient identifier. 
Regulatory authorities and pertinent Ethics Committees (IRB/ERB) may have access to pa-
tient data on-site. ETOP audit or monitoring personnel will also have access to such data on-
site. 


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21.9. 
Record retention 
The centre must 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 are to be stored until at least 15 years after the 
termination of the trial. ETOP guarantees access and availability of the data entered into 
ETOPdata for at least 15 years after the termination of the trial. 
Longer retention may be required for participating centres according to national regulations. 
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 has to be given to ETOP and the local Ethics 
Committee at least 1 month in advance. 
22. 
References  
1. National 
CIB. 
SEER 
Cancer 
Statistics 
Review, 
1975-2006. 
Available 
at 
http://seer.cancer.gov/csr/1975_2006 2009. 
2. Devesa SS, Bray F, Vizcaino AP, Parkin DM. International lung cancer trends by 
histologic type: male:female differences diminishing and adenocarcinoma rates rising. 
Int J Cancer 2005; 117: 294-299. 
3. Antony GK, Bertino E, Franklin M et al. Small cell lung cancer in never smokers: report 
of two cases. J Thorac Oncol 2010; 5: 747-748. 
4. De Ruysscher D, Botterweck A, Dirx M et al. Eligibility for concurrent chemotherapy 
and radiotherapy of locally advanced lung cancer patients: a prospective, population-
based study. Ann Oncol 2009; 20: 98-102. 
5. Field JK, Duffy SW. Lung cancer screening: the way forward. Br J Cancer 2008; 99: 557-
562. 
6. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. World Health Organization 
Classification of Tumours. Pathology and genetcs of Tumours of the Lung, Pleura, 
Thymus and Heart. In. Lyon: IARC Press 2004. 
7. Franklin W, Noguchi M, Gonzalez A. Molecular and Cellular Pathology of Lung Cancer. 
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SAP_001.pdf: 
 
 
 
 
 
STIMULI 
ETOP/IFCT 4-12 
A randomized open-label phase II trial of consolidation with nivolumab 
and ipilimumab in limited-stage SCLC after chemo-radiotherapy 
 
 
Statistical Analysis Plan (SAP) for 
Final analysis 
 
 
NCT02046733 
 
 
 
 
A clinical trial of ETOP 
 
 
 
SAP VERSION & DATE: 1.0 – MAY 2020 
 


Statistical Analysis Plan                                                                                                                                                                            ETOP/IFCT 4-12 STIMULI 
 
Page 2 of 27 
Contents 
INTRODUCTION .......................................................................................................................................................................... 4 
Trial oversight (as per protocol version 2.0, Amendement1; AM1) ..................................................................... 5 
1.1 
Objectives and Endpoints .................................................................................................................................... 6 
1.2 
Most important eligibility criteria .................................................................................................................... 7 
1.3 
Trial treatment ......................................................................................................................................................... 8 
1.4 
Statistical design, sample size and power ..................................................................................................... 9 
1.4.1 
Based on protocol AM1 ............................................................................................................................... 9 
1.4.2 
Modifications after premature accrual closure ................................................................................. 9 
1.5 
Total trial duration .............................................................................................................................................. 10 
1.6 
Previous protocol version (original protocol) ......................................................................................... 10 
2 
Statistical considerations for final analysis ........................................................................................................ 12 
2.1 
Analysis timing ...................................................................................................................................................... 12 
2.2 
Study’s endpoints ................................................................................................................................................. 12 
2.2.1 
Primary endpoint ....................................................................................................................................... 12 
2.2.2 
Secondary endpoints ................................................................................................................................ 12 
2.2.3 
Exploratory endpoints ............................................................................................................................. 12 
2.2.4 
(Serious) Adverse Events ........................................................................................................................ 13 
2.3 
Analysis population ............................................................................................................................................. 15 
3 
Primary efficacy analysis of PFS .............................................................................................................................. 17 
4 
Additional secondary analysis .................................................................................................................................. 19 
4.1 
Patient accrual, balance of stratifications factors & baseline characteristics ............................. 19 
4.2 
Follow-up information and Treatment administration ....................................................................... 19 
4.3 
Secondary (efficacy) and exploratory endpoints .................................................................................... 20 
4.3.1 
Overall survival ........................................................................................................................................... 20 
4.3.2 
Time to treatment discontinuation ..................................................................................................... 21 
4.3.3 
Objective response rate ........................................................................................................................... 21 
4.3.4 
Graphical illustration of tumour responses .................................................................................... 21 
4.3.5 
Duration of response ................................................................................................................................ 22 
4.4 
Subgroup analysis ................................................................................................................................................ 22 


Statistical Analysis Plan                                                                                                                                                                            ETOP/IFCT 4-12 STIMULI 
 
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4.5 
Sensitivity analysis .............................................................................................................................................. 22 
4.6 
Descriptive analysis of the per-protocol cohort ...................................................................................... 23 
4.7 
Safety analysis ....................................................................................................................................................... 23 
5 
Technical details............................................................................................................................................................. 25 
 
 


Statistical Analysis Plan                                                                                                                                                                            ETOP/IFCT 4-12 STIMULI 
 
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INTRODUCTION 
The aim of this Statistical Analysis Plan (SAP) is to describe an analytic and solid framework that 
will be followed in order for the final efficacy analysis of the STIMULI trial to be implemented 
(based on protocol amendment-1 [AM1]). 
A short description of the contents of this statistical analysis plan is provided below: 
1. Trial outline/oversight: trial’s schema, objectives and trial endpoints, eligibility criteria, 
trial treatment, statistical design (sample size and power), trial duration, previous 
protocol versions 
2. Statistical considerations for final analysis: analysis timing, definition of primary, 
secondary and exploratory endpoints, (serious) adverse events definition, analysis 
populations 
3. Primary efficacy analysis of Progression free-survival (PFS) 
4. Additional secondary analysis: accrual and baseline characteristics, treatment 
administration and follow-up, secondary and exploratory analysis 
5. Technical issues: data retrieval, testing, handling of missing data, reporting conventions  


Statistical Analysis Plan                                                                                                                                                                            ETOP/IFCT 4-12 STIMULI 
 
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Trial oversight (as per protocol version 2.0, Amendement1; AM1) 
STIMUI is a randomized open-label phase II international multicentre clinical trial aiming to 
demonstrate superiority of consolidation with nivolumab and ipilimumab versus observation 
after chemo-radiotherapy and prophylactic cranial irradiation (PCI), in patients with radically 
treated limited-stage small cell lung cancer (SCLC). 
 
SCHEMA 1. Trial design under protocol AM1 
STIMULI is a trial with block stratified randomization balanced by institution. After completion of 
the 4 cycles of chemotherapy, thoracic radiotherapy and PCI, patients who have not progressed 
can be randomized to one of the two treatment arms. The two stratification factors are: number 
of fractions of radiotherapy (twice-daily vs once-daily) and positron emission tomography–
computed tomography (PET-CT) (done vs not done) 
 
 
 


Statistical Analysis Plan                                                                                                                                                                            ETOP/IFCT 4-12 STIMULI 
 
Page 6 of 27 
1.1 Objectives and Endpoints 
Primary objective 
According to protocol AM1, the primary objective of the study is to evaluate if patients treated 
with chemo-radiotherapy and PCI followed by consolidation treatment (nivolumab plus 
ipilimumab) have a better outcome in terms of progression-free survival (PFS) and overall 
survival (OS) compared to patients treated with chemo-radiotherapy and prophylactic cranial 
irradiation without consolidation treatment.  
 
Co-primary endpoints:  
• 
Progression-free survival (PFS) according to RECIST 1.1 criteria based on the local 
radiologist assessment 
• 
Overall survival (OS) 
 
Important notes: 
• 
Following a subsequent modification in trial design, without requiring protocol 
amendment, PFS alone was set to be the primary endpoint of the trial, with OS becoming 
a secondary endpoint. This is further described in section 1.4.2. 
• 
PFS (measured from randomization) are compared between treatment arms only for 
randomized patients.  
• 
Patients randomized to ipilimumab monotherapy before the protocol AM1, i.e., under the 
original protocol version, will be excluded from the present final efficacy analysis, and will 
be evaluated separately. 
 
Secondary endpoints:  
• 
Objective response determined by RECIST 1.1 criteria 
• 
Time to treatment failure (TTF) 
• 
Adverse events graded according to CTCAE v4.0 
Exploratory endpoints: 
• 
Time to treatment discontinuation (TTD) 
• 
Duration of response (DoR) 
 
Details on the calculation of endpoints are provided in section 2.2. 
 


Statistical Analysis Plan                                                                                                                                                                            ETOP/IFCT 4-12 STIMULI 
 
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1.2 Most important eligibility criteria 
Inclusion criteria at enrolment:  
• 
Histologically or cytologically confirmed small cell lung carcinoma 
• 
Untreated (with the exception of 1 cycle of chemotherapy given prior to enrolment) 
limited stage disease (LD) as defined by stage I-IIIB based on 7th TNM classification (IASLC 
classification for SCLC proposal). M0 proven by 
o Whole body FDG-PET CT including a contrast-enhanced CT of thorax and upper 
abdomen (incl. liver, kidney, adrenals); OR contrast-enhanced CT of thorax and 
upper abdomen (incl. liver, kidney, adrenals) and bone scan;  
AND 
o Brain MRI (or contrast enhanced CT of the brain).   
Within 28 days before start of chemotherapy  
• 
Age ≥18 years  
• 
ECOG performance status 0-1  
• 
Adequate hematological, renal, hepatic and liver function  
• 
Pulmonary function FEV1 of 1.0L or >40% predicted value and DLCO >40% predicted value 
Exclusion criteria at enrolment:  
• 
Patients with mixed small-cell and non-small-cell histologic features 
• 
Patients with pleural or pericardial effusions proven to be malignant 
• 
Documented history of severe autoimmune or immune mediated symptomatic disease 
that required prolonged (>2 months) systemic immunosuppressive treatment (e.g. 
steroids) such as ulcerative colitis and Crohn´s disease, rheumatoid arthritis, systemic 
progressive sclerosis (scleroderma), systemic lupus erythematosus, or autoimmune 
vasculitis (eg, Wegener’s granulomatosis) 
• 
Patients with an autoimmune paraneoplastic syndrome requiring concurrent 
immunosuppressive treatment 
• 
Interstitial lung disease or pulmonary fibrosis 
• 
Women who are pregnant or in the period of lactation 
• 
Patients with any concurrent anticancer systemic therapy (except for chemotherapy cycle 
1) 
• 
HIV, Hepatitis B or Hepatitis C infection 
• 
Patients who have had in the past 5 years any previous or concomitant malignancy 
EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma 
of the cervix or bladder, in situ ductal carcinoma of the breast 
• 
Previous radiotherapy to the thorax (prior to inclusion) 
• 
Planned mean lung dose >20 Gy or V20 >35% 
Inclusion criteria at randomization: 
• 
Chemo-radiotherapy completed per protocol: 4 cycles of chemotherapy, 85% of PTV of 
thoracic radiotherapy, as well as completed, mandatory PCI 
• 
Non-PD after chemo-radiotherapy and PCI 
 


Statistical Analysis Plan                                                                                                                                                                            ETOP/IFCT 4-12 STIMULI 
 
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1.3 Trial treatment 
After enrolment, the patient will receive or, if included after the first chemotherapy cycle, 
continue receiving standard of care treatment for limited disease SCLC consisting of chemo-
radiotherapy and PCI.  
• 
Chemotherapy: will be started in the week following enrolment (alternatively, maximum 
1 cycle of chemotherapy may be administered before enrolment), and consists of a total of 
4 cycles of cisplatin (25 mg/m2 i.v. on days 1 – 3 or 75 mg/ m2 on day 1) or carboplatin 
(AUC 5-6, calculated according Calvert formula, i.v. on day 1), plus etoposide (100 mg/ m2 
i.v. days 1 – 3), repeated every 3 weeks (+/- 3 days without cycle delay).  
• 
Concomitant Thoracic Radiotherapy: Accelerated twice-daily administration of 45 Gy in 
30 twice-daily fractions of 1.5 Gy (6-8 hours apart), 5 days per week for 3 weeks, or an 
allowed, but not-recommended schedule of 56 Gy, given in 28 once-daily fractions of 2 Gy, 
5 days per week for 6 weeks. Two options are allowed: Thoracic radiotherapy MUST start 
either from day 1 of cycle 1 or day 1 of cycle 2. Radiotherapy start at day 1 of cycle 3 is 
allowed if patient is enrolled after the first cycle only but should be exceptional. Optimally, 
radiotherapy should start at the latest on day 1 of cycle 2. 
• 
PCI: 25 Gy in 10 fractions starting between day 8 and day 15 of chemotherapy cycle 4 and 
finished not later than day 29 from start of cycle 4. 
After randomization, which should take place within 5-6 weeks after day 1 of cycle 4 (between 
days 35 and 42 of cycle 4) 
Experimental arm 
Induction phase: 
To start within 6-8 weeks (42-56 days) after the start of chemotherapy cycle 4, and not more than 
2 weeks (14 days) after the date of randomization. 
– Nivolumab at a dose of 1 mg/kg i.v. over a period of 30 minutes,  
followed (on the same day) by 
– Ipilimumab at a dose of 3 mg/kg i.v. over a period of 90 minutes, once every 3 weeks (+/- 
3 days, without dosing delay), 4 cycles 
Maintenance phase: 
To start 3 weeks (21 days) after the last Investigational Medical Product (IMP) dose of induction 
phase. 


Statistical Analysis Plan                                                                                                                                                                            ETOP/IFCT 4-12 STIMULI 
 
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– Nivolumab 240 mg i.v. over a period of 30 minutes, once every 2 weeks (+/- 2 days, 
without dosing delay), for a maximum of 12 months from start of maintenance phase.  
Observation arm 
No further treatment. 
 
1.4 Statistical design, sample size and power 
1.4.1 Based on protocol AM1 
This is a 1:1 randomized phase II trial (stratified by twice-daily vs once-daily radiotherapy and 
PET-CT done vs not done) with co-primary endpoints PFS and OS. The overall one-sided 
significance level of 0.05 is split to 0.01 for PFS and 0.04 for OS. A total of 325 patients are 
expected to be enrolled in 36 months of accrual time, leading to 260 patients randomized to the 
two arms based on a 20% attrition rate due mainly to early progression events during the first 4 
months after enrolment. An additional 3% loss to follow-up is assumed during the trial after 
randomization. A trial duration of 87 months is necessary for the required 212 deaths to be 
observed, while the main analysis of PFS will be performed when 148 PFS events have occurred, 
which is expected at approximately 45 months. Using the log-rank test, the achieved power is 80% 
for PFS at the 45-months evaluation and 78% for OS at the end of the trial. 
Median PFS and OS for the observation arm are expected to be 13.1 and 20.7 months, as measured 
of randomization. Taking into account that the patients randomized are of better prognosis than 
the total patients enrolled, the expected increase in medians for the cohort of patients in the 
experimental arm is 9.7 months and 9 months for PFS and OS respectively. This translated 
to a PFS HR of 0.57 and OS HR of 0.70. 
The trial will end when either the total number of 212 deaths has been observed or at a maximum 
of 7.5 years from the first patient enrolment date. 
Calculations are performed using the EAST package and simulations were run in the R statistical 
package. 
1.4.2 Modifications after premature accrual closure 
Because of the low accrual rate as well as additional strategic considerations unrelated to the 
scientific rational of the trial design, trial’s funding source (Bristol-Myers Squibb, BMS) informed 
ETOP on 18 March 2019 that cannot continue funding the STIMULI trial. Therefore, the Trial 
Steering Committee decided to close the accrual into the trial prematurely as of 30 April 2019. 
Note that no safety concerns led to the decision of accrual closing. 
Patients who already consented were still allowed to be enrolled until 30 April 2019. After this 
date, no new patients would be allowed to be enrolled into the trial. Treatment and follow-up for 


Statistical Analysis Plan                                                                                                                                                                            ETOP/IFCT 4-12 STIMULI 
 
Page 10 of 27 
all included patients continued as per protocol. Patients in the chemoradiotherapy phase who 
meet the criteria, would be still allowed to be randomized. 
Thus, taking into account the reduced number of randomized patients and the corresponding 
initially required events (148 PFS events, 212 OS events) which were not possible to be observed 
anymore, the statistical design was modified. 
According to this latest statistical modification, the primary endpoint of the trial is now defined 
as only the PFS (previous: co-primary PFS and OS) using the overall one-sided significance level 
of 0.05 (previous: 0.04 for PFS and 0.01 for OS). The hypotheses for PFS remain the same (PFS 
HR=0.57, with 13.1 months median PFS assumed in the observation arm versus 22.8 in the 
experimental). In this setting, the number of the required PFS events, for testing the PFS 
hypothesis with 80% power, at 5% significance level, is 81 (in: 148 events). 
 
1.5 Total trial duration 
Patient accrual was expected to be completed within 3 years including a run-in-period of 3 
months. The total trial duration would be approximately 7.5 years including the 36 months 
recruitment period. Patients would be followed until death – thus follow-up was estimated to last 
up to 4.5 years following the enrolment of the last patient. 
The trial will end with the preparation of the final report, initially scheduled for 7.5 years after the 
inclusion of the first patient. However due to premature accrual closure the final report will be 
prepared earlier, expected approximately 4.5 years after the inclusion of the first patient. 
 
1.6 Previous protocol version (original protocol) 
STIMULI trial, original protocol v1.0, was activated in December 2013 and the first patient was 
enrolled on the 28th of July 2014. 
The low accrual rate experienced in the first few months of the STIMULI study, along with recently 
presented results showing significant benefits with Nivolumab treatment with or without 
Ipilimumab [Antonia S.J., JCO 2015; Larkin J., NEJM 2015; Postow M.A., NEJM 2015], led the 
protocol team to decide to procced to protocol amendment (AM1). The protocol amendment has 
been completed and distributed to the sites (21st of September 2015) for submission to the 
corresponding authorities. The first subject was enrolled under AM1 on the 18th of December 
2015.  
The main modifications introduced by the amendment were: 
• 
the addition of Nivolumab to consolidation therapy 


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• 
the addition of carboplatin to standard therapy as an alternative to cisplatin 
• 
addition of PFS as co-primary endpoint 
• 
the option of contrast enhanced CT of the brain as an alternative to MRI at screening 
• 
allowing one cycle of chemotherapy before enrolment of patient. 
 


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2 Statistical considerations for final analysis 
2.1 Analysis timing 
According to the modified statistical design, the final efficacy analysis will be performed when the 
81 required PFS events have been observed among all STIMULI patients randomized under AM1. 
 
2.2 Study’s endpoints 
2.2.1 Primary endpoint 
The primary endpoint of the analysis is PFS, defined as the time from the date of randomization 
until documented progression (based on RECIST 1.1 criteria) or death, if progression is not 
documented. Censoring (patients without progression/death) for PFS will occur at the last 
tumour assessment. In the frame of a sensitivity analysis, if the last tumour assessment is «Non 
evaluable», censoring will occur to the more recent tumour assessment where an overall 
evaluable result is recorded.  
2.2.2 Secondary endpoints  
Secondary endpoints include OS, ORR, TTF and adverse events (AEs) graded according to CTCAE 
v4.0. More specifically: 
– OS is defined as the time from the date of randomization until death from any cause. 
Censoring (patients without death) for OS will occur at the last follow-up date. 
– ORR is defined as the rate of best overall response (complete or partial response) 
according to RECIST 1.1 criteria across all assessment time-points, during the period from 
randomization to termination of trial treatment. Of note, the determination of ORR will be 
restricted to patients who have not attained a CR during chemo-radiotherapy. 
– TTF is defined as the time from the date of randomization to treatment failure for any 
reason (including progression of disease, treatment toxicity, refusal, lost to follow-up and 
death). Censoring for TTF (patients without failure) will occur at the last-follow-up date. 
– Toxicity, defined as adverse events classified according to CTCAE v4.0. 
2.2.3 Exploratory endpoints  
– TTD is defined as the time from the randomization to treatment discontinuation for any 
reason (including progression of disease, treatment toxicity, refusal, lost to follow-up and 
death). Censoring for TTD (patients on treatment or completed treatment), will occur at 
the last-follow-up date 


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– DoR is defined as the time from the documentation of tumour response (either partial or 
complete response) to disease progression or death. Censoring will occur at the last 
tumour assessment with response other than progression. 
2.2.4 (Serious) Adverse Events 
Adverse Events (AEs) 
The main criterion for treatment tolerability is the occurrence of toxicities and adverse events. 
The severity and causality will be classified according to the NCI CTCAE version 4 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
An adverse event is defined as any untoward medical occurrence that occurs from the day of 
enrolment in the Remote Data Entry (RDE) until 100 days after the final dose of IMP regardless of 
whether it is considered related to a medication. The relation of the adverse event with the 
administered trial treatment has to be indicated as: unrelated, unlikely, possible, probable or 
definite. In addition, any known untoward event that occurs subsequent to the adverse event 
reporting period that the investigator assesses as possibly related to the protocol treatment 
should be considered an adverse event.  
Immune-related Adverse Events (irAEs) 
The following adverse events are of special interest and must be documented after randomization 
in both treatment arms:  
CTCAE Version 4.0 system organ class / preferred terms:  
Nervous system disorders:  
- 
Peripheral motor neuropathy  
- 
Peripheral sensory neuropathy  
- 
Meningismus  
- 
Limbic Encephalitis  
- 
Nervous system disorders - Other, specify (Guillain-Barré, myasthenia gravis, aseptic or 
non-infectious meningitis)  
Skin and subcutaneous tissue disorders:  
- 
Stevens-Johnson syndrome  
- 
Toxic epidermal necrolysis  
- 
Bullous dermatitis  
- 
Rash acneiform  
- 
Rash maculo-papular  
- 
Pruritus  
- 
Skin and subcutaneous tissue disorders - Other, specify 
Gastrointestinal disorders: 
- 
Colitis 


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- 
Diarrhea 
- 
Colonic perforation 
- 
Small intestinal perforation 
- 
Gastric perforation 
- 
Gastrointestinal disorders - Other, specify 
Hepatobiliary disorders: 
- 
Hepatic failure 
- 
Hepatitis viral 
- 
Drug-induced liver injury (DILI) 
Investigations: 
- 
Alanine aminotransferase increased 
- 
Aspartate aminotransferase increased 
- 
Blood bilirubin increased 
Endocrine: 
- 
Adrenal insufficiency 
- 
Hypothyroidism 
- 
Endocrine disorders - Other, specify (hypopituitarism, hypophysitis) 
Respiratory, thoracic and mediastinal disorders: 
- 
Pneumonitis 
Renal and urinary disorders: 
- 
Renal and urinary disorders - Other, specify (nephritis) 
Eye disorders: 
- 
Uveitis 
- 
Eye disorders - Other, specify (iritis) 
Blood and lymphatic system disorders: 
- 
Blood and lymphatic system disorders- Other, specify (haemolytic anaemia) 
Cardiac disorders: 
- 
Myocarditis 
Serious Adverse Events (SAEs) 
An SAE is defined in general as any undesirable medical occurrence/adverse drug experience that 
occurs during or within 100 days after stopping study treatment that, at any dose, results in any 
of the following: 
- 
is fatal (any cause) 
- 
life-threatening, 
- 
requires or prolongs inpatient hospitalization, 
- 
results in persistent or significant disability/incapacity 
- 
is a congenital anomaly or birth defect 
- 
is a secondary malignancy 
- 
is a medically important event 
- 
overdose (although this event is not always serious by regulatory definition, overdose 
must be handled as SAE) 


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- 
pregnancy  
Second (non-SCLC) malignancies are always considered SAEs, no matter when they are diagnosed. 
Other significant/important medical events which may jeopardize the patient are also considered 
SAEs. Serious also includes any other event that the investigator or the ETOP Safety Office judges 
to be serious or which is defined as serious by the regulatory agency in the country in which the 
event occurred. 
Severity Grade 
The adverse event severity grade provides a qualitative assessment of the extent or intensity of 
an adverse event, as determined by the investigator or as reported by the patients. The severity 
grade does not reflect the clinical seriousness of the event, only the degree or extent of the affliction 
or occurrence (e.g. severe nausea, mild seizure), and does not reflect the relationship to study 
drug. 
Severity grade for other adverse events not covered in the toxicity grading scale: 
Grade 1 
Mild- transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
Grade 2 
Moderate- mild to tolerate limitation in activity; some assistance may be 
needed; no or minimal medical intervention/therapy required 
Grade 3 
Severe- marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible 
Grade 4 
Life-threatening- extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice 
care probable 
Grade 5 
Fatal- the event results in death 
 
2.3  Analysis population 
Efficacy cohort: The efficacy cohort is the Intention-to-treat (ITT) population of the trial and 
includes all randomized subjects under protocol AM1. Patients will be evaluated in the treatment 
arms to which they were randomly assigned, regardless of the treatment actually received, 
including patients who were randomized but did not receive any trial treatment.   
Safety cohort: The safety cohort consists of all subjects who have received at least one dose of 
IMP treatment plus all patients randomized to observation arm (under protocol AM1). 


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Patients will be evaluated according to the treatment they actually received, irrespective of their 
allocated treatment at randomization. 
Per-Protocol cohort: Per-protocol cohort includes all patients enrolled under protocol AM1.  
Per-Protocol safety cohort: Per-protocol safety cohort includes all patients enrolled under 
protocol AM1, who received at least one dose of chemo-radiotherapy after enrollment.  
 


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3 Primary efficacy analysis of PFS 
Primary efficacy analysis of PFS (primary endpoint) will be performed on all randomized 
patients under AM1 protocol, based on their initial treatment assignment (ITT, efficacy 
cohort). PFS time is measured from time of randomization. 
Formal hypothesis testing 
Based on the protocol AM1 and after the modifications arose from the premature study accrual 
termination, the trial  is designed to test the hypotheses that treatment with chemoradiotherapy 
and PCI followed by consolidation treatment (nivolumab plus ipilimumab) will lead to an increase 
in median PFS to 22.8 months, from 13.1 months under treatment with chemoradiotherapy and 
PCI without consolidation treatment. According to the study design, this corresponds to a PFS 
HR of 0.57. Using 80% power and a one-sided type I error of 5%, a total of 81 PFS events are 
needed to observed in order to achieve the trial goal. 
In the frame of final efficacy analysis, the formal comparison of the PFS between the two 
treatment arms, will be based on stratified log-rank test (with number of fractions of 
radiotherapy [1/2] and administration of FDG-PET-CT [Yes/No] being the stratification factors). 
Unstratified log-rank test will be also calculated. This would be of particular value in case at least 
one stratum level has very low number of patients.  
Further PFS analyses 
The following PFS analyses will also be performed and presented 
- 
The total number (%) of PFS events observed, overall and by treatment arm will be 
presented. In addition, 6-month and 1/2-year PFS estimates, median PFS and respective 
95% CI will be provided. Respective results by stratifications factors will be also 
presented. 
- 
Kaplan-Meier plots by treatment arm as well as by treatment arm within each 
stratification factor will be created. 
- 
Number of PFS events, median PFS and unstratified/unadjusted HRs (along with 95% CI) 
will be summarized for the subgroups defined by the following clinicopathological 
variables of interest: gender, smoking history, ECOG performance status at randomization, 
stage of tumour, age (appropriately categorized) and biological markers (if available). This 
information will be depicted in a tabular format in the report (a corresponding forest plot 
will be subsequently produced for presentation/publication). 


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- 
To assess the effect of trial treatment and other clinicopathological variables on PFS, Cox 
proportional hazard models will be fitted.  
o Initially a univariate (stratified and unstratified) Cox model will be fitted in the 
model and the statistical significance of trial treatment will be tested at the 5% 
significance level. 
o Subsequently, multivariate Cox models (stratified and unstratified) will be 
estimated, adjusted for the clinicopathological variables of interest as defined 
above (in case of unstratified model, the stratification factors will be also included 
in the covariates of the model). The backward elimination method, with a removal 
criterion at 10% will be used to conclude on the statistically significant variables 
of the model. The HRs along with the corresponding 95% CIs for all significant 
predictors (in the multivariate Cox model) will be summarized in a tabular format 
in the report (a corresponding forest plot will be subsequently produced for 
presentation/publication).  
o The proportionality assumption of Cox model will be explored by Schoenfeld’s 
residuals and by testing for time-dependent effect of covariates in extended Cox 
models. In cases that non-proportionality is detected further appropriate measures 
will be used 
▪ 
Use of variable(s), for which proportionality assumption is violated, as 
stratification factor(s) 
▪ 
Use of weighted tests, alternatives to log-rank for the comparison of 
survivals, such as the Wilcoxon test 
▪ 
Estimation of Restricted Mean Survival Time (RMST) at specific time points 
(close to median follow and covering the full follow-up time for the majority 
of patients) 
▪ 
Calculation of HR for separate time intervals 
 
 
 


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4 Additional secondary analysis 
In this section, we present in detail the additional analysis that will be performed in the frame of 
final efficacy analysis for STIMULI trial. 
4.1 Patient accrual, balance of stratifications factors & baseline characteristics 
- 
A consort diagram will be created to graphically depict the flow of patients and the phases of 
the trial.  
- 
Patient accrual by center and country will be presented in tabular format (including enrolled, 
randomized and ineligible patients) 
- 
For patients deemed ineligible a table summarizing the reasons for non-enrolment will be 
provided1  
- 
Observed vs. expected accrual over time will be graphically displayed. 
- 
Balance of treatment allocation by center and by stratification factors will be summarized 
- 
Patient and tumour baseline characteristics at enrolment (categorical: gender, smoking 
history, ECOG performance status at diagnosis, stage (based on 7th TNM classification), TNM 
stage and continuous: age at enrolment), will be presented for the full cohort of enrolled 
patients. The same characteristics will be presented for the cohort of randomized patients 
overall and separately by treatment arm. Note that the ECOG PS reported for the randomized 
patients is the PS recorded just before the randomization. Frequencies and corresponding 
percentages will be presented for categorical variables (if missing cases exist, a separate 
category named “Missing” will be created.), while the following descriptive measures will be 
considered for the continuous ones: n (non-missing sample size), mean, 95% CI for the mean, 
median, maximum and minimum values.  Balance of baseline characteristics (at 
randomization) by treatment arm will be assessed via the Fisher’s exact test for categorical 
variables and the Mann-Whitney U test for continuous.  
- 
Available information on medical history will be summarised, by treatment arm. 
4.2  Follow-up information and Treatment administration 
Follow-up time of the patients will be presented as: 
- 
Median follow-up (FU) of the randomized patients (overall and by treatment arm) along 
with the respective interquartile range (IQR) and the number (%) of patients that are still 
on FU.  
 
1 Note: This table includes the number of patients registered in the database and characterized as ineligible, but this 
does not represent the full set of screened patients since, it is not mandatory by the protocol to enter in the 
database all screened patients, even if not eligible. 


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- 
A Kaplan-Meier (K-M) plot will be provided for a graphical representation of follow-up 
time, overall and by treatment arm. 
Treatment information will be summarized first for the chemo-radiotherapy phase and then for 
the randomization phase overall and separately by treatment arm. More specifically the following 
information will be presented: 
- 
No. of patients enrolled (under protocol AM1) 
- 
No. of patients stopped the trial before starting any treatment 
- 
No. of patients started chemo-radiotherapy treatment 
- 
No. of treatment failures during chemo-radiotherapy treatment (including failure reasons) 
- 
No. of patients completed chemo-radiotherapy phase 
- 
No. of patients not completed PCI for specific reasons 
- 
No. of patients received (and completed) PCI after chemo-radio therapy phase 
- 
No. of unrandomizable patients  
- 
No. of randomized patients (by arm) 
- 
No. of patients that started treatment with the IMP 
- 
No. of patients that completed treatment 
- 
No. and reasons of treatment failures during randomization phase (by arm) 
- 
No. of patients that completed treatment and they experienced a failure afterwards.  
- 
6-month, 1/2-year TTF rate (%) and median TTF estimates, along with corresponding 
95%CI and log-rank test p-value for comparison of the two treatment arms 
- 
A Kaplan Meier curve for TTF by treatment arm 
- 
For those patients who progressed, information on further lines of treatment (if available) 
will be provided by treatment arm. 
 
4.3 
Secondary (efficacy) and exploratory endpoints 
4.3.1 Overall survival  
Similar to PFS the following will be presented for OS: 
- 
Total number (%) of OS events, overall and by treatment arm (as well as by stratification 
factor) 
- 
1-year/2-year OS estimates, median and respective 95% CIs (comparison between 
treatment arms based on stratified and unstratified log-rank).  
- 
Kaplan- Meier plot by treatment arm  


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- 
Subgroup analysis (number of events, median time and unstratified/unadjusted HRs 
(along with 95% CIs) and variables of interest) 
- 
Univariate and multivariate Cox proportional hazards model, adjusted for the 
stratification factors and clinicopathological variables of interest; HRs and corresponding 
95% CIs for all significant predictors will be presented in a table. 
- 
Summary table of the death causes overall and by treatment arm (e.g., lung cancer, toxicity, 
other, etc) 
4.3.2 Time to treatment discontinuation 
- 
Total number (%) of TTD events, overall and by treatment arm 
- 
6-month and 1/2-year TTD estimates, median and respective 95% CIs (comparison 
between the arms based on stratified log-rank).  
- 
Kaplan- Meier plot by treatment arm  
- 
Summary table of the reason of (permanent) treatment discontinuations overall and by 
treatment arm (e.g., lung cancer, toxicity, other, etc) 
4.3.3 Objective response rate 
- 
Overall best responses and objective response rate (ORR) will be presented overall and 
separately for the two treatment arms, along with a 95% exact binomial CI.  ORR will be 
compared between the two treatment groups using Fisher’s exact test and Cochran-
Mantel-Haenszel test stratified by the stratification factors of the trial. 
- 
Logistic regression models will be further applied to investigate the treatment effect on 
ORR, adjusting for stratification factors and variables of clinical interest. 
- 
Note: ORR will be calculated based on the randomized patients who have not attained 
complete response during chemo-radio therapy.  
4.3.4 Graphical illustration of tumour responses 
- 
A waterfall plot will be created by treatment arm to present the best percentage change in 
tumour size from the baseline tumour assessment before randomization (sum of target 
lesions diameters).   
- 
The percentage changes in tumour size from the baseline tumour assessment before 
randomization (sum of target lesions diameters) over the time will be depicted graphically 
by a spider plot 


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4.3.5 Duration of response  
- 
Median DOR, along with 95% CI will be presented, for all responders and separately for 
the two treatment groups.  
- 
Duration of response will be compared between the two treatment arms using the log-
rank testing and graphically illustrated by Kaplan-Meier curves. 
- 
Graphical representation of duration of response will be also performed via swimmer plot. 
 
4.4 Subgroup analysis 
To determine whether the treatment effect is consistent across various subgroups the between-
group treatment effect for the primary and secondary efficacy endpoints will be estimated within 
each category of the following pre-specified variables. 
Main subgroup analyses:  
- 
Number of radiotherapy fractions per day (once or twice per day) 
- 
Tumour stage (I/II/III by 7th TNM classification) 
- 
Gender 
Other pre-planned subgroup analyses: 
- 
Age group 
- 
ECOG performance status (at randomization) 
- 
Smoking history 
- 
Status according to biological markers (if available) 
Notes: 
1. In case of imbalance in number of patients with the subgroups created by treatment and 
the variables of interest, this subgroup analysis will not count in the multiple comparison 
adjustment.  
2. These analyses are also described above in the description of PFS, OS analyses. 
 
4.5 Sensitivity analysis 
In a sensitivity analysis framework, PFS, OS and TTF (efficacy cohort) will be evaluated having as 
start date the date of enrolment. In case of patients enrolled after their first chemotherapy cycle, 
further adjustment will be made to the start date (start date will be the date of 2nd chemotherapy 
cycle minus 21 days).  
 


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4.6 Descriptive analysis of the per-protocol cohort 
For all patients enrolled under protocol AM1, irrespective of whether they were subsequently 
randomized or not, the following will be presented: 
• 
Objective response to chemo-radiotherapy based on the tumour assessment performed 
before randomization. 
• 
All reasons for non-randomization (included in section 4.2). 
• 
OS analysis (KM plot, median OS, 1 and 2-year rates with 95% CIs) with start date the 
enrolment date, further adjusted for patients enrolled after the first chemotherapy cycle. 
 
4.7  Safety analysis 
The safety analysis will be based on the safety cohort, i.e.., all patients who have received at 
least 1 dose of IMP treatment (experimental arm) plus all patients randomized to observation 
arm, and will include the following: 
- 
Overview of the number of patients who experienced an AE and/or a SAE, as well as 
the number of patients in the safety cohort who did not experience an event, along with 
respective percentages will be shown. This information will be presented overall and by 
treatment arm. Also, number of patients that entered the study with baseline symptoms 
will be reported. 
- 
Number of AEs/SAEs will be presented overall and by treatment arm.  
- 
Number of patients experiencing a specific number of AEs/SAEs, overall and by treatment 
arm. 
- 
Distribution of (S)AEs by grade and CTCAE category, separately for the two treatment 
arms. Six columns, one for each grade and one for all (any) grades, will be shown (for each 
arm). An additional column (by arm) indicating which events were also SAEs will be also 
available. In this column, the frequency of the SAEs and the severity grade will be given. 
The percentages that will accompany the frequencies will be based on the respective 
frequency of an event over the total number of patients in the safety cohort and specific 
treatment arm. This table will include all (S)AEs irrespective of their relation to the trial 
treatment. 
- 
Analogous table focusing only on the treatment related (S)AEs. 
- 
Number and corresponding percentages of treatment related (S)AEs by grade, leading 
either to treatment discontinuation or death will be summarized for the two treatment 
arms.  


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- 
Maximum severity of adverse events (AE/SAE) for patients, overall and by treatment arm.  
- 
Number of SAEs by center 
- 
Detailed information of pulmonary AEs/SAEs of grade ≥3 will be summarized for the two 
treatment arms.  
- 
The risk difference between the two treatment arms, along with corresponding 95% 
CIs for specific adverse evets (most frequent i.e. ≥15%, of any grade, or perhaps focus 
on grade ≥3, irrespective of relation to treatment or treatment-related).  
Analogous (more concise) information will be reported for the adverse events during the 
chemo-radiotherapy phase of all enrolled patients who received at least one dose of chemo-
radiotherapy (per-protocol safety cohort). 
 
  
 
 
 
 
 
 


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5 Technical details 
Data will be primarily analysed using the SAS software package (version 9.4), while the R 
statistical software will be also used for specific analysis and plots.  
All analysis and reviews will be performed according to the Standard Operating Procedures 
(SOPs) of FSFH statistical team for the final analysis. A second statistician, the reviewing 
statistician, will independently reproduce all analysis and summary statistics. The reviewing 
statistician will have an overview of the entire analysis and will explicitly check the code 
producing tables and figures, as well as any other pieces of code as desired. 
 
Data retrieval information 
The final analysis will be based on the database download, that will take place, as soon as the total 
number of 81 PFS events required according to the statistical design of the trial are observed. 
Using this database extraction, a set of queries will be produced and forwarded to trial’s data 
manager with the expectation to be answered in a pre-specified time period (approximately four 
weeks). Corrections and responses based on these queries, will be used for correcting the 
previously downloaded database, in order to create the final clean dataset to be used for the 
analysis. 
 
Missing data 
- 
Baseline characteristics 
For categorical baseline characteristics if missing cases exist, a separate category named “Missing” 
will be created. As far as continuous values, missing cases will not be replaced by any statistics 
calculated over non-missing data. 
- 
Dates: 
If the day of the month is missing for any date used in the analysis, the 15th of the month will be 
used to replace the missing date unless the calculation results in a negative time duration (eg, date 
of onset cannot be prior to day one date). In this case, the date resulting in one day of duration 
will be used. If the day of the month and the month are missing for any date used in a calculation, 
i.e., January 1 will be used to replace the missing date. Missing dates for adverse events will be 
imputed based on the similar principle. 


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- 
Incomplete tumour assessment information 
In patients who have no on-study assessments: 
o If death is recorded prior to the first planned tumour assessment, the death date will be 
considered as the date of the PFS event. 
o If clinical progression is recorded prior to the first planned tumour assessment, the date 
of the reported clinical progression will be considered as the date of the PFS event. 
o In all other cases, the patient will be censored at the date of randomization plus 1 day. 
 
Reporting conventions 
Regarding the estimates presented in the report, the following rules will be adopted: 
- 
P-values ≥0.001 will be reported with three decimal places  
- 
P-values >0.010 will be reported with two significant demical digits 
- 
P-values less than 0.001 will be reported as “<0.001” 
- 
Means, medians, 95% confidence limits (Cis), quantiles, and any other summary statistics, 
will be reported with one decimal digit 
- 
Hazard ratios (HRs) and their 95% CI’s will be reported to two decimals 
- 
Estimated parameters, not on the same scale as raw observations (e.g. regression 
coefficients) will be reported to three significant figures. 
 
Multiple recordings of an event for the same patient 
There are some cases where a patient may experience the same event (AE/SAE) more than once. 
In such cases, the event will be counted only once for the calculation of the total number of events 
reported for the overall safety cohort.  
 
Presentation of results 
The results will be presented through tables and figures. A summary of the results will also 
accompany the main report. First, a short synopsis of the results will be presented through bullets, 
where only the most important findings will be shown. Following that, a more detailed description 
of the results will be provided, sectioned in the following order: 
• 
Patient accrual and baseline characteristics  
• 
Follow-up and Treatment administration  


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• 
Efficacy analysis 
• 
Safety analysis  
All tables and figures will be included in an appendix.