Conditions: Pleural Mesothelioma Malignant Advanced
Keywords: MPM
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 144
Healthy volunteers: no

Brief summary:
Trial comparing standard treatment (chemotherapy) with pembrolizumab treatment in patients with advanced pretreated malignant mesothelioma.

Detailed description:
Mesothelioma is an aggressive malignancy usually affecting the surfaces of body coelomic cavities. It most commonly originates from the pleura with a propensity to the lower parietal pleura and costo-diaphragmatic recess, and is almost always caused by asbestos exposure, with a usual lag time of 30 years between exposure and presentation. Outcomes for most patients are invariably fatal, with median survival from presentation around 9-12 months in most series due to difficulties in achieving a complete microscopic surgical resection and tumour relative chemo-refractoriness. Whilst initially considered rare, due to the demand of asbestos of all varieties associated with industrialization following the Second World War, the background incidence of mesothelioma of 1/million has risen to 40/million in some countries. In the UK, where substantial asbestos exposure continued until the 1970s, the death rate is the highest in the world with a current epidemic of new cases, predicted to continue for another 5-10 years. Two main histological subtypes of mesothelioma are identified. The epitheliod subtype is the commonest, accounting for around 40% of cases, whilst the sarcomatoid subtype is observed in 20% of cases; the latter being typically aggressive and chemorefractory. Around 35% cases have features of both epitheliod and sarcomatoid subtypes and are termed biphasic subtype.

For patients with pleural mesothelioma, in whom surgery is not considered appropriate, systemic chemotherapy (platinum combined with pemetrexed) remains the international standard of care. Cisplatin/pemetrexed is associated with a response rate of 41% and confers an OS advantage of 3 months over cisplatin alone, and is the only licensed systemic therapy for mesothelioma in Europe. Despite this, the median survival is 9-12 months from most series in unresectable cases. At relapse, after platinum-based chemotherapy, no anti-cancer systemic therapies are licensed. Whilst several small phase II studies and retrospective series have suggested potential efficacy for chemotherapy with agents including carboplatin/gemcitabine, or vinorelbine, none thus far have demonstrated efficacy benefit in a randomised study, with median PFS rates reported of about 3 months for both gemcitabine and vinorelbine. There is therefore a huge unmet need for effective therapy for patients with relapsed pleural mesothelioma. The largest trial ever performed of systemic therapy in relapsed pleural mesothelioma in 661 patients documented the natural outcome of this group of relapsed mesothelioma patients, reporting a median OS of 27.1 weeks (6 months) and median PFS for 6.1 weeks (1.5 months) for placebo.

Programmed cell death-1 (PD-1) is a co-inhibitory molecule at the immunological synapse that acts as a major regulator of adaptive immunity, and is exploited by tumour cells to result in adaptive immune resistance (tolerance). This occurs when PD-1 binds to the ligands PD-L1 (B7H1) or PD-L2, which are expressed on many tumour types. High PD-L1 expression on tumours is associated with poorer outcomes. Mesothelioma has been shown to express PD-L1, with a small study identifying PDL1 expression in up to 40% of mesotheliomas. Moreover, immunologically-mediated inflammation is known to be a key driver for mesothelioma development via the Nalp3 imflammasome.

Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

There is a need to identify new ways for the systemic therapy of malignant mesothelioma and immune checkpoint inhibition is a promising way forward. Results from the proposed trial will contribute to overcoming tumour-specific immune suppression with immune checkpoint inhibition.

Arms:
arm 1: Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment. arm 2: Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated.

Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.

Interventions: intervention 1: Pembrolizumab intervention 2: Gemcitabine intervention 3: Vinorelbine
Intervention descriptions: intervention 1: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection. intervention 2: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the "faulty" nucleoside, resulting in apoptosis (cellular "suicide"). intervention 3: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.

Protocol document:
Prot_000.pdf: 
ETOP 9-15 PROMISE-meso v1.0 20161031 
 
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ETOP 9-15 PROMISE-meso 
 
 
A multicentre randomised phase III trial comparing pembrolizumab 
versus standard chemotherapy for advanced pre-treated malignant 
pleural mesothelioma 
 
 
PROMISE-meso: PembROlizuMab Immunotherapy versus Standard 
chemotherapy for advanced prE-treated malignant pleural mesothelioma 
 
Sponsor: European Thoracic Oncology Platform (ETOP) 
 
 
EudraCT number: 2016-002062-31 
 
Merck Sharp & Dohme number: 3475-594 
 
 
ETOP c/o IBCSG Coordinating Centre, Effingerstrasse 40, CH- 3008 Bern 
Phone: +41 31 511 94 00 
Fax: +41 31 511 94 01 
 
 
Version 1.0 
 
 
 


ETOP 9-15 PROMISE-meso v1.0 20161031 
 
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Contacts 
 
Trial 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 Chair 
Alessandra Curioni-
Fontecedro, MD 
Address 
 
 
Tel:  
Fax: 
Email: 
Clinic of Oncology 
University Hospital Zuerich  
CH-8044 Zürich, Switzerland  
+41 44 255 22 14 
 
Alessandra.Curioni@usz.ch 
Trial Co-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 07 37 
solange.peters@etop-eu.org 
ETOP Chairman 
Rolf Stahel, MD 
Address 
 
 
 
Tel: 
Fax: 
Email:  
Clinic of Oncology 
University Hospital Zuerich  
Raemistrasse 91 
CH-8091 Zürich, Switzerland  
+41 44 255 22 19 
+41 44 255 97 80 
rolf.stahel@usz.ch 
Translational Research 
Coordinator 
Rosita Kammler 
Address 
 
 
 
Tel:  
Fax: 
Email:  
ETOP Coordinating Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 28 
+41 31 511 94 01 
rosita.kammler@ibcsg.org 
Central Laboratory 
 
 
CHUV - Department of oncology 
Center for Experimental Therapeutics (CTE) 
Hôpital Orthopédique 
HO 05/1552 
Av. Pierre-Decker 4 
CH-1011 Lausanne, Switzerland 
Statistics 
Urania Dafni, ScD 
 
 
 
 
 
Varvara 
Polydoropoulou 
Address 
 
 
Tel:  
Fax: 
Email: 
Email: 
Frontier Science Foundation – Hellas 
116 Papadiamantopoulou Str. 
15773, Zografou, Athens, Greece 
+30 2107710902 
+30 2107710903 
udafni@frontier-science.gr 
vpolydoropoulou@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 31 511 94 34 
+41 31 511 94 01 
PROMISE-meso@etop-eu.org 
+41 31 511 94 21 
ETOPDataManagement@etop-eu.org 


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Drug supply 
Barbara Ruepp, 
PharmD 
Address 
 
 
 
Tel:  
Fax: 
Email:  
ETOP Drug Supply Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 16 
+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 31 511 94 16 
+41 31 389 92 29 
regulatoryoffice@etop-eu.org 
ETOP Medical Affairs 
 
 
 
 
 
Manuela Rabaglio, 
MD 
Address 
 
 
 
Tel. 
Fax : 
Email : 
ETOP Medical Affairs 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 20 
+41 31 511 94 01 
medical.affairs@ibcsg.org 
ETOP Coordinating 
Office 
Anita Hiltbrunner 
 
 
 
 
 
Heidi Roschitzki, 
PhD 
 
Address 
 
 
Tel:  
Fax: 
Email: 
Tel:  
Fax: 
Email: 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 42 
+41 31 511 94 01 
anita.hiltbrunner@etop-eu.org 
+41 31 511 94 18 
+41 31 511 94 01 
heidi.roschitzki@etop-eu.org 
Electronic data capture 
(EDC) system  
Anne-Christine 
Piguet, PhD 
Technical assistance 
Email: 
 
Email: 
ETOPDataManagement@etop-eu.org 
 
richard.king@etop-eu.org 
 
In collaboration with Merck Sharp & Dohme Corp.  
 
 
 




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Principal Investigator Protocol Signature Page 
 
A multicentre randomised phase III trial comparing pembrolizumab 
versus standard chemotherapy for advanced pre-treated malignant 
pleural mesothelioma 
 
ETOP 9-15 PROMISE-meso 
 
I have read the 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 
furnished 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 information collected during the trial for a minimum period of 15 years. 
 
 
Name of Principal Investigator:  
 
 
 
Institution’s name and place: 
 
 
 
 
 
 
 
 
 
Signature 
Date 
 
 
 


ETOP 9-15 PROMISE-meso v1.0 20161031 
 
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TABLE OF CONTENTS  
Section 
Page 
1. 
Protocol summary ...................................................................................................... 9 
2. 
Trial schedule ........................................................................................................... 14 
3. 
List of abbreviations ................................................................................................ 17 
4. 
Background and rationale ........................................................................................ 20 
4.1. 
Disease background ............................................................................................. 20 
4.2. 
Treatment background ......................................................................................... 21 
4.3. 
Background pembrolizumab ................................................................................ 21 
4.4. 
Choice of design and comparator ........................................................................ 23 
4.5. 
Overall risk/benefit assessment ........................................................................... 23 
4.6. 
Rationale for performing the trial ........................................................................ 23 
5. 
Objectives and endpoints ......................................................................................... 24 
5.1. 
Primary objective ................................................................................................. 24 
5.2. 
Secondary objectives ........................................................................................... 24 
5.3. 
Primary endpoint ................................................................................................. 24 
5.4. 
Secondary endpoints ............................................................................................ 24 
5.5. 
Correlative endpoints ........................................................................................... 24 
6. 
Trial design, duration and termination ..................................................................... 25 
6.1. 
Trial design .......................................................................................................... 25 
6.2. 
Sample size and trial duration ............................................................................. 25 
7. 
Patient selection ....................................................................................................... 26 
7.1. 
Inclusion criteria .................................................................................................. 26 
7.2. 
Exclusion criteria ................................................................................................. 27 
8. 
Patient screening and randomisation ....................................................................... 28 
8.1. 
Screening ............................................................................................................. 28 
8.2. 
Randomisation and stratification ......................................................................... 29 
9. 
Investigational medicinal product ............................................................................ 29 
9.1. 
Pembrolizumab .................................................................................................... 29 
9.2. 
Formulation ......................................................................................................... 29 
9.3. 
Packaging and labeling ........................................................................................ 29 
9.4. 
Clinical supplies disclosure ................................................................................. 29 
9.5. 
Storage and handling ........................................................................................... 30 
10. 
Trial treatments ........................................................................................................ 30 
10.1. 
Overview of trial treatment.................................................................................. 30 
10.2. 
Treatment in the experimental arm ...................................................................... 31 
10.3. 
Treatment in the control arm ............................................................................... 40 
10.4. 
Treatment of pleural effusion .............................................................................. 41 
10.5. 
Prohibited and restricted concomitant therapies during trial treatment 
(pembrolizumab, vinorelbine or gemcitabine) .................................................... 42 
10.6. 
Contraception, nursing, pregnancy ...................................................................... 42 
11. 
Safety of trial treatments .......................................................................................... 43 
11.1. 
Adverse effects of pembrolizumab ...................................................................... 43 
11.2. 
Immune-related adverse effects of pembrolizumab ............................................ 44 
11.3. 
Adverse effects of chemotherapy in the control arm ........................................... 44 
12. 
Adverse event and serious adverse event reporting ................................................. 45 
12.1. 
Adverse event (AE) ............................................................................................. 45 
12.2. 
Adverse reaction (AR) ......................................................................................... 45 


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12.3. 
Unexpected adverse reaction (UAR) ................................................................... 45 
12.4. 
Serious adverse events (SAE) .............................................................................. 45 
12.5. 
Serious adverse reaction (SAR) ........................................................................... 48 
12.6. 
Suspected unexpected serious adverse reaction (SUSAR) .................................. 48 
12.7. 
Severity / intensity of (serious) adverse events ................................................... 48 
12.8. 
Causality of adverse events ................................................................................. 49 
12.9. 
Duration of adverse events .................................................................................. 49 
12.10. Action taken ......................................................................................................... 49 
12.11. Reporting SAEs and ECIs ................................................................................... 49 
12.12. Pregnancy ............................................................................................................ 50 
12.13. Reference safety information............................................................................... 51 
13. 
Response evaluation ................................................................................................ 52 
13.1. 
CT schedule for response evaluation ................................................................... 52 
13.2. 
Response evaluation criteria in solid tumours (RECIST version 1.1) ................. 52 
14. 
Endpoints definition ................................................................................................. 58 
14.1. 
Progression-free survival ..................................................................................... 58 
14.2. 
Objective response ............................................................................................... 58 
14.3. 
Overall survival ................................................................................................... 58 
14.4. 
Time to treatment failure ..................................................................................... 58 
14.5. 
Toxicity ................................................................................................................ 58 
15. 
Biological material and translational research ......................................................... 58 
15.1. 
Biobanking........................................................................................................... 58 
15.2. 
Mandatory biomaterial ........................................................................................ 59 
15.3. 
Optional biomaterial ............................................................................................ 60 
15.4. 
Translational research .......................................................................................... 60 
15.5. 
Submission of biomaterial ................................................................................... 61 
16. 
Trial procedures ....................................................................................................... 62 
16.1. 
Tumour assessment.............................................................................................. 62 
16.2. 
Baseline evaluations before randomisation ......................................................... 62 
16.3. 
Evaluations in the experimental arm (pembrolizumab treatment) ...................... 63 
16.4. 
Evaluations in the control arm (chemotherapy treatment) .................................. 65 
16.5. 
Evaluations at disease progression ...................................................................... 65 
16.6. 
Evaluations after cross-over to pembrolizumab treatment .................................. 66 
16.7. 
Evaluations at the end of treatment visit ............................................................. 67 
16.8. 
Evaluations in the follow-up phase (post treatment) before progression ............ 68 
16.9. 
Evaluations in the follow-up phase (post treatment) beyond progression ........... 68 
17. 
Case report forms and documentation ..................................................................... 69 
17.1. 
Case report forms schedule .................................................................................. 69 
18. 
Statistical considerations ......................................................................................... 71 
18.1. 
Primary objective ................................................................................................. 71 
18.2. 
Sample size determination ................................................................................... 71 
18.3. 
Trial duration ....................................................................................................... 71 
18.4. 
Analysis populations............................................................................................ 71 
18.5. 
Evaluation of primary and secondary objectives ................................................. 72 
18.6. 
Early safety evaluation ........................................................................................ 72 
19. 
Criteria for termination of the trial .......................................................................... 72 
19.1. 
General criteria for termination of the trial ......................................................... 72 
19.2. 
Discontinuation of protocol treatment for individual patients ............................. 73 
19.3. 
Withdrawal of consent ......................................................................................... 73 
20. 
Ethics aspects, regulatory approval, and patient informed consent ......................... 73 


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20.1. 
Ethical Review Board/Ethics Committee ............................................................ 74 
20.2. 
Regulatory approval procedures .......................................................................... 74 
20.3. 
Informed consent ................................................................................................. 74 
21. 
Governance and administrative issues ..................................................................... 75 
21.1. 
Final report .......................................................................................................... 75 
21.2. 
Steering Committee ............................................................................................. 75 
21.3. 
Independent Data Monitoring Committee ........................................................... 75 
21.4. 
Publication ........................................................................................................... 76 
21.5. 
Clinical trial insurance ......................................................................................... 76 
21.6. 
Quality assurance ................................................................................................. 76 
21.7. 
Protocol adherence .............................................................................................. 76 
21.8. 
Data protection .................................................................................................... 76 
21.9. 
Record retention .................................................................................................. 77 
22. 
References ................................................................................................................ 78 
 
Appendices: 
1. Template for patient information and informed consent form  
2. ETOP publication guidelines 
 
Index of tables 
Table 1 Vinorelbine-based chemotherapy as second and beyond line therapy in MPM ....... 21 
Table 2 Overview of trial treatments ..................................................................................... 30 
Table 3 Pembrolizumab infusion reaction treatment guidelines............................................ 32 
Table 4 Treatment delay and supportive care guidelines for pembrolizumab-related adverse 
events ..................................................................................................................................... 35 
Table 5 Chemotherapy options .............................................................................................. 41 
Table 6: Measurable disease - overall response ..................................................................... 57 
Table 7: Non-measurable Disease - Overall Response .......................................................... 57 
Table 8: Overview of translational research studies .............................................................. 60 
Table 9 Case report forms ...................................................................................................... 69 
 
 
 


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1. 
Protocol summary  
 
ETOP 9-15 PROMISE-meso 
 
A multicentre randomised phase III trial comparing pembrolizumab 
versus standard chemotherapy for advanced pre-treated malignant 
pleural mesothelioma 
 
PROMISE-meso: PembROlizuMab Immunotherapy versus Standard 
chemotherapy for advanced prE-treated malignant pleural MESOthelioma 
 
Sponsor:  
European Thoracic Oncology Platform (ETOP) 
Pharma Partner: Merck Sharp & Dohme Corp 
Population:  
Advanced Malignant Pleural Mesothelioma 
 
Design: 
Randomised phase III multicentre clinical trial to demonstrate superiority of pembrolizumab 
versus standard, institutional-choice chemotherapy (gemcitabine or vinorelbine). Patients 
randomised to chemotherapy will be allowed to cross over to receive pembrolizumab at 
progression. 
 
Sample size: 
142 randomised patients 
Randomisation:  
stratified by predominantly epitheloid vs non-epitheloid histological 
subtype 
 
Malignant pleural mesothelioma
after/on previous platinum based 
chemotherapy 
1 : 1
R
Pembrolizumab 200mg fixed dose i.v. day 1 of each 3-week cycle 
Chemotherapy by institutional choice
Gemcitabine 1000 mg/m2 d1/d8, q3w i.v. or
Vinorelbine
30 mg/m2
d1/d8, q3w i.v. or
Vinorelbine
60/80 mg/m2 d1/d8 q3w p.o.

CT
CT
3
Week
6
9
18
27
0
-4
39

until PD by RECIST 1.1
for max 2 years*
Blood
FFPE
Blood
Blood
CT
CT
CT
CT
Progression 
of 
disease
(FFPE)
Progression 
of 
disease

* continuation beyond PD in 
case of clinical benefit


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Rationale: 
Mesothelioma is an aggressive malignancy usually affecting the surfaces of body coelomic 
cavities. It most commonly originates from the pleura with a propensity to the lower parietal 
pleura and costo-diaphragmatic recess, and is almost always caused by asbestos exposure, 
with a usual lag time of 30 years between exposure and presentation. Outcomes for most 
patients are invariably fatal, with median survival from presentation around 9-12 months in 
most series due to difficulties in achieving a complete microscopic surgical resection and 
tumour relative chemo-refractoriness. Whilst initially considered rare, due to the demand of 
asbestos of all varieties associated with industrialization following the Second World War, 
the background incidence of mesothelioma of 1/million has risen to 40/million in some 
countries. In the UK, where substantial asbestos exposure continued until the 1970s, the 
death rate is the highest in the world with a current epidemic of new cases, predicted to 
continue for another 5-10 years. Two main histological subtypes of mesothelioma are 
identified. The epitheliod subtype is the commonest, accounting for around 40% of cases, 
whilst the sarcomatoid subtype is observed in 20% of cases; the latter being typically 
aggressive and chemorefractory. Around 35% cases have features of both epitheliod and 
sarcomatoid subtypes and are termed biphasic subtype.  
For patients with pleural mesothelioma, in whom surgery is not considered appropriate, 
systemic chemotherapy (platinum combined with pemetrexed) remains the international 
standard of care. Cisplatin/pemetrexed is associated with a response rate of 41% and confers 
an OS advantage of 3 months over cisplatin alone, and is the only licensed systemic therapy 
for mesothelioma in Europe. Despite this, the median survival is 9-12 months from most 
series in unresectable cases. At relapse, after platinum-based chemotherapy, no anti-cancer 
systemic therapies are licensed. Whilst several small phase II studies and retrospective 
series have suggested potential efficacy for chemotherapy with agents including 
carboplatin/gemcitabine, or vinorelbine, none thus far have demonstrated efficacy benefit in 
a randomised study, with median PFS rates reported of about 3 months for both gemcitabine 
and vinorelbine. There is therefore a huge unmet need for effective therapy for patients with 
relapsed pleural mesothelioma. The largest trial ever performed of systemic therapy in 
relapsed pleural mesothelioma in 661 patients documented the natural outcome of this group 
of relapsed mesothelioma patients, reporting a median OS of 27.1 weeks (6 months) and 
median PFS for 6.1 weeks (1.5 months) for placebo. 
Tremelimumab, a CTLA4-directed therapy, has shown some efficacy in two small single-
arm phase II studies, reporting partial remissions in 7% of cases, disease control in 31% of 
cases, 6.2 months median PFS and 10.7 months median OS when delivered every 90 days. 
With an intensified tremelimumab schedule, immune-related ORR was 14%, with a 51% 
disease control rate, immune-related PFS was 6.2 months, and OS 11.3 months. Toxicity 
with this compound was as expected, with 90% patients reporting grade 1-2 toxicities and 
7% grade 3-4 toxicities. 
Programmed cell death-1 (PD-1) is a co-inhibitory molecule at the immunological synapse 
that acts as a major regulator of adaptive immunity, and is exploited by tumour cells to 
result in adaptive immune resistance (tolerance). This occurs when PD-1 binds to the 
ligands PD-L1 (B7H1) or PD-L2, which are expressed on many tumour types. High PD-L1 
expression on tumours is associated with poorer outcomes. Mesothelioma has been shown 
to express PD-L1, with a small study identifying PDL1 expression in up to 40% of 


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mesotheliomas. Moreover, immunologically-mediated inflammation is known to be a key 
driver for mesothelioma development via the Nalp3 imflammasome. 
Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal 
antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2.  
In the phase I trial in unselected NSCLC, the objective response rate was 19.4%, the median 
duration of progression-free survival 3.7 months, and the median overall survival 
12.0 months. Among patients with strong PD-L1 expression (at least 50% of positive cells) 
the response rate was 45.2, median progression-free survival was 6.3 months; median 
overall survival not reached in naive and 15.4 months in pretreated patients respectively [1, 
2]. 
More recently, KEYNOTE-010 demonstrated that pembrolizumab improves overall survival 
(OS) over docetaxel in patients with previously treated NSCLC with membranous PD-L1 
expression on ≥1% of tumour cells (hazard ratio [HR] 0.71, P = 0.0008 for pembrolizumab 
2 mg/kg Q3W; HR 0.61, P < 0.0001 for pembrolizumab 10 mg/kg Q3W) [3]. 
 
Objectives and endpoints:  
Primary objective: 
To investigate whether treatment with pembrolizumab improves progression-free survival 
(PFS), as assessed by independent radiological review, compared to standard, institutional-
choice chemotherapy (gemcitabine or vinorelbine). 
Secondary objectives: 
 To evaluate secondary measures of clinical efficacy including objective response 
(OR), investigator assessed PFS, overall survival (OS), and time to treatment failure 
(TTF)  
 To assess the safety and tolerability of the treatment 
 
Primary endpoint: 
 Progression-free survival according to RECIST 1.1 criteria based on independent 
radiological review 
Secondary endpoints: 
 Objective response determined by RECIST 1.1 criteria 
 Overall survival 
 Time to treatment failure 
 Investigator assessed progression-free survival determined according to RECIST 1.1 
criteria 
 Tolerability assessed by adverse events graded according CTCAE v4.0 
 


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Correlative endpoints: 
 Responses according to PD-L1 expression levels, measured by IHC 
 TILs analysis 
 Mutation load 
 
Most important eligibility criteria (see Section 7 for complete list):  
Inclusion criteria 
 Histologically confirmed malignant pleural mesothelioma (all subtypes are eligible) 
 Progressing after or on previous platinum based chemotherapy.  
 Availability of tumour tissue for translational research 
 Male and female patients aged 18 years 
 ECOG performance status 0-1 
 Life expectancy of at least 3 months 
 Measurable or evaluable disease according to RECIST 1.1 criteria 
 Adequate haematological, renal, and liver function 
Exclusion criteria 
 Prior therapy with an anti-PD-1, anti-PD-L1/L2, anti-CD137, or anti-CTLA-4 
antibody 
 Prior therapy with gemcitabine or vinorelbine 
 Known active central nervous system metastases and/or carcinomatous meningitis. 
 Active autoimmune disease that has required systemic treatment in past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Treatment arms: 
Experimental arm:  
Pembrolizumab, 200 mg fixed dose i.v. on day 1 of every 3-week (3 days) cycle until 
progression of disease determined according to RECIST 1.1 criteria or lack of tolerability or 
until further protocol treatment is declined by the patient, for a maximum of 2 years.  
In case of clinical benefit, with physician and patient agreement, pembrolizumab treatment 
can continue beyond documented disease progression according to RECIST 1.1 criteria until 
a maximum of 2 years on pembrolizumab treatment is reached. Patients need to meet the 
following criteria: 
 ECOG performance status 0-1 
 Absence of rapid progression of disease. 
 Absence of progressive tumour at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention. 


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Control arm:  
For the control chemotherapy options, the choice of vinorelbine (p.o.) or vinorelbine (i.v.) or 
gemcitabine chemotherapy will be made on a per-patient basis prior to randomisation. 
 Gemcitabine 1000 mg/m2 i.v., day 1 and day 8 of every 3-week (3 days) cycle 
 Vinorelbine i.v. 30 mg/m2 i.v., day 1 and day 8 of every 3-week (3 days) cycle 
 Vinorelbine 60/80 mg/m2 p.o., day 1 and day 8 of every 3-week (3 days) cycle 
At documented disease progression according to RECIST 1.1 criteria, patients in the control 
arm are allowed to receive pembrolizumab, if they meet the cross-over criteria: 
 ECOG performance status 0-1 
 Absence of progressive tumours at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention. 
 
Statistical considerations: 
This is a 1:1 randomised phase III trial, designed to detect with 80% power, using a one-
sided test at significance level of 0.025, an increase of the median PFS from 3.5 months on 
the chemotherapy arm to 6 months on pembrolizumab. This corresponds to a 6-month PFS 
of 30% vs 50% for the chemotherapy and the pembrolizumab group respectively (HR=0.58). 
A cumulative drop-out of 5% is assumed. A total of 110 events need to be observed to 
achieve the trial goal. 
The expected accrual rate is 2 patients per month for the first 6 months, increasing to 
10 patients per month thereafter. A total sample size of 142 patients accrued over a period of 
19 months would be required to observe the total number of 110 events with a maximum 
total trial follow-up of 24 months. 
The primary analysis is expected to be available 36 months after the inclusion of the first 
patient. The trial treatment phase will continue for a maximum of 2 years from the inclusion 
of the last patient and the trial is expected to end at all sites approximately 43 months after 
the inclusion of the first patient. 
 
Total trial duration: 43 months from randomisation of the first patient 
 


 
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2. 
Trial schedule  
 
Before 
randomisation(1) 
Treatment Period(2) 
PD(7) 
End of 
Treatment 
visit 
Post treatment visit 
Every 12 (2) weeks. 
Experimental 
arm(3) 
Control 
arm(4) 
In addition  
on day 1 of  
cycle 3(5) 
Beyond  
PD(4)(6) 
Before PD 
After PD 
Written informed consent: before any trial 
specific evaluations and intervention 
 
 
 
 
 
 
 
 
 
Medical history: smoking history, 
comorbidities and allergies 
 
 
 
 
 
 
 
 
 
Physical examination: PS, blood pressure, 
heart rate, temperature, body weight, height 
(only at baseline) 
 
Within 72 hours before start of 
each treatment cycle 
 
 
 
 
 
 
 
Baseline symptoms 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
Survival(8) 
 
 
 
 
 
 
 
 
 
Laboratory tests 
Thyroid function:(9) TSH, with reflex free 
T3/4 
 
every 2nd 
treatment cycle 
 
 
every 2nd 
treatment cycle 
 
 
 
 
HIV test 
 
 
 
 
 
 
 
 
 
Pregnancy test(10) 
Repeated within 
72 hours before 
treatment start 
every 2nd 
treatment cycle 
 
 
every 2nd 
treatment cycle 
 
only for 
pembrolizumab 
 
 
Chemistry: serum albumin, glucose, 
potassium, sodium, calcium, amylase, lipase 
and LDH 
 
Within 72 hours before start of 
each treatment cycle 
 
 
 
 
 
 
Haematology: haemoglobin, platelet count, 
white blood cell count including differential 
(lymphocytes and absolute neutrophil 
count) 
 
Within 72 hours before start of 
each treatment cycle 
 
 
 
 
 
 
 
 


 
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Before 
randomisation(1) 
Treatment Period(2) 
PD(7) 
End of 
Treatment 
visit 
Post treatment visit 
Every 12 (2) weeks. 
Experimental 
arm(3) 
Control 
arm(4) 
In addition  
on day 1 of  
cycle 3(5) 
Beyond  
PD(4)(6) 
Before PD 
After PD 
Coagulation profile (INR) 
 
every 2nd 
treatment cycle 
 
 
every 2nd 
pembrolizumab 
cycle 
 
 
 
 
Liver function tests: total bilirubin, ALT, 
AST, ALP, GGT 
 
Within 72 hours before start of 
each treatment cycle 
 
 
 
 
 
 
Renal function tests: urea, uric acid, serum 
creatinine and creatinine clearance 
calculated according to Cockroft-Gault 
 
Within 72 hours before start of 
each treatment cycle 
 
 
 
 
 
 
Urine analysis: specific gravity, pH, 
proteins, glucose, blood using a dipstick; 
elements and microscopic examination if 
needed 
 
every 2nd 
treatment cycle 
 
 
 
 
 
 
 
Treatment 
Pembrolizumab(11) 
 
 
 
 
 
 
 
 
 
Chemotherapy(12) 
 
 
 
 
 
 
 
 
 
Further lines of treatment 
 
 
 
 
 
 
 
 
 
Disease evaluation 
Radiological tumour assessment(13) 
 
First 6 months: every 9 weeks, 
then every 12 weeks 
 
 
 
If not done 
within last 
6 weeks 
 
 
Pulmonary function (FEV1 and FCV)(14) 
strongly encouraged 
 
 
strongly 
encouraged 
 
strongly 
encouraged 
 
 
 
Biological material 
FFPE(15) 
 
 
 
 
 
optional 
 
 
 
Blood samples(16) 
 
 
 
 
 
 
 
 
 
 
 
 
Mandatory evaluation / intervention 
 


 
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(1) 
Evaluations to be done within 5 weeks (35 days) before randomisation. If examinations were done prior to 5 weeks (35 days) before start of randomisation, they have to be repeated. 
(2) 
Every 3 weeks (3days). 
(3) 
Patients in the experimental arm (and patients in the control arm after cross-over): assessments have to be done on day 1 of every treatment cycle (or within 3 days before these dates) 
(4) 
Patients in the control arm: assessments have to be done on day 1 of every treatment cycle (or within 3 days before these dates). After cross-over to pembrolizumab treatment, biological material  
collection, examinations and documentation follow the schedule for the experimental arm (see footnote 3) starting at pembrolizumab cycle 1.  
(5) 
On day 1 of treatment cycle 3 (or within 3 days before this date) for both experimental and control arm. 
(6) 
In case of clinical benefit, with physician and patient agreement, pembrolizumab treatment can continue beyond progression until a maximum of 2 years on pembrolizumab treatment of therapy is 
reached. 
(7) 
Disease progression: determined according to RECIST 1.1 criteria. 
(8) 
Survival status: to be collected during the follow-up visits. 
(9) 
Thyroid function test: TSH value. In case of abnormal TSH, free T3 and T4 also have to be measured. 
(10) 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 beta HCG pregnancy test within 
35 days before randomisation. The test has to be repeated 72 hours before pembrolizumab treatment start and then every 2nd cycle of pembrolizumab treatment and at end of treatment visit. 
(11) Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 (3 days) of every 3-week cycle until progression of disease determined according to RECTIST 1.1 criteria or lack of 
tolerability for a maximum of 2 years. In case of clinical benefit, with physician and patient agreement, and if cross-over criteria are met, pembrolizumab treatment can continue beyond PD until a 
maximum of 2 years on pembrolizumab treatment is reached. 
(12) Chemotherapy: for the control chemotherapy options, the choice of vinorelbine (p.o.) or vinorelbine (i.v.) or gemcitabine chemotherapy will be made on a per-patient basis prior to randomisation. 
- Gemcitabine 1000 mg/m2 i.v., day 1 and day 8 of every 3-week (3 days) cycle or 
- Vinorelbine 30 mg/m2 i.v., day 1 and day 8 of every 3-week (3 days) cycle or 
- Vinorelbine 60/80 mg/m2 p.o., day 1 and day 8 of every 3-week (3 days) cycle 
At documented disease progression according to RECIST 1.1 criteria control arm patients that meet the cross-over criteria are allowed to receive pembrolizumab for a maximum of 2 years. 
Examinations, blood sample collection and documentation for cross-over patients have to follow the schedule of the experimental arm and start at pembrolizumab cycle 1. 
(13) Radiological tumour assessment by CT scans of thorax / upper abdomen (from top of thorax until adrenal glands and full liver and kidney included, preferred) or alternatively (and only after the 
first CT at baseline) CT of thorax and ultrasonography of upper abdomen, following the schedule indicated below; until tumour progression determined according to RECIST 1.1 criteria. If 
pembrolizumab treatment is continued beyond progression, radiological tumour assessment by CT has to continue until treatment stop. The same imaging technique, acquisition, and processing 
parameters should be used for each patient throughout the trial.  
 
  
At baseline: 
within 5 weeks before randomisation 
  
First 6 months (up to week 27):  
every 9 weeks* (63 days) 
at week 9, 18, 27 (±4 days) 
Up to 2 years: 
 
every 12 weeks* (84 days) 
at week 39, 51, 63, …99 (±7 days) 
 
* from start of trial treatment and during cross-over to pembrolizumab  
(14) Pulmonary function: strongly encouraged: forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) at baseline, on day 1 of treatment cycle 3 and at disease progression. 
(15) FFPE material: formalin-fixed, paraffin embedded (FFPE) archival tumour material from primary diagnosis. In addition, a fresh biopsy sample taken close to the start of trial treatment (after first-
line therapy) should be submitted, if available. (A fresh FFPE biopsy sample is mandatory if the archival tumour material from diagnosis is fully depleted. If tumour tissue block is not available, 
5 slides with FFPE tumour tissue sections of 4-5 µm thickness are an acceptable alternative). FFPE material has to be shipped to the central laboratory within 4 weeks after randomisation. 
(16) Blood samples: 2.5 mL whole blood for DNA analysis at baseline, 2.5 mL RNA whole blood for RNA analysis and 5 mL serum samples will be collected at baseline, on day 1 of treatment cycle 3 
and at disease progression.


 
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3. 
List of abbreviations  
 
AE 
Adverse Event 
ALT 
Alanine transaminase 
ALP 
Alkaline phosphatase  
ANC 
Absolute Neutrophil Count 
APC 
Antigen presenting cell 
AST 
Aspartate transaminase 
BID 
Bis In Die (lat.), twice-daily  
BMS 
Bristol-Myers Squibb 
BOR 
Best Overall Response 
BORR 
Best Overall Response Rate 
CNS 
Central Nervous System 
COPD 
Chronic Obstructive Pulmonary Disease 
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 
ECI 
Event of Clinical Interest 
ECL  
Electrochemiluminescent 
eCRF 
Electronic Case Report Form 
ED 
Extensive Stage Disease 
EDC 
Electronic Data Capture 
EEA 
European Economic Area 
EGFR 
epidermal growth factor receptor 
EP 
Etoposide - Cisplatinum 
ERB 
Ethical Review Board 
FVC 
Forced vital capacity 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography 
FFPE 
Formalin Fixed, Paraffin Embedded 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-Glutamyl Transpeptidase 
GI 
Gastrointestinal 
GTV 
Gross Tumour Volume  
IA 
Interim Analysis 
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 
ILD 
Interstitial Lung Disease 


 
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INR 
International Normalised Ratio 
IMP 
Investigational Medicinal Product 
irAE 
Immune-related Adverse Events 
irPFS 
Immune-related Progression Free Survival 
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 
MIP 
Maximum Intensity Projection  
MLD 
Mean Lung Dose 
MPM 
Malignant Pleural Mesothelioma 
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 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Protein 1 
PD-L1 
Programmed Cell Death Ligand 1 
PFS 
Progression Free Survival 
PIS 
Patient Information Sheet 
PK 
Pharmacokinetics 
PPK 
Population Pharmacokinetic 
PR 
Partial Response 
PS 
Performance Status 
QD 
Quaque Die, once daily 
PTV  
Planning Target Volume 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RT 
Radiotherapy 
SAE 
Serious Adverse Event 
SADR 
Serious Adverse Drug Reaction 
SBRT 
Stereotactic Body Radiation Therapy 
SCC 
Squamous-Cell Carcinoma 
SCLC 
Small cell lung carcinoma 
SD 
Stable Disease 
SIAD 
Syndrome of Inappropriate Diuresis 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUV 
Standard uptake volume 
Tc99mDTPA 
Technetium-99m Diethyl Triamine Penta-Acetic Acid 
TIL 
Tumour Infiltrating Lymphocyte 
Treg 
Regulatory T-cells (CD4+CD25+) 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal lab value 


 
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VALG 
Veterans Administration Lung Study Group 
VEGF 
Vascular endothelial growth factor 
WBC 
White Blood Cell Count 
WBRT 
Whole Brain Radiotherapy 
WC 
Withdrawal of Consent 
 
 


 
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4. 
Background and rationale 
4.1. 
Disease background 
Mesothelioma is an aggressive malignancy usually affecting the surfaces of body coelomic 
cavities. It most commonly originates from the pleura with a propensity to the lower parietal 
pleura and costo-diaphragmatic recess, and is almost always caused by asbestos exposure, 
with a usual lag time of 30 years between exposure and presentation [4]. Outcomes are 
invariably fatal, with median survival from presentation around 9-12 months in most series 
due to difficulties in achieving a complete microscopic surgical resection and tumour 
relative chemo-refractoriness [5]. Whilst initially considered rare, due to the demand of 
asbestos of all varieties associated with industrialization following the Second World War, 
the background incidence of mesothelioma of 1/million has risen to 40/million in some 
countries. In the UK, where substantial asbestos exposure continued until the 1970s, the 
death rate is the highest in the world with a current epidemic of new cases, predicted to 
continue for another 5-10 years [6]. Two main histological subtypes of mesothelioma are 
identified. The epitheliod subtype is the commonest, accounting for around 40% of cases, 
whilst the sarcomatoid subtype is observed in 20% of cases; the latter being typically 
aggressive and chemorefractory. Around 35% cases have features of both epitheliod and 
sarcomatoid subtypes and are termed biphasic subtype [7]. For patients with pleural 
mesothelioma, in whom surgery is not considered appropriate, systemic chemotherapy 
(platinum combined with pemetrexed) remains the international standard of care [5]. 
Cisplatin/pemetrexed is associated with a response rate of 41% and confers an OS 
advantage of 3 months over cisplatin alone, and is the only licensed systemic therapy for 
mesothelioma [8]. 
Despite this, in unresectable cases, the median survival is 9-12 months from most series [4, 
8]. At relapse, after platinum-based chemotherapy, no anti-cancer systemic therapies are 
licensed. Several small phase II studies and retrospective series have suggested potential 
efficacy for chemotherapy with agents including carboplatin/gemcitabine, or vinorelbine. 
There is therefore a huge unmet need for effective therapy for patients with relapsed pleural 
mesothelioma. The largest trial ever performed of systemic therapy in relapsed pleural 
mesothelioma in 661 patients [9] documented the natural outcome of this group of relapsed 
mesothelioma patients reporting a median OS of 27.1 weeks (6 months) and median PFS for 
6.1 weeks (1.5 months) for placebo.  
Tremelimumab, a CTLA4-directed therapy, has shown some efficacy in two small single-
arm phase II studies, reporting partial remissions in 7% of cases, disease control in 31% of 
cases, 6.2 months median PFS and 10.7 months median OS when delivered every 90 days 
[10]. With an intensified tremelimumab schedule, immune-related ORR was 14%, with a 
51% disease control rate, immune-related PFS was 6.2 months, and OS 11.3 months [11]. 
Toxicity with this compound was as expected, with 90% patients reporting grade 1-2 
toxicities and 7% grade 3-4 toxicities [11]. There is a need to identify new ways for the 
systemic therapy of malignant mesothelioma and immune checkpoint inhibition is a 
promising way forward. Results from the proposed trial will contribute to overcoming 
tumour-specific immune suppression with immune checkpoint inhibition. 
 
 


 
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4.2. 
Treatment background 
4.2.1. 
Gemcitabine  
Gemcitabine (Gemzar; Eli-Lilly and Company, Indianapolis, IN) is a broadly active 
antifolate with acitivity and EMA license in a variety of solid tumours, including NSCLC, 
pancreatic cancer, and breast cancer. It has demonstrated activity in malignant 
mesothelioma with an activity as a single agent ranging from 0% to 31% [12] and it is not 
known to be cross-resistant with pemetrexed. Moreover, as a single agent or in combination, 
gemcitabine was the most commonly used agent in pre-treated patients who were treated in 
the phase III pemetrexed trial. It is therefore considered an active standard therapeutic 
option in the second-line setting after pemetrexed-based chemotherapy [13]. 
4.2.2. 
Vinorelbine 
Vinorelbine (Navelbine; Pierre Fabre, Castres, France) is a vinca alkaloid cytotoxic 
chemotherapy that is available in intravenous and oral preparations with EMA licenses in 
lung cancer and breast cancer. It has been evaluated as single agent both in the first-line and 
second-line settings [14], both in prospective small phase II trials and also in retrospective 
cohorts (second or third-line) using either intravenous or oral formulations (see Table 1). 
 
Table 1 Vinorelbine-based chemotherapy as second and beyond line therapy in MPM 
Author [ref] 
Regimen 
# pts 
Line 
RR 
DCR 
mTTP/PFS 
mOS 
Stebbing [15]a) 
i.v. VNR 
63 
100% 2L 
16% 
84% 
NR 
9.6 mo 
Sørensen [16]a) 
p.o. VNR 
15 
100% 2L 
7% 
NR 
2.3 mo 
2.5 mo 
Zucali [17]b) 
i.v. VNR 
59 
58% 2L, 42% 3L 
15% 
49% 
2.3 mo 
6.2 mo 
Zauderer [18, 19]b) 
i.v. VNR 
45 
53 2L 47% 3L 
0% 
52% 
2.5 mo 
5.0 mo 
Zucali [13]a) 
i.v. VNR + GEM 
30 
100% 2L 
10% 
43% 
2.8 mo 
10.9 mo 
Toyakawa [20]a) 
i.v. VNR + GEM 
17 
100% 2L 
18% 
82% 
6.0 mo 
11.2 mo 
Ref = Reference; i.v. = intravenous; p.o. = oral; VNR = vinorelbine; GEM = gemcitabine; Line = line of therapy; RR = response rate; 
DCR = disease control rate (response rate + stable disease); mTTP/PFS = median time to progression or progression-free susrvival; mOS 
= median overall surial; mo = months. a) prospective studies; b) retrospective studies. Adapted from [14]. 
 
No randomised trials of vinorelbine have been performed for relapsed pleural mesothelioma. 
Responses observed to date have varied between 0-16%, and toxicities observed, are similar 
to those known for the compound. Despite these limitations, vinorelbine has gained 
popularity as an acceptable treatment option in the relapsed setting, as highlighted by 
several of the retrospective studies. 
4.3. 
Background pembrolizumab 
Programmed cell death-1 (PD-1) is a co-inhibitory molecule at the immunological synapse 
that acts as a major regulator of adaptive immunity, and is exploited by tumour cells to 
result in adaptive immune resistance (tolerance) [21]. This occurs when PD-1 binds to the 
ligands PD-L1 (B7H1) or PD-L2, which are expressed on many tumour types. High PD-L1 
expression on tumours is associated with poorer outcomes. Mesothelioma has been shown 
to express PD-L1, with a small study identifying PD-L1 expression in up to 40% of 
mesotheliomas [22]. Moreover, immunologically-mediated inflammation is known to be a 
key driver for mesothelioma development via the Nalp3 imflammasome [23]. MK-3475 


 
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(pembrolizumab) is a potent and highly selective humanised monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2. It has demonstrated activity in a number of different tumour 
types including melanoma and non-small cell lung cancer (NSCLC), with a favourable 
toxicity profile in NSCLC (9.5% grade 3-5 treatment-related adverse events, 0.6% diarrhoea, 
n=495), and marked efficacy with a 40% one-year PFS rate for previously treated patients 
with strong PD-L1 expression (>50%) (Garon 2015). 
Pembrolizumab has also demonstrated superior efficacy to ipilimumab in metastatic 
melanoma [24]. Of major interest are the results of the KEYNOTE-028 basket trial, where 
25 PD-L1 weak/strong positive (1% PD-L1 expression) relapsed mesothelioma patients of 
all histological subtypes treated with pembrolizumab at 10 mg/kg q14 showed an 
unprecedented 76% disease control rate, supported by a 28% PR rate and a 48% SD rate. At 
time of reporting, 64% patients, including all responders, remained on treatment (duration 
8+ to 24+ weeks) (Alley A, AACR 2015). 
Additional data from KEYNOTE-028 presented at the World Lung Congress 2015 (Alley A, 
WCLC 2015) with a June 2015 data cut-off demonstrated that PD-L1 positivity (>1%) was 
observed in 45% of screened samples (newly obtained or archival) and that a 28% PR rate 
with a 48% SD rate had been maintained, supporting a 76% disease control rate. 61% of 
patients had evidence of tumour shrinkage, with duration of response ranging from 10.4 to 
40.3+ weeks. Exploratory analyses demonstrated no relationship between magnitude of PD-
L1 expression and presence/absence of response. Median PFS was 5.8 months. 
4.3.1. 
Rationale for pembrolizumab fixed dosing 
The choice of the 200 mg i.v. every 3 weeks as an appropriate dose for the fixed dosing, is 
based on simulations performed using the population PK model of pembrolizumab showing 
that the fixed dose of 200 mg every 3 weeks will provide exposures that i) are optimally 
consistent with those obtained with the 2 mg/kg dose every 3 weeks, ii) will maintain 
individual patient exposures in the exposure range established in melanoma as associated 
with maximal efficacy response and iii) will maintain individual patient’s exposure in the 
exposure range established in melanoma that are well tolerated and safe. A fixed dose 
regimen will simplify the dosing regimen, be more convenient for physicians and reduce 
potential for dosing errors. A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
The rationale for further exploration of 200 mg fixed doses of pembrolizumab in solid 
tumours is based on: i) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg every 3 weeks in melanoma patients, ii) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg to 
10 mg/kg every 3 weeks, iii) the lack of effect of tumour burden on distribution of 
pembrolizumab (as assessed by the population PK model) and iv) the assumption that the 
dynamics of PD-1 target engagement will not vary meaningfully with tumour type. In 
addition, preliminary data from 45 previously treated, advanced or metastatic NSCLC 
patients treated at the 2 mg/kg every 3 weeks dose/schedule indicates a 20% BOR by 
RECIST 1.1 criteria (35% by irRECIST). This is in comparison to the 22.4% ORR observed 
at the 10 mg/kg every 2 weeks, suggesting lack of dose responsiveness and additional 


 
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justification for the inclusion of a fixed dose of 200 mg Q3W pembrolizumab in KEYNOTE 
024 [NCT02142738; www.clinicaltrials.gov]. 
4.4. 
Choice of design and comparator 
Gemcitabine represents a standard of treatment for mesothelioma in the second-line setting 
after treatment with pemetrexed [25]. This chemotherapy has shown a variable activity in 
first and second line. The EORTC-Lung Cancer Group (LCG) examined gemcitabine in 
mesothelioma at a dose of 1,250 mg/m2 i.v. over 30 minutes on days 1, 8, and 15 of each 
28-day cycle. Here a response rate of 7% in 27 patients was observed [26]. The CALGB 
conducted a phase II multicenter trial evaluating the activity of gemcitabine in 
chemotherapy naïve patients with MPM, but among the 17 patients treated, there were no 
partial or complete responses and median survival was 4.7 months. Another phase II trial of 
gemcitabine in chemotherapy naïve patients with MPM demonstrated 2 objective responses 
among 27 patients (7%) and a median survival of 8 months [27]. 
4.5. 
Overall risk/benefit assessment 
First-line chemotherapy is the standard treatment of patients not assessable for surgical 
interventions. Since palliative first-line chemotherapy results in a median overall survival of 
12 months, new therapeutic approaches have to be developed. However, immunological 
approaches can be associated with the risk of off-target toxicity. Toxicity of immune 
checkpoint inhibitors is manageable and severe toxicities are rare. Moreover there is clear 
evidence that immune checkpoint inhibitors can be effective in advanced cancers, and 
pembrolizumab, especially in mesothelioma, has shown responses (partial responses and 
stable disease) in the vast majority of patients. 
Taken together, for patients in a palliative setting with a median life expectancy of about 
12 months the risk is reasonable in comparison to possible benefit. Moreover this trial is 
designed to let patients randomised to the chemotherapy arm cross over to receive 
pembrolizumab after progression, a treatment that would not be otherwise available for 
patients with incurable malignant pleural mesothelioma. 
4.6. 
Rationale for performing the trial 
Pembrolizumab has shown significant activity in a population of pre-treated mesothelioma 
patients. To date, no therapeutical treatments have shown an impact on the survival of 
patients in this setting. There is a need to identify new ways for the systemic therapy of 
malignant mesothelioma and immune checkpoint inhibition is a promising way forward.  
 
 


 
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5. 
Objectives and endpoints 
5.1. 
Primary objective 
To investigate whether treatment with pembrolizumab improves progression-free survival 
(PFS), as assessed by independent radiological review, compared to standard, institutional-
choice chemotherapy (gemcitabine or vinorelbine).  
5.2. 
Secondary objectives 
5.2.1. 
To evaluate secondary measures of clinical efficacy including objective response 
(OR), investigator assessed PFS, overall survival (OS), and time to treatment 
failure (TTF).  
5.2.2. 
To assess the safety and tolerability of the treatment. 
5.3. 
Primary endpoint 
5.3.1. 
Progression-free survival (PFS) according to RECIST 1.1 criteria based on 
independent radiological review. For definition, see Section 14.1. 
5.4. 
Secondary endpoints 
5.4.1. 
Objective response determined by RECIST 1.1 criteria 
5.4.2. 
Overall survival 
5.4.3. 
Time to treatment failure 
5.4.4. 
Investigator assessed progression-free survival determined according to RECIST 
1.1 criteria. 
5.4.5. 
Adverse events graded according to CTCAE v4.0 
5.5. 
Correlative endpoints 
5.5.1. 
Responses according to PD-L1 expression levels, measured by IHC 
5.5.2. 
TILs analysis 
5.5.3. 
Mutation load 
 
 
 


 
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6. 
Trial design, duration and termination  
6.1. 
Trial design 
This is a randomised phase III multicentre clinical trial designed to demonstrate superiority 
of pembrolizumab over institutional-choice standard chemotherapy (gemcitabine or 
vinorelbine), stratified by predominantly epitheloid vs non-epitheloid histological subtype. 
Patients randomised to the control arm will be allowed to cross over to receive 
pembrolizumab at progression. 
Patients will undergo CT imaging every 9 weeks for the first 6 months (until week 27) and 
every 12 weeks thereafter. 
Cross-over: for patients in the control arm, at progression determined by RECIST 1.1 
criteria according to local investigator assessment. 
 
 
6.2. 
Sample size and trial duration 
Patient accrual is expected to be completed within 19 months including a run-in period of 
6 months. A total sample size of 142 patients will be required with a maximum total trial 
follow-up of 24 months. 
Approximately 12 sites, including 7 from Switzerland and 5 from the United Kingdom, will 
participate in this trial. 
Results of the primary analysis are expected to be available 36 months after the inclusion of 
the first patient. The trial treatment phase will continue for a maximum of 2 years from the 
inclusion of the last patient and the trial is expected to end at all sites approximately 
43 months after the inclusion of the first patient. 
 
 
Malignant pleural mesothelioma
after/on previous platinum based 
chemotherapy 
1 : 1
R
Pembrolizumab 200mg fixed dose i.v. day 1 of each 3-week cycle 
Chemotherapy by institutional choice
Gemcitabine 1000 mg/m2 d1/d8, q3w i.v. or
Vinorelbine
30 mg/m2
d1/d8, q3w i.v. or
Vinorelbine
60/80 mg/m2 d1/d8 q3w p.o.

CT
CT
3
Week
6
9
18
27
0
-4
39

until PD by RECIST 1.1
for max 2 years*
Blood
FFPE
Blood
Blood
CT
CT
CT
CT
Progression 
of 
disease
(FFPE)
Progression 
of 
disease

* continuation beyond PD in 
case of clinical benefit


 
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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 including the submission of mandatory biomaterial. 
7.1. 
Inclusion criteria 
7.1.1. 
Histologically confirmed MPM (all subtypes are eligible) 
7.1.2. 
Progressing after or on previous platinum based chemotherapy. 
7.1.3. 
Availability of tumour tissue for translational research (see Section 15.2.1) 
7.1.4. 
Female and male patients aged 18 years 
7.1.5. 
ECOG performance status 0-1 
7.1.6. 
Life expectancy of at least 3 months 
7.1.7. 
Measurable or evaluable disease according to RECIST 1.1 criteria (see 
Section 13.2) 
7.1.8. 
Adequate renal function: 
- 
Creatinine 1.5 × ULN OR 
- 
Calculated creatinine clearance 40 mL/min (using the Cockroft-Gault formula 
below) 
 
Cockroft-Gault formula Switzerland: 
mL
min =
(140-age[years])×actual body weight [kg]
72×Creatinineserum (mg
dL)
(×0.85 if female) 
 
Cockroft-Gault formula UK: 
mL
min = (140-age[years])×actual body weight [kg]
Creatinineserum [M]
×A 
 A= 1.23 [male] and 1.04 [female] 
7.1.9. 
Adequate haematological function: 
- 
Haemoglobin 90 g/L or 5.6 mmol/L 
- 
WBC 1.0 × 109/L 
- 
Lymphocytes 0.5 g/L 
- 
Absolute neutrophils count (ANC) 1.5 × 109/L 
- 
Platelet count 100 × 109/L 


 
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7.1.10. Adequate liver function: 
ALT and AST 2.5 × ULN. If the patient has liver metastases, ALT and AST must 
be ≤5 × ULN  
7.1.11. 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 35 days before randomisation (the test has to be repeated 72 hours before 
pembrolizumab treatment start). 
7.1.12. Written informed consent (IC) must be signed and dated by the patient and the 
investigator prior to any trial-related intervention including the submission of 
mandatory biomaterial.  
7.2. 
Exclusion criteria  
7.2.1. 
Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-
cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-
stimulation or checkpoint pathways). 
7.2.2. 
Prior therapy with gemcitabine or vinorelbine. 
7.2.3. 
Known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Patients with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least 
4 weeks prior to randomisation and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to randomisation. This exception does not include 
carcinomatous meningitis, which is excluded regardless of clinical stability. 
7.2.4. 
Known or suspected hypersensitivity to pembrolizumab or any of its excipients. 
7.2.5. 
Known unstable or unresolved surgical or chemotherapy-related toxicity that would 
compromise the patient’s capacity to participate in the trial. 
7.2.6. 
Previous allogeneic tissue/solid organ transplant. 
7.2.7. 
Live vaccines within 30 days prior to first dose of pembrolizumab. 
7.2.8. 
Regular intake of immune-modulating drugs (such as interferon, methotrexate). 
7.2.9. 
History of (non-infectious) pneumonitis that required steroids, evidence of 
interstitial lung disease (ILD) or active, non-infectious pneumonitis. 
7.2.10. Active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) or topical therapy 
(e.g., steroids) for psoriasis or eczema is not considered a form of systemic 
treatment. 


 
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7.2.11. Ongoing clinically serious infections requiring systemic antibiotic or antiviral, 
antimicrobial, or antifungal therapy. 
7.2.12. HIV infection. 
7.2.13. Known active hepatitis B or hepatitis C. 
7.2.14. Known history of active tuberculosis. 
7.2.15. Patients with diagnosed immunodeficiency or receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to 
randomisation. 
7.2.16. Patients with other serious diseases or clinical conditions, including but not limited 
to uncontrolled active infection and any other serious underlying medical condition 
that could affect the patient’s capacity to participate in the trial. 
7.2.17. Substance abuse, medical, psychological or social conditions that may interfere 
with the patient’s participation in the trial or evaluation of the trial results. 
7.2.18. Women who are pregnant or in the period of lactation. 
7.2.19. Sexually active men and women of childbearing potential who are not willing to 
use an effective contraceptive method during the trial and up to 120 days following 
cessation of trial treatment (see Section 10.6.1). 
8. 
Patient screening and randomisation 
This trial will use a web-based registration and randomisation system. Each participating 
centre will access the system directly to randomise patients into the trial. Specific details for 
the inclusion of patients are in the PROMISE-meso 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 include a patient into this trial. Please consult 
the PROMISE-meso Procedures Manual for detailed instructions. 
Note that written informed consent has to be obtained from the patient prior to any trial-
specific intervention including the submission of mandatory biomaterial. 
Verify eligibility and randomise the patient in the EDC system ETOPdata according to the 
information in the PROMISE-meso Procedures Manual. The dates the informed consent 
form and the consent to the pathology material submission section of the informed consent 
form were signed by the patient and by the investigator are required to complete the 
eligibility checklist. 
 


 
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8.2. 
Randomisation and stratification 
Patients with malignant pleural mesothelioma who have progressed after or during previous 
platinum based chemotherapy will be randomised to one of two treatment arms. 
Patient eligibility must be checked before randomisation (see Section 7). Please complete 
and submit the Eligibility for randomisation eCRF (see Section 17). Then submit the 
randomisation eCRF in ETOPdata in order to randomise the patient.  
Randomisation should take place at least 3 weeks after last dose of previous platinum based 
chemotherapy. 
Trial treatment for both arms has to start within 7 days after randomisation. 
Block stratified randomisation balanced by institution will be performed, stratified by 
histological subtype (predominantely epitheloid vs non-epitheloid) [28]. 
9. 
Investigational medicinal product 
Pembrolizumab (MK-3475) is the investigational medicinal product (IMP) used in this trial. 
Merck will provide the IMP at no cost for this trial. 
Complete details of the investigational medicinal product logistics, distribution, packaging, 
labeling and handling as well as accountability are described in the PROMISE-meso Drug 
Supply Manual. 
9.1. 
Pembrolizumab 
Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 
and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target 
lymphocytes to facilitate tumour regression and ultimately immune rejection. 
9.2. 
Formulation 
Refer to the current version of the pembrolizumab Investigator’s Brochure (IB) for 
pharmaceutical formulation information. 
Clinical supplies will be provided by Merck. For details please refere to the Drug Supply 
Manual. 
9.3. 
Packaging and labeling 
Clinical supplies will be affixed with a clinical trial label in accordance with regulatory 
requirements. 
9.4. 
Clinical supplies disclosure 
This trial is open-label; therefore, the patient, the trial site personnel, ETOP and/or designee 
are not blinded to treatment. Drug identity (name, strength) is included in the label text. 


 
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9.5. 
Storage and handling 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. The Principal Investigator shall take responsibility for and 
shall take all steps to maintain appropriate records and ensure appropriate supply, storage, 
handling, distribution and usage of investigational product in accordance with the protocol 
and any applicable laws and regulations. 
10. 
Trial treatments 
10.1. 
Overview of trial treatment 
The treatments to be used in this trial are outlined in Table 2 below. The treatment in the 
experimental arm consists of 200 mg fixed dose pembrolizumab i.v. on day 1 (3 days) of 
every 3-week cycle until progression of disease determined according to RECIST 1.1 
criteria or lack of tolerability for a maximum of 2 years (expected maximum of 36 doses). 
For the control chemotherapy options, the choice of vinorelbine (p.o.) or vinorelbine (i.v.) or 
gemcitabine chemotherapy must be made prior to randomisation. 
Trial treatment for both arms should begin on the day of randomisation or as close as 
possible to this date (preferably within 7 days after randomisation).  
 
Table 2 Overview of trial treatments 
Drug 
Dose 
Dose frequency 
Route of 
administration 
Regimen 
Experimental arm 
Pembrolizumab 
200 mg 
Q3W 
i.v. 
Day 1 (3 days) 
of each 3-week 
cycle 
Control arm 
Gemcitabine 
1000 mg/m2 
Q3W 
i.v 
Day 1 & day 8 
of each 3-week 
(3 days) cycle 
Vinorelbine 
30 mg/m2 
Q3W 
i.v 
Day 1 & day 8 
of each 3-week 
(3 days) cycle 
Vinorelbine 
60 mg/m2 
(increase to 
80 mg/m2 from 
cycle 2 on if well 
tolerated) 
Q3W 
p.o 
Day 1 & day 8 
of each 3-week 
(3 days) cycle 
 
 
 


 
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10.2. 
Treatment in the experimental arm 
10.2.1. Pembrolizumab dose 
Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3-week 
(3 days) cycle for a maximum or 2 years (expected maximum of 36 doses), or until 
progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, 
or until the patient declines further treatment.  
In case of clinical benefit, with physician and patient agreement, pembrolizumab treatment 
can continue beyond progression for a maximum of 2 years of therapy (see Section 10.2.7). 
10.2.2. Dose delay criteria for pembrolizumab treatment 
 
Note: There will be no dose modifications for pembrolizumab allowed for the 
management of toxicities of individual patients. 
Pembrolizumab will be withheld for all grade ≥3 drug-related toxicities including laboratory 
abnormalities, and severe or life-threatening AEs. 
If a dose of pembrolizumab is withheld for toxicity (other than those listed in Table 4 for 
which permanent discontinuation is required after the first occurrence of the toxicity), then 
patients may resume dosing with pembrolizumab when the toxicity has improved as 
described below: 
 If toxicity does not resolve to grade 0-1 within 12 weeks after last infusion, trial 
treatment should be discontinued after consultation with the ETOP medical reviewer.  
 Patients who require corticosteroids to manage drug-related adverse events must be 
at an equivalent dose of ≤10 mg per day of prednisone to resume dosing with 
pembrolizumab. If the corticosteroid dose to manage a drug-related adverse event 
cannot be reduced to the equivalent of ≤10 mg prednisone per day within 12 weeks 
of last pembrolizumab dose the investigator should contact the ETOP medical 
reviewer to discuss the continuation of trial treatment.  
 With investigator and ETOP medical reviewer agreement, patients with a laboratory 
adverse event still at grade 2 after 12 weeks may continue trial treatment only if the 
toxicity is asymptomatic and controlled. This includes patients who experience drug 
induced 
hypothyroidism 
requiring 
replacement 
therapy. 
Resumption 
of 
pembrolizumab may occur once the patient is stable on adequate doses of 
replacement therapy and is clinically asymptomatic.  
 For the occurrence and management of immune-related adverse effects, please refer 
to Section 10.2.4 and Table 4 in conjunction with the latest version of the 
pembrolizumab Investigator’s Brochure. 
10.2.3. Treatment of pembrolizumab related infusion reactions 
Since pembrolizumab is a human immunoglobulin protein, it is unlikely to be immunogenic 
and induce an infusion or hypersensitivity reaction. However, if such a reaction were to 
occur, it might manifest with fever, chills, rigours, headache, rash, pruritis, arthralgias, 


 
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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 CTCAE (version 4.0) guidelines. 
Treatment recommendations are provided in Table 3 and may be modified based on local 
treatment standards and guidelines as appropriate: 
 
Table 3 Pembrolizumab infusion reaction treatment guidelines 
CTCAE grade 
Pembrolizumab Treatment 
Premedication at subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital 
signs as medically indicated 
until the patient is deemed 
medically stable in the opinion 
of the investigator. 
None. 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, i.v. fluids); 
prophylactic medications 
indicated for 24 hrs 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
- 
i.v. fluids 
- 
Antihistamines 
- 
NSAIDS 
- 
Acetaminophen 
- 
Narcotics 
Increase monitoring of vital 
signs as medically indicated 
until the patient is deemed 
medically stable in the opinion 
of the investigator. 
If symptoms resolve within one 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion 
rate (e.g., from 100 mL/hr to 
50 mL/hr). Otherwise dosing 
will be held until symptoms 
resolve and the patient should 
be premedicated for the next 
scheduled dose. 
Patients who develop second 
grade 2 toxicity despite 
adequate premedication 
should be permanently 
discontinued from further 
trial treatment 
administration. 
Patient may be premedicated 1.5 hours 
(±30 minutes) prior to infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg p.o. (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e. not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
Stop Infusion. 
Patient is permanently 
discontinued from further 
trial treatment 
administration. 
Additional appropriate medical 
No subsequent dosing. 


 
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CTCAE grade 
Pembrolizumab Treatment 
Premedication at subsequent dosing 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support 
indicated 
therapy may include but is not 
limited to: 
- 
i.v. fluids 
- 
Antihistamines 
- 
NSAIDS 
- 
Acetaminophen 
- 
Narcotics 
- 
Oxygen 
- 
Pressors 
- 
Corticosteroids 
- 
Epinephrine 
Increase monitoring of vital 
signs as medically indicated 
until the patient is deemed 
medically stable in the opinion 
of the investigator. 
Hospitalization may be 
indicated. 
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration. 
For toxicity grading, please refer to the common terminology criteria for adverse events v4.0 (CTCAE V4.0) 
 
10.2.4. Treatment of immune-related adverse effects of pembrolizumab 
An immune-related adverse effect (irAE) is defined as a clinically significant adverse event 
of any organ that is associated with trial drug exposure, is of unknown aetiology, and is 
consistent with an immune-related mechanism.  
For the occurrence and management of immune-related adverse effects (which may include 
hypothyroidism, hyperthyroidism, pneumonitis or colitis), please refer to Table 4, in 
conjunction with the latest version of the pembrolizumab IB.  
Potential immune-related adverse events (irAEs) are primary events of clinical interest 
(ECIs) and should be reported as SAEs (see Section 12.4.4 for details). 
10.2.5. Supportive care during pembrolizumab treatment 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined in Table 4. Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the steroid 
dose is decreased. For each disorder, attempts should be made to rule out other causes such 
as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to pembrolizumab. It may be necessary to perform 
conditional procedures such as bronchoscopy, endoscopy, or skin photography as part of 
evaluation of the event.  


 
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Table 3 shows treatment guidelines for patients who experience an infusion reaction 
associated with administration of pembrolizumab. 
For patients who experience a recurrence of the same AE(s) at the same grade or greater 
with rechallenge of pembrolizumab, a consultation between the ETOP medical reviewer and 
investigator should occur to determine whether the patient should continue in the trial. 
However, if a patient experiences a recurrence of the same Serious Adverse Event at the 
same grade or greater with rechallenge of pembrolizumab, the patient must discontinue trial 
medication. Refer to Table 4 and contact ETOP medical reviewer for guidance.  
For the description and reporting of Events of Clinical Interest (ECI) see Section 12.4.4. 
 
Note: Permanently discontinue for any grade 3 (grade 2 for pneumonitis) drug-related 
AE that recurs, or any life-threatening event. 
 


 
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Table 4 Treatment delay and supportive care guidelines for pembrolizumab-related adverse events 
Toxicity 
Grade 
Action to be 
taken 
Timing for restarting 
treatment 
Dose/schedule 
for restarting 
treatment 
Permanent 
discontinuation1) 
Supportive care 
Pneumonitis 
any 
grade 
N/A 
N/A 
N/A 
N/A 
Add prophylactic antibiotics for opportunistic infections in the 
case of prolonged steroid administration. 
1 
continue 
treatment 
N/A 
N/A 
N/A 
2 
hold treatment 
Toxicity resolves to 
grade 0-1 within 
12 weeks of last 
infusion and 
prednisone or 
equivalent was reduced 
to 10 mg/day within 
12 weeks. 
Same dose and 
schedule 
Permanently 
discontinue if 
toxicity does not 
resolve within 
12 weeks of last 
infusion. 
Treat with systemic corticosteroids(2). Initial dose of 1–2 
mg/kg/day prednisone or equivalent followed by a taper. 
 
3-4 
hold treatment 
N/A 
N/A 
Permanently 
discontinue 
treatment. 
Immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed. 
Diarrhea/ 
colitis 
any 
grade 
N/A 
N/A 
N/A 
N/A 
Patients should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in 
stool, with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus). 
All patients who experience diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient oral fluid 
intake is not feasible, fluid and electrolytes should be substituted 
via i.v. infusion. For grade 2 or higher diarrhea, consider GI 
consultation and endoscopy to confirm or rule out colitis. 
1 
continue 
treatment 
N/A 
N/A 
N/A 
2 
 
hold treatment 
Toxicity resolves to 
grade 0-1 within 
12 weeks of last 
infusion and 
prednisone or 
equivalent was reduced 
to 10 mg/day within 
12 weeks. 
Same dose and 
schedule 
Permanently 
discontinue if 
toxicity does not 
resolve within 
12 weeks of last 
infusion. 
Administer oral corticosteroids(2). 1–2 mg/kg/day prednisone or 
equivalent followed by a taper. 


 
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Toxicity 
Grade 
Action to be 
taken 
Timing for restarting 
treatment 
Dose/schedule 
for restarting 
treatment 
Permanent 
discontinuation1) 
Supportive care 
3 
hold treatment 
Toxicity resolves to 
grade 0-1 within 
12 weeks of last 
infusion and 
prednisone or 
equivalent was reduced 
to 10 mg/day within 
12 weeks. 
Same dose and 
schedule 
Permanently 
discontinue if 
toxicity does not 
resolve within 
12 weeks of last 
infusion. 
Treat with intravenous steroids followed by high dose oral 
steroids(1). 1–2 mg/kg/day prednisone or equivalent followed by a 
taper. 
4 
hold treatment 
N/A 
N/A 
Permanently 
discontinue. 
Treat with intravenous steroids followed by high dose oral 
steroids(1). 1–2 mg/kg/day prednisone or equivalent followed by a 
taper. 
Hepatic toxicity 
(AST, ALT, 
increased bilirubin) 
1 
continue 
treatment 
N/A 
N/A 
N/A 
N/A 
2 
hold treatment 
Toxicity resolves to 
grade 0-1 within 
12 weeks of last 
infusion. 
Same dose and 
schedule 
Permanently 
discontinue if 
toxicity does not 
resolve within 
12 weeks of last 
infusion. 
Monitor liver function tests more frequently until returned to 
baseline values (consider weekly)  
Treat with i.v. or oral corticosteroids(1). Initial dose of 0.5–1 
mg/kg/day prednisone or equivalent followed by a taper. 
3-4 
hold treatment 
N/A 
N/A 
Permanently 
discontinue(3) 
Treat with intravenous corticosteroids for 24 to 48 hours(1).  
1–2 mg/kg/day prednisone or equivalent followed by a taper. 
Haematological 
Toxicity 
1 & 2 
continue 
treatment 
N/A 
N/A 
N/A 
 
3 
hold treatment 
 
Exception: 
grade 1-3 
neutropenia 
Toxicity resolves to 
grade 0-1 within 
12 weeks of last 
infusion. 
Same dose and 
schedule 
Permanently 
discontinue if 
toxicity does not 
resolve within 
12 weeks of last 
infusion and for 
any severe event  
 
4 
hold treatment 
N/A 
N/A 
Permanently 
discontinue 
 
Diabetes mellitus 
type I (T1DM) 
including 
T1DM 
and 
DKA 
hold treatment 
When patient is 
clinically and 
metabolically stable. 
Same dose and 
schedule 
N/A 
Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for grade 3-4 hyperglycemia associated with 
metabolic acidosis or ketonuria.  


 
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Toxicity 
Grade 
Action to be 
taken 
Timing for restarting 
treatment 
Dose/schedule 
for restarting 
treatment 
Permanent 
discontinuation1) 
Supportive care 
ketoacidosis [DKA] 
or  
grade ≥3 hyper-
glycemia(4) 
3-4 
hold treatment 
When patient is 
clinically and 
metabolically stable. 
Same dose and 
schedule 
N/A 
Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
Hypophysitis 
1 
continue 
treatment 
N/A 
N/A 
N/A 
N/A 
2 
hold treatment 
Toxicity resolves to 
grade 0-1 within 
12 weeks of last 
infusion. 
 
Same dose and 
schedule 
Permanently 
discontinue if 
toxicity does not 
resolve within 
12 weeks of last 
infusion. 
Treat with corticosteroids. When symptoms improve to grade 1 or 
less, steroid taper should be started and continued over no less 
than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
 
3-4 
hold treatment 
Toxicity resolves to 
grade 0-1 within 
12 weeks of last 
infusion. 
Same dose and 
schedule 
Permanently 
discontinue if 
toxicity does not 
resolve within 
12 weeks of last 
infusion. 
Treat with an initial dose of i.v. corticosteroids followed by oral 
corticosteroids. 
When symptoms improve to grade 1 or less, steroid taper should 
be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is 
tapered. 
Hyperthyroidism 
1 
continue 
treatment 
N/A 
N/A 
N/A 
N/A 
2 
hold treatment 
Toxicity resolves to 
grade 0-1 within 
12 weeks of last 
infusion. 
 
Same dose and 
schedule 
Permanently 
discontinue if 
toxicity does not 
resolve within 
12 weeks of last 
infusion. 
Non-selective beta-blockers (e.g., propranolol) are suggested as 
initial therapy. 
3 
hold treatment 
Toxicity resolves to 
grade 0-1 within 
12 weeks of last 
infusion. 
 
Same dose and 
schedule 
Permanently 
discontinue if 
toxicity does not 
resolve within 
12 weeks of last 
infusion. 
Treat with an initial dose of i.v. corticosteroid followed by oral 
corticosteroids1 
Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
 
4 
hold treatment 
N/A 
N/A 
Permanently 
discontinue3) 
Treat with an initial dose of i.v. corticosteroid followed by oral 
corticosteroids(1) 
Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
 


 
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Toxicity 
Grade 
Action to be 
taken 
Timing for restarting 
treatment 
Dose/schedule 
for restarting 
treatment 
Permanent 
discontinuation1) 
Supportive care 
Hypothyroidism 
1 
continue 
treatment 
N/A 
N/A 
N/A 
N/A 
2-4 
continue 
treatment 
Treatment can continue 
while thyroid 
replacement therapy is 
instituted 
Same dose and 
schedule 
N/A 
Thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
Infusion reaction 
any 
grade 
N/A 
N/A 
N/A 
N/A 
Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of 
completion of infusion. 
Table 3 shows treatment guidelines for patients who experience 
an infusion reaction associated with administration of 
pembrolizumab. 
2 
hold treatment 
Toxicity resolves to 
grade 0-1 within 
12 weeks of last 
infusion. 
 
Same dose and 
schedule 
Permanently 
discontinue if 
toxicity does not 
resolve within 
12 weeks of last 
infusion. 
If symptoms resolve within one hour of stopping drug infusion, 
the infusion may be restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr). Otherwise dosing will be 
held until symptoms resolve and the patients should be 
premedicated for the next scheduled dose. Please refer to Table 3 
“Infusion reaction treatment guidelines” for further management 
details. 
3-4 
hold treatment 
N/A 
N/A 
Permanently 
discontinue 
 
Renal failure or 
nephritis 
1 
continue 
treatment 
N/A 
N/A 
N/A 
N/A 
2 
hold treatment 
Toxicity resolves to 
grade 0-1 within 
12 weeks of last 
infusion and 
prednisone or 
equivalent was reduced 
to 10 mg/day within 
12 weeks of last 
infusion. 
Same dose and 
schedule 
Permanently 
discontinue if 
toxicity does not 
resolve within 
12 weeks of last 
infusion. 
Treat with corticosteroids1. Initial dose of 1–2 mg/kg/day 
prednisone or equivalent followed by a taper. 
3-4 
hold treatment 
N/A 
N/A 
Permanently 
discontinue 
Treat with systemic corticosteroids(1). Initial dose of 1–
2 mg/kg/day prednisone or equivalent followed by a taper. 
All other drug-
related toxicites 
1 
continue 
treatment 
N/A 
N/A 
N/A 
N/A 


 
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Toxicity 
Grade 
Action to be 
taken 
Timing for restarting 
treatment 
Dose/schedule 
for restarting 
treatment 
Permanent 
discontinuation1) 
Supportive care 
2 
hold treatment 
At physician discretion 
until toxicity resolves to 
0-1 within 12 weeks of 
last infusion. 
Same dose and 
schedule 
Permanenty 
discontinue for 
persistent grade 2 
adverse reaction 
for which trial 
treatment has 
been held. 
N/A 
3 
hold treatment 
Toxicity resolves to 
grade 0-1 within 
12 weeks of last 
infusion and 
prednisone or 
equivalent was reduced 
to 10 mg/day within 
12 weeks of last 
infusion. 
Same dose and 
schedule 
Permanently 
discontinue if 
toxicity does not 
resolve within 
12 weeks of last 
infusion. 
N/A 
4 
hold treatment 
N/A 
N/A 
Permanently 
discontinue 
N/A 
Note: Patients who experience a recurrence of the same event (all grade 3; grade 2 for pneumonitis) at the same grade or greater after rechallenge of pembrolizumab should be discontinued from 
trial treatment 
 
N/A: not applicable 
1) After consultation with ETOP medical reviewer 
2) When symptoms improve to grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, attempts should be made to rule out other causes such as metastatic disease or bacterial or viral infection, which 
might require additional supportive care. 
3) Exception: patients with liver metastasis who begin treatment with grade 2 AST or ALT can resume treatment, if AST or ALT increases by less than 50% relative to baseline and for less 
than 1 week. 
4) If associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
 


 
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10.2.6. Dose administration for pembrolizumab 
Please refer to the PROMISE-meso Drug Supply Manual for specific instructions 
regarding preparation of the infusion fluid, and administration. 
Pembrolizumab 200 mg fixed dose will be administered as a 30 minute i.v. infusion on 
day 1 (3 days) of every 3-week cycle until progression of disease determined according to 
RECIST 1.1 criteria or lack of tolerability for a maximum of 2 years. Sites should make 
every effort to target infusion duration to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window of minus 5 minutes and 
plus 10 minutes is permitted (i.e. infusion time is 25-40 minutes). Please refer to Table 3 for 
the management of infusion reaction.  
Planning the time of trial drug infusion (e.g., time of the week for first administration; time 
of the day for each administration) should take trial visit procedures into consideration. All 
trial treatments will be administered on an out-patient basis (hospitalization <24h). 
10.2.7. Criteria to continue pembrolizumab treatment in case of progression 
Disease progression is determined according to local investigator assessment by RECIST 
1.1 criteria. Patients in the experimental arm with progression of disease may still benefit 
from the continuation of pembrolizumab treatment. This includes patients who develop new 
symptomatic brain lesions without extracranial progression. Continuation of pembrolizumab 
treatment (until a maximum of 2 years is completed) for such patients must be discussed 
with ETOP medical reviewer (please contact PROMISE-meso@ETOP-eu.org). 
Patients in the experimental arm need to be stable and have to meet the following criteria to 
continue pembrolizumab treatment: 
 ECOG performance status 0-1 
 Absence of rapid progression of disease. 
 Absence of progressive tumour at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention. 
Any patient deemed clinically unstable should be discontinued from trial treatment at 
radiologic evidence of progressive disease. 
10.2.8. Stop of pembrolizumab treatment 
Patients will receive pembrolizumab treatment for a maximum of 2 years (calculated from 
the date of the first dose), until progression of disease (see Section 10.2.7 above), lack of 
tolerability, or until further protocol treatment is declined by the patient. 
10.3. 
Treatment in the control arm 
10.3.1. Dose administration for gemcitabine or vinorelbine chemotherapy 
A control chemotherapy drug (either gemcitabine or vinorelbine) will be chosen on a per-
patient basis. Systemic therapy treatment will be delivered according to local standards and 
can consist either of gemcitabine (i.v.) or vinorelbine (i.v. or p.o.). Chemotherapy will be 
administered on days 1 and 8 of every 3-week (21 3 days) cycle (see Table 5). 


 
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A maximum number of treatment cycles is not mandated. Patients are not allowed to switch 
between vinorelbine and gemcitabine chemotherapy for any reason. Patients may, however, 
switch between oral and intravenous formulations of vinorelbine if clinically indicated. 
Chemotherapy options should be administered according to local practice. 
For additional details regarding dispensing or reconstitution, preparation of the infusion 
fluid, and administration for each of the standard of care chemotherapy regimens, please 
refer to the approved product labels and local policies for gemcitabine and vinorelbine. 
 
Table 5 Chemotherapy options 
Option Compound 
Dose 
Schedule 
1 
Gemcitabine i.v. 
1000 mg/m2 
d1 and d8, q3w (3 days) 
2 
Vinorelbine i.v. 
30 mg/m2 
d1 and d8, q3w (3 days) 
3 
Vinorelbine p.o. 
60/80 mg/m2 (increase to 
80 mg/m2 on cycle 2 in case of 
good tolerability) 
d1 and d8, q3w (3 days) 
10.3.2. Dose modification and delay criteria for gemcitabine or vinorelbine chemotherapy 
Dose modification, reductions and holds should be performed according to local practice. 
Please refer to approved product labels for patients receiving these regimens. 
10.3.3. Cross-over to pembrolizumab treatment for patients in the control arm 
At documented disease progression according to RECIST 1.1 criteria, patients in the control 
arm are allowed to receive pembrolizumab, if they meet the cross-over criteria: 
 ECOG performance status 0-1. 
 Absence of progressive tumour at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention. 
10.3.4. Pembrolizumab treatment after cross-over  
Administration of pembrolizumab will follow the same schedule as for patients in the 
experimental arm, i.e. 200 mg fixed dose as a 30 minute i.v. infusion on day 1 of every 3-
week (3 days) cycle for a maximum of 2 years or until trial termination. Please refer to 
Section 16.6 for details. Tumour assessment and biological sample collection after cross-
over follows the same schedule as the experimental arm (see Sections 13.1 and 15). 
10.4. 
Treatment of pleural effusion 
Puncture of the thoracic effusion and installation of a tunnelled drainage catheter are 
allowed whenever clinically indicated. Talc- or fibrin-pleurodesis are not allowed during 
trial treatment. Further surgical interventions for the treatment of mesothelioma, including 
pleurectomy decortication or pleuro-pneumonectomy, are not allowed during trial treatment. 
In case of a local infection and especially in case of an abscess, local treatment including 
decortication of the abscess is allowed. However, the patient is not allowed to commence or 
continue trial treatment until a complete resolution of the infection is documented. 


 
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10.5. 
Prohibited and restricted concomitant therapies during trial treatment 
(pembrolizumab, vinorelbine or gemcitabine) 
Locoregional therapy is left to the investigator’s discretion according to medical need (for 
treatment of pleural effusions see Section 10.4) with the exception of prohibited therapies 
listed below.  
Patients are prohibited from receiving the following therapies during the treatment phase of 
this trial: 
 Cytoreductive surgery (e.g., pleurectomy, extra-pleural pneumonectomy, or 
radiofrequency ablation). 
 Anti-cancer systemic chemotherapy or biological therapy. 
 Immunotherapy not specified in this protocol. 
 Chemotherapy not specified in this protocol. 
 Investigational agents other than pembrolizumab. 
 Live vaccines within 30 days prior to the first dose of trial treatment and while on 
trial treatment. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-
Mist®) are live attenuated vaccines, and are not allowed. 
 Glucocorticoids (more than 10 mg prednisolone equivalent) for any purpose other 
than for management of events of clinical importance, as pre-medication for the 
control chemotherapies, and/or a premedication for i.v. contrast allergies or 
reactions. The use of physiologic doses of corticosteroids (prednisone 10 mg orally 
daily or equivalent) is at the discretion of the investigator. 
 
Note: Palliative doses of radiation therapy and SBRT to a symptomatic solitary lesion or to 
the brain is allowed. Pembrolizumab treatment needs to be interrupted during palliative 
radiotherapy. 
10.6. 
Contraception, nursing, pregnancy 
10.6.1. Contraception 
Female patients who are not of childbearing potential due to being postmenopausal (2 years 
without menstruation) 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 from the start of trial treatment until 120 days after the last dose of any trial 


 
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treatment (pembrolizumab, vinorelbine or gemicitabine). The following contraception 
methods are considered highly effective: 
 Hormonal 
(estrogen 
and 
progesterone) 
contraception 
(oral, 
intravaginal, 
transdermal) associated with inhibition of ovulation 
 Progesterone-only hormonal contraception (oral, injectable, implantable) associated 
with inhibition of ovulation 
 Intrauterine deviced (IUD) or intrauterine hormone releasing systems (IUS) 
 Bilateral tubal occlusion 
 Vasectomy 
Women who become pregnant while participating in the trial must discontinue trial 
treatment immediately. The pregnancy must be reported following procedures detailed in 
Section 12.7. Also any pregnancy that occurs in a female partner of a male trial participant 
must be reported. 
Patients should be informed that taking the trial medication may involve unknown risks to 
the fetus if pregnancy were to occur during the trial. In order to participate in the trial they 
must adhere to the contraception requirement (described above) for the duration of the trial 
up to 120 days after the last dose of any trial treatment. If there is any doubt whether a 
patient will reliably comply with the requirements for contraception, that patient should not 
be entered into the trial. 
10.6.2. Use in pregnancy 
If a patient inadvertently becomes pregnant while on any trial treatment, trial treatment will 
be stopped immediately for the patient and the event reported immediately, see 
Section 12.12. The site will contact the patient at least monthly and document the patient’s 
status until the pregnancy has been completed or terminated. The outcome of the pregnancy 
will be reported to ETOP without delay and within 24 hours if the outcome is a serious 
adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn). The trial investigator will make every 
effort to obtain permission to follow the outcome of the pregnancy and report the condition 
of the fetus or newborn to ETOP.  
10.6.3. Use in nursing women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, patients who are breast-feeding are not eligible for randomisation. 
11. 
Safety of trial treatments 
11.1. 
Adverse effects of pembrolizumab 
As of 30 June 2015, 9400 patients had been treated with pembrolizumab at several dose 
schedules. The safety of pembrolizumab has been evaluated in 1012 patients across three 


 
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doses (2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks) in clinical studies. Most 
common adverse reactions (reported in ≥20% of patients) included fatigue, cough, nausea, 
pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. The majority of 
adverse reactions reported were of grade 1 or 2 severity. The most serious adverse reactions 
were immune-related adverse reactions and severe infusion-related reactions. 
As of 14 August 2015, data of 409 patients treated with 200 mg fixed dose were reviewed. 
The adverse events reviewed were consistent with the known adverse event profile for 
pembrolizumab; no new significant findings were evident. 
11.2. 
Immune-related adverse effects of pembrolizumab 
An immune-related adverse effect (irAE) is defined as a clinically significant adverse event 
of any organ that is associated with trial drug exposure, is of unknown aetiology, and is 
consistent with an immune-related mechanism.  
Immune-related adverse reactions are presented based on 2117 patients with melanoma and 
with NSCLC. The safety profile was generally similar for patients with melanoma and 
NSCLC. The most commonly reported irAEs across the dose-schedules are hypothyroidism 
(7.8%), hyperthyroidism (2.9%), pneumonitis (2.4%), and colitis (1.7 %). 
For the occurrence and management of immune-related adverse effects, please refer to 
section 10.2.2 in conjunction with the latest version of the pembrolizumab IB. 
Based on literature review and consideration of mechanism of action of pembrolizumab, 
potential immune-related adverse events (irAEs) are primary events of clinical interest 
(ECIs) and should be reported as SAEs (see Section 12.4.4 for details). 
11.3. 
Adverse effects of chemotherapy in the control arm 
11.3.1. Adverse effects of vinorelbine 
The most commonly reported adverse drug reactions are bone marrow depression with 
neutropenia, anaemia and thrombocytopenia, gastrointestinal toxicity with nausea, vomiting, 
diarrhoea, stomatitis and constipation. Fatigue and fever were also reported very commonly. 
The most commonly system organ classes involved are: 'Blood and lymphatic system 
disorders', 'Gastrointestinal disorders', 'Infections and infestations' and 'General disorders 
and administration site conditions'. This information is consistent with the pre-marketing 
experience (from SPC). 
11.3.2. Adverse effects of gemcitabine 
The most commonly reported adverse drug reactions associated with Gemcitabine treatment 
include: nausea with or without vomiting, raised liver transaminases (AST/ALT) and 
alkaline phosphatase, reported in approximately 60% of patients; proteinuria and haematuria 
reported in approximately 50% patients; dyspnoea reported in 10-40% of patients (highest 
incidence in lung cancer patients); allergic skin rashes occur in approximately 25% of 
patients and are associated with itching in 10% of patients (from SPC). 


 
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12. 
Adverse event and serious adverse event reporting 
ICH GCP and the EU Directive 2001/20/EC require that both investigators and sponsors 
follow specific procedures when notifying and reporting adverse events/reactions in clinical 
trials. These procedures are described in this section of the protocol. 
 
The main criterion for tolerability is the occurrence of toxicities and adverse events. The 
severity and causality will be classified according to the CTCAE version 4.0. The CTCAE is 
available for downloading on the internet at http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
An interactive version can be found at https://safetyprofiler-ctep.nci.nih.gov/. 
12.1. 
Adverse event (AE) 
An adverse event (AE) is defined as any untoward medical occurrence that occurs from the 
date of signature of informed consent until 30 days after all trial treatment discontinuation, 
regardless of whether it is considered related to a medication. 
Any grade of any observed AE should be reported on the AE eCRFs. 
12.2. 
Adverse reaction (AR) 
An adverse reaction (AR) is defined as “any noxious and unintended response to an IMP 
related to any dose administered”. 
All adverse events judged by either the reporting investigator or the ETOP medical reviewer 
as having a reasonable causal relationship (see Section 12.8) to an IMP qualify as adverse 
reactions. The expression “suspected/related” means to convey in general that there is 
evidence or argument to suggest a causal relationship to the trial treatment. 
12.3. 
Unexpected adverse reaction (UAR) 
An unexpected adverse reaction (UAR) is any adverse reaction, the nature, or severity of 
which is not consistent with the applicable product information. 
When the outcome of the adverse reaction is not consistent with the IB or summary of 
product characteristics (SPC), this adverse reaction should be considered as unexpected. 
12.4. 
Serious adverse events (SAE) 
A serious adverse event (SAE) is defined as any undesirable medical occurrence/adverse 
drug experience that at any dose: 
 results in death (any cause, except progression of cancer under study) 
 is life-threatening 
 requires or prolongs inpatient hospitalisation (see Section 12.4.1) 
 results in persistent or significant disability/incapacity 
 constitutes an important medical event 
 is a congenital anomaly or birth defect (including neonatal deaths) 
 is a secondary malignancy (see Section 12.4.3) 


 
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 is an event of clinical interest (see Section 12.4.4) 
12.4.1. Inpatient hospitalisation 
A hospital stay equal to, or greater than, 24 hours. Hospitalisations occurring under the 
following circumstances are not considered to be SAEs:  
 elective surgery 
 occur on an outpatient basis and do not result in admission (hospitalisation <24h) 
 are part of the normal treatment or monitoring of the studied treatment 
12.4.2. Important medical events 
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalisation, or disability, but may jeopardise the patient or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an AE should 
be considered serious. 
12.4.3. Secondary malignancies 
Primary malignancy 
A second primary malignancy is one that is unrelated to the treatment of a previous 
malignancy (and is NOT a metastasis from the previous malignancy). 
Secondary malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the previous malignancy. 
12.4.4. Events of clinical interest (ECI) 
The following events of clinical interest (ECIs) are not necessarily SAEs, but should be 
reported as such on the SAE eCRFs (SAE Initial Reports) by indicating that this is an 
“event of clinical interest”. 
 Drug induced liver injury (DILI): AST or ALT elevations ≥3x ULN with 
concurrent elevation of total bilirubin ≥2× ULN and, at the same time, alkaline 
phosphatase (AP) <2 × ULN. 
 Overdose: All overdoses with and without an AE must be reported by the 
investigator to ETOP safety office within 24 hours. 
 
 


 
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12.4.5. Pembrolizumab overdose 
An overdose of pembrolizumab is defined as ≥1000 mg (5 times the dose) of 
pembrolizumab. No specific information is available on the treatment of overdose of 
pembrolizumab. In the event of overdose, pembrolizumab should be discontinued and the 
patient should be observed closely for signs of toxicity. Appropriate supportive treatment 
should be provided if clinically indicated. 
If an AE is associated with (“results from”) the overdose of pembrolizumab, the AE is 
reported as SAE, even if no other seriousness criteria are met. 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported 
reported on the SAE Initial Report eCRF as ECI, using the terminology “accidental or 
intentional overdose without adverse effect.” 
All reports of overdose with and without an AE must be reported within 24 hours of 
awareness. 
12.4.6. Exceptions to the SAE definition  
The following situations do not need to be reported as SAEs:  
 Elective hospitalisation for pre-existing conditions that have not been exacerbated by 
trial treatment.  
 A hospitalisation which was planned before the patient consented for trial 
participation and where admission did not take longer than anticipated (see 
section 12.4.1). 
 A hospitalisation planned for protocol related treatment or protocol related procedure 
as per institutional standard timelines. 
 Social and/or convenience admission to a hospital.  
 Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an (serious) AE.  
 Situations where an untoward medical occurrence did not occur (palliative care, 
rehabilitation). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the trial that do not worsen significantly. 
 Progression of cancer under study: 
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 considers that their clinical 
significance deserves reporting. 


 
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12.5. 
Serious adverse reaction (SAR) 
A serious adverse reaction (SAR) is defined as any SAE which is considered related to the 
protocol treatment. 
12.6. 
Suspected unexpected serious adverse reaction (SUSAR) 
Suspected unexpected serious adverse reactions (SUSARs) occurring in clinical 
investigations qualify for expedited reporting to the appropriate regulatory authorities within 
the following timeframes:  
 Fatal or life-threatening SUSARs within 7 calendar days  
 Non-fatal or non-life-threatening SUSARs within 15 calendar days 
12.7. 
Severity / intensity of (serious) adverse events 
The (serious) AE severity grade provides a qualitative assessment of the extent or intensity 
of a specific event, as determined by the investigator or as reported by the patient. 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 trial drug. A severe event may be of relatively minor medical significance 
(such as severe headache). The term “severe” not the same as “serious” which is based on 
patient/event outcome or action criteria associated with events that pose a threat to a 
patient’s life or functioning. Seriousness, not severity, serves as a guide for defining 
regulatory obligations. 
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 moderate 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, hospitalisation is possible 
 Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalisation or 
hospice care probable 
 Grade 5 = Death – the event results in death 
 
 


 
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12.8. 
Causality of adverse events 
The investigator must determine the relationship between the administration of trial drug(s) 
and the occurrence of an AE/SAE following the definitions indicated below: 
Not suspected 
The temporal relationship of the adverse event to trial drug(s) 
administration makes a causal relationship unlikely or remote, 
or other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed 
event. 
Suspected 
The temporal relationship of the adverse event to trial drug(s) 
administration makes a causal relationship possible, and other 
medications, therapeutic interventions, or underlying conditions 
do not provide a sufficient explanation for the observed event. 
 
 
Relationship to the protocol treatment 
Not suspected  
Suspected / related to trial treatment 
- 
unrelated 
- 
unlikely 
- 
possible 
- 
probable 
- 
definite 
12.9. 
Duration of adverse events 
For both AEs and SAEs, the investigator will provide a record of the start and stop dates of 
the event. 
12.10. Action taken 
The investigator will report the action taken with trial drug(s) because of an AE or SAE, as 
applicable (e.g., discontinuation of trial drug(s), medication needed for the treatment of an 
AE) and in case of an SAE report if concomitant and/or additional treatments were given for 
the event. 
12.11. Reporting SAEs and ECIs 
Any SAE and any ECI, whether related to trial drug or not, occurring in a patient after 
providing written informed consent (IC) within 90 days after last dose of trial treatment or 
within 30 days following cessation of trial treatment, if the patient initiates a new anticancer 
therapy, must be reported. Information about all such events will be collected and recorded 
on the SAE eCRFs (SAE Initial Reports). 
After completion of trial treatments, report all SAEs beyond 90 days (or beyond 30 days 
following cessation of trial treatment, if the patient initiates new anticancer therapy) that are 
considered at least possibly related to previous trial treatment. Cases of secondary (non-
pleura) malignancies and congenital abnormalities and neonatal deaths are to be cosidered 


 
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as SAEs, regardless of whether they occur during or after trial treatment. These events 
should be reported during the whole trial duration on the serious adverse event eCRFs (SAE 
Initial Reports) 
To ensure patient safety, ETOP must be informed of each SAE and each ECI using the 
procedures described below: 
 The investigator/MD responsible for the patient must complete an SAE Initial 
Report eCRF in English within 24 hours of awareness in the EDC system ETOPdata. 
 Queries may be issued by the ETOP safety office; a timely response by the 
investigator to all SAE-related queries is crucial. 
 The SAE outcome must be reported within 15 days after initial reporting by online 
submitting the SAE Follow-up Report eCRF. In case the SAE is reported as ongoing 
after 15 days, a second follow-up report has to be submitted with the final outcome. 
Submission of SAE is done via the EDC system, or in case of unavailability, by sending the 
SAE form by fax to the ETOP Safety Office: 
+41 31 389 92 29 
As soon as the EDC system is available again, the SAE eCRF has to be completed and 
submitted by the site. 
The ETOP safety office will inform Merck Global Safety and other appropriate persons 
about all SAEs and ECIs within 24 hours of receipt at the ETOP safety office.  
The ETOP Safety Office will record the SAE/ECI and prepare a summary report of all 
SAEs/ECIs received. Listings of SAEs will be prepared as required. 
12.12. Pregnancy 
Please refer to section 10.6 for information on contraception, nursing, pregnancy and highly 
effective contraception methods. 
12.12.1. Maternal exposure 
In the case of pregnancy occurring during the course of the trial or within 120 days after 
treatment discontinuation, the investigator shall immediately (within 24 hours after 
awareness of pregnancy) notify ETOP by completing the pregnancy eCRF in ETOPdata in 
accordance with the SAE reporting procedures. 
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported (within 
14 days) by submitting a second pregnancy eCRF in ETOPdata. All neonatal deaths that 
occur within 28 days of birth should be reported, irrespective of causality, as SAEs. In 
addition, any infant death after 28 days, irrespective of causality should also be reported 
within 24 hours of the investigator’s knowledge of the event using the SAE forms. 
 
 


 
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12.12.2. Paternal exposure 
Pregnancy that occurs in a female partner of a male trial participant is not considered to be 
an adverse event. However, the outcome of all pregnancies (spontaneous miscarriage, 
elective termination, ectopic pregnancy, normal birth or congenital abnormality) should be 
reported to during the course of the trial or within 120 days after treatment discontinuation 
by completing the pregnancy eCRF in ETOPdata. 
 
12.13. Reference safety information 
The pembrolizumab IB edition 10 Section 7 served as reference document for the 
determination of the expectedness of the serious adverse events of pembrolizumab. 
The currently EU approved summary of product characteristics (SPC) of vinorelbine and 
gemcitabine serve as reference safety information to assess the expectedness of vinorelbine 
and gemcitabine related serious adverse events. 
 
 


 
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13. 
Response evaluation 
13.1. 
CT schedule for response evaluation 
Radiological tumour assessment by CT scans of thorax / upper abdomen (from top of thorax 
until adrenal glands and full liver and kidney included, preferred) or alternatively (and only 
after the first CT at baseline) CT of thorax and ultrasonography of upper abdomen following 
the schedule indicated below; until tumour progression determined according to 
RECIST 1.1 criteria. If pembrolizumab treatment is continued beyond progression, 
radiological tumour assessment by CT has to continue until pembrolizumab treatment stop. 
The same imaging technique, acquisition, and processing parameters should be used in a 
patient throughout the trial. 
At baseline: 
within 5 weeks before randomisation 
First 6 months (up to week 27): 
 
every 9 weeks* (63 days) 
at week 9, 18, 27 (±4 days) 
Up to 2 years: 
every 12 weeks* (84 days) 
at week 39, 51, 63, …99 (±7 days) 
* from start of pembrolizumab/chemotherapy treatment  
 
CT schedule after cross-over 
Patients in the control arm are allowed to cross over to receive pembrolizumab beyond 
determined progression determined according to RECIST 1.1 criteria, for a maximum of 
2 years from start of pembrolizumab treatment. Radiological tumour assessment by CT 
scans of thorax / upper abdomen (from top of thorax until adrenal glands and full liver and 
kidney included) will be done according to the schedule indicated below, until further 
tumour progression determined according to RECIST 1.1 criteria or until a maximum of 
2 years from start of pembrolizumab treatment, or trial termination. If pembrolizumab 
treatment is continued beyond further progression, radiological tumour assessment by CT 
has to continue until pembrolizumab treatment stop. 
First 6 months (up to week 27): 
 
every 9 weeks* (63 days) 
at week 9, 18, 27 (±4 days) 
Up to 2 years: 
every 12 weeks* (84 days) 
at week 39, 51, 63, …99 (±7 days) 
* from start of pembrolizumab  
13.2. 
Response evaluation criteria in solid tumours (RECIST version 1.1) 
13.2.1. Introduction 
All included patients will be evaluated for disease response and progression according to the 
revised response evaluation criteria in solid tumours (RECIST version 1.1) [29]. 
In this trial, patients must have measurable or evaluable disease (see definitions below). 
13.2.2. Methods of assessment 
In this trial, CT scans will be used to evaluate response.  


 
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The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumour effect of a treatment. 
CT scan is the best currently available and reproducible method to measure lesions selected 
for response assessment. CT scan should generally be performed using a ≤5 mm contiguous 
reconstruction algorithm. MRI is acceptable for certain situations, e.g., body scans. 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules) and ≥10 mm. In the case of skin lesions, documentation by colour photography 
including a ruler to estimate the size of the lesion is recommended. 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT scan is preferable. 
Ultrasound is not useful in assessment of lesion size and is not accepted as a method of 
assessment. 
FDG-PET is not foreseen for regular response assessments. It may, however, be used to 
detect or confirm the appearance of new lesions. Attenuation correction CT scans performed 
as part of a PET/CT scan frequently show lower resolution; therefore, dedicated CT scans 
are preferred. However, if the site can demonstrate that the CT scan performed as part of a 
PET/CT is of the same diagnostic quality as a diagnostic CT scan (with i.v. and oral 
contrast), then the CT scan portion of the PET/CT can be used for RECIST measurements. 
13.2.3. Measurable disease 
Measurable disease is defined as the presence of at least one measurable lesion. 
Measurable lesions: 
 Tumour lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
- 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
- 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
- 20 mm by chest X-ray 
Reminder: A lesion in a previously irradiated area is not eligible for measurable 
disease. 
 Malignant lymph nodes: to be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by CT 
scan, assuming the slice thickness is ≤5 mm. At baseline and in follow-up, only the 
short axis will be measured. 
13.2.4. Non-measurable disease 
Non-measurable disease is defined as lesions or sites of disease that cannot be measured.  
Non-measurable lesions/sites of disease and special considerations:  


 
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 Small non-nodal lesions (longest diameter <10 mm in CT scan) 
 Small lymph nodes (short axis ≥10 and <15 mm). Lymph nodes that have a short 
axis <10 mm are considered non-pathological and should not be recorded or 
followed as measurable or non-measurable disease. 
 Bone lesions. Lytic bone lesions or mixed lytic-blastic lesions, with identifiable 
soft tissue components, can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above. Blastic bone 
lesions are non-measurable. 
 Leptomeningeal disease 
 Ascites 
 Pleural or pericardial effusion 
 Lymphangitic involvement of skin or lung 
 Cystic lesions. Cystic lesions thought to represent cystic metastases may be 
considered as measurable lesions. However, if non-cystic lesions are present, these 
are preferred as target lesions 
 Tumour lesions situated in a previously irradiated area, or subjected to other 
locoregional therapy. Such lesions may be considered measurable if there has been 
demonstrated progression in the lesion 
 Abdominal masses/abdominal organomegaly identified by physical exam that are 
not measurable by reproducible imaging techniques 
13.2.5. Selection of target lesions 
Target lesions should be identified, measured and recorded at baseline. At baseline, there 
can be up to a maximum of 5 lesions representative of all involved organs, and up to 2 per 
organ. Target lesions should be selected on the basis of their size and their suitability for 
accurate repetitive measurements. A sum of diameters for all target lesions will be 
calculated and reported as the baseline sum of diameters. Lymph nodes selected as target 
lesions should always have the short axis recorded. All other lesions should always have 
their longest diameters recorded. The sum of diameters will be used as reference to further 
characterize the objective tumour response of the measurable dimension of the disease. 
13.2.6. Selection of non-target lesions  
All other lesions (or sites of disease) not identified as target lesions should also be recorded 
as non-target lesions at baseline.  
For non-target lesions, measurements are not required, but the presence or absence of each 
should be noted throughout follow-up. It is possible to record multiple non-target lesions as 
a single item on the eCRF. 
Note: pleural effusion is a non-target lesion. 
 
 


 
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13.2.7. Evaluation of target lesions 
All target lesions will be measured at each tumour assessment, and the sum of their 
diameters will be compared to previous assessments in order to assign the response status as 
specified below. 
 Complete response (CR): Disappearance of all target lesions. Lymph nodes selected 
as target lesions must each have reduction in the short axis to <10 mm in order for 
the response to be considered complete. In this case, the sum of diameters may be  > 
0. 
 Partial response (PR): At least a 30% decrease in the sum of diameters of target 
lesions taking as reference the baseline sum of diameters. 
 Progression (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum recorded on study. In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm. The appearance of one or more new lesions (see section 13.2.9) denotes disease 
progression. 
 Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest sum of diameters recorded 
on study. 
Note: All target lesions, including lymph nodes, should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm). If the 
radiologist does not feel comfortable assigning an exact measure and reports a lesion as "too 
small to measure", a default value of 5 mm should be recorded. If a target lesion is thought 
likely to have disappeared, use "0 mm." 
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. 
13.2.8. Evaluation of non-target lesions  
 Complete response (CR): Disappearance of all non-target lesions; lymph nodes 
selected as non-target lesions must be non-pathological in size (<10 mm). 
 Non-CR/non-PD: Persistence of one or more non-target lesions (non-CR). 
 Progression (PD): unequivocal progression of existing non-target lesions. 
Unequivocal means: comparable in magnitude to the increase that would be required 
to declare PD for measurable disease, or an overall substantial increase in tumour 
burden that merits treatment discontinuation. 
When no imaging is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point. If only a subset of lesions are evaluated at an assessment, usually the case is 
also considered NE at that time point, unless a convincing argument can be made that the 


 
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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. 
13.2.9. Determination of new lesions 
The appearance of any new malignant lesions denotes disease progression. The finding of a 
new lesion should be unequivocal, i.e. not attributable to differences in scanning technique 
or findings thought to represent something other than tumour. If a new lesion is equivocal, 
e.g., because of its small size, the patient will stay on treatment (if the decision on PD is 
based on this lesion only). If the repeat scans confirm there is definitely a new lesion, then 
progression should be declared using the date of the previous scan when the lesion was 
discovered. 
Lesions or sites of disease found in a new location not included in the baseline scan (e.g., 
brain metastases) are considered new lesions. The detection of new lesions is not restricted 
to the examination methods used at baseline. 
Note: the "re-appearance" of a previously "disappeared" target or non-target lesion does not 
in itself necessarily qualify as PD; this is the case only if the overall evaluation meets the 
PD criteria, or if the patient was previously in CR. 
13.2.10. Additional considerations 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumour has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an effusion 
may be a side effect of the treatment) and progressive disease. 
13.2.11. When the patient has only non-measurable disease 
This circumstance arises in some phase III trials when it is not a criterion of study entry to 
have measurable disease. The same general concepts apply here as noted above, however, in 
this instance there is no measurable disease assessment to factor into the interpretation of an 
increase in non-measurable disease burden. Worsening in non-target disease cannot be 
easily quantified (by definition: if all lesions are truly non-measurable). 
A useful test that can be applied when assessing patients for unequivocal progression is to 
consider if the increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to declare PD for 
measurable disease: i.e.an increase in tumour burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable 
lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’ or an 
increase in lymphangitic disease from localised to widespread. Some illustrative examples 
are shown in Figs. 5 and 6 in Appendix II of reference [29]. 
If ‘unequivocal progression’ is seen, the patient should be considered to have had overall 
PD at that point. While it would be ideal to have objective criteria to apply to non-


 
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measurable disease, the very nature of that disease makes it impossible to do so, therefore 
the increase must be substantial. 
13.2.12. Determination of time point response 
Based on the responses of target lesions, non-target lesions, and the presence or absence of 
new lesions, the overall response will be determined at each tumour evaluation time point, 
according to the table below. 
13.2.13. For patients with measurable disease 
Table 6: Measurable disease - overall 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 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any  
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes  
PD 
*Non-CR/non-PD should be used rather than SD for categorizing non-target lesions.  
 
13.2.14. For patients with non-measurable disease 
Table 7: Non-measurable Disease - Overall Response 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR / non-PD* 
No 
Non-CR / non-PD* 
Not evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any  
Yes 
PD 
*Non-CR/non-PD should be used rather than SD for categorizing non-target lesions.  
 
13.2.15. Determination of best overall response 
Best overall response is defined as best response recorded from the start of treatment across 
all time points until disease progression. Confirmation of partial or complete response by an 
additional scan is not requested in this trial. 


 
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13.2.16. Storage of images 
All CT images must be stored locally in electronic format for later central review, please 
consult the PROMISE-meso Procedures Manual for details. 
14. 
Endpoints definition 
14.1. 
Progression-free survival  
PFS 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 or refuses further documentation of follow-up. 
14.2. 
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 
response to pembrolizumab treatment will be determined using RECIST 1.1 criteria (see 
Section 13.2). 
14.3. 
Overall survival  
OS is defined as time from the date of randomisation until death from any cause. Censoring 
will occur at the last follow-up date. 
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 CTCAE version 4.0. 
15. 
Biological material and translational research 
15.1. 
Biobanking 
A biobank for all biological material collected from every patient randomised in this trial 
will be created with centralised samples for translational research, integral to the trial. The 
required pathological material (described below) is submitted to, catalogued, and maintained 
at the central laboratory: Tumour tissue blocks, whole blood, and serum samples will be 
centrally collected and biobanked at the Center for Experimental Therapeutics CTE, CHUV 
Lausanne, Switzerland. The material will be centrally archieved and subjected to central 
histology review and biomarker testing. Eventually, the biological material will be made 
available for translational research, following completion of the primary trial translational 
research objectives. 


 
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15.2. 
Mandatory biomaterial 
15.2.1. FFPE-material 
FFPE tumour tissue availability must be confirmed at time of randomisation and material 
shipped within 4 weeks thereafter. 
 Formalin-fixed, paraffin embedded (FFPE) archival tumour material from primary 
diagnosis must be submitted centrally. In addition, a fresh biopsy sample taken close 
to the start of trial treatment (after first-line therapy) should be submitted, if 
available. A fresh FFPE biopsy sample is mandatory if the archival tumour material 
from diagnosis is fully depleted. 
 Submission of an FFPE tumour tissue block is strongly preferred but, if not available, 
5 slides with FFPE tumour tissue sections of 4-5 µm thickness are an acceptable 
alternative. All slides should be freshly cut and shipped to the central reference 
laboratory within 1 week of sectioning. 
 Cytological specimens are not accepted in this trial. 
15.2.2. Blood and serum samples 
 2.5 mL whole blood will be collected in PAXgene RNA tubes (for RNA profiling) at 
baseline, on day 1 of treatment cycle 3, and at disease progression. 
 2.5 mL whole blood will be collected in PAXgene DNA tubes (for germline 
mutation assessment as a reference for tumour somatic mutation analysis) at baseline. 
 Serum samples from 5 mL blood taken at baseline, on day 1 of treatment cycle 3 
(week 6), and at disease progression. 
 All samples should be immediately frozen at -80ºC. 
 
 
Malignant pleural mesothelioma
after/on previous platinum based 
chemotherapy 
1 : 1
R
Pembrolizumab 200mg fixed dose i.v. day 1 of each 3-week cycle 
Chemotherapy by institutional choice
Gemcitabine 1000 mg/m2 d1/d8, q3w i.v. or
Vinorelbine
30 mg/m2
d1/d8, q3w i.v. or
Vinorelbine
60/80 mg/m2 d1/d8 q3w p.o.

CT
CT
3
Week
6
9
18
27
0
-4
39

until PD by RECIST 1.1
for max 2 years*
Blood
FFPE
Blood
Blood
CT
CT
CT
CT
Progression 
of 
disease
(FFPE)
Progression 
of 
disease

* continuation beyond PD in 
case of clinical benefit


 
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15.3. 
Optional biomaterial 
15.3.1. FFPE-material 
FFPE tumour block (preferred) or alternatively 5 tissue sections of 4-5 µm thickness, and 
10-15 tumour tissue sections of 15-20 µm thickness from re-biopsy at disease progression. 
If blocks were not submitted, an additonal 10-15 tumour tissue sections of 15-20 µm 
thickness from archival tumor and/or fresh biopy, if feasible. 
15.4. 
Translational research 
The following table gives an overview of all biological material collected during the trial 
and the associated translational research projects under consideration. These projects will be 
continuously adapted according to the growing knowledge about immunological 
modification and potential biomarkers of immune checkpoint inhibitor therapy. 
Translational research studies will be conducted by ETOP-internal and -external 
collaborators in line with the ETOP iBiobank policy. 
 
Table 8: Overview of translational research studies 
Sample 
Time point 
Potential analyses 
Diagnosis 
(archival) 
Baseline 
Day 1 of 
cycle 3(1) 
PD 
FFPE (To be shipped to the central laboratory within 4 weeks after randomisation) 
 
- Tumour block 
 
OR 
X 
X 
 
optional 
- IHC/mutational analyses 
listed below 
- min. 5 sections 
of 
 
4-5 μm 
X 
X 
 
optional 
- PD-L1 (IHC) 
- TILs analysis (H&E) 
- 5-10 sections 
 
of 15-20 μm 
optional 
optional 
 
optional 
- Mutation load 
- PD-L2 (IHC) 
- PD-L1 (IHC) with different 
antibody? 
- DNA/RNA (NGS) 
Archival tumour material from primary diagnosis must be submitted. In addition, a fresh biopsy sample taken 
close to the start of trial treatment (after first-line therapy) should be submitted, if available. (A fresh FFPE 
biopsy sample is mandatory if the archival tumour material from diagnosis is fully depleted). 
Blood samples (Frozen samples kept at site at -80°C until centrally arranged shipment) 
Whole blood – 
RNA 
 
2.5 mL 
2.5 mL 
2.5 mL 
- RNA profiling 
Whole blood – 
DNA 
 
2.5 mL 
 
 
- Germline mutation 
reference (HLA haplotype) 
Serum 
 
5 mL 
5 mL 
5 mL 
- Cytokines 
- ctDNA 
- IL6 
- Mesothelin 
- CRP 
(1) For patients in the control arm and crossing over to pembrolizumab, these samples will be collected twice, on day 1 of cycle 3 and at 
PD on chemotherapy as well as on day 1 of cycle 3 and at PD on pembrolizumab treatment. 


 
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15.5. 
Submission of biomaterial 
All biological samples collected during the conduct of the trial must be marked with the 
patient identifier issued by the EDC system and registered in the system. FFPE tumour 
tissue and blood samples will be shipped to the central reference laboratory in Lausanne 
(Ludwig Institute for Cancer Research, University of Lausanne, Switzerland). 
15.5.1. Submission of FFPE material 
 FFPE tumour material as defined in Section 15.2.1. and Section 15.3.1. 
 Pathology report from diagnostic biopsy and from biopsy after first-line therapy (all 
information allowing identification of the patient, e.g., patient name, day and month 
of birth, must be removed). 
 Pathology report from re-biopsy at progression (all information allowing 
identification of the patient, e.g., patient name, day and month of birth, must be 
removed). 
Tumour material should be submitted as soon as obtained (but not no later than 4 weeks 
after patient randomisation), and documented in the Biological Material Tracking eCRF in 
the database. On request, blocks can be returned to the submitting site within a reasonable 
time frame (est. 3 months) and after slides for the planned analyses have been cut. 
All reports, slides, and blocks must be marked with the patient identification number issued 
by the EDC system.  
Please ensure that the blocks and/or slides are carefully packaged according to the 
PROMISE-meso Procedures Manual, as otherwise they could easily get damaged during 
transport. 
Samples have to be sent to: 
CHUV - Department of Oncology 
 
Center for Experimental Therapeutics (CTE) 
 
Hôpital Orthopédique, HO 05/1552 
 
Av. Pierre-Decker 4 
 
CH-1011 Lausanne, Switzerland 
 
Anonymised pathology reports should be uploaded via the EDC system. Please consult the 
PROMISE-meso Procedures Manual for specific instructions. 
15.5.2. Submission of blood samples 
For blood collection and serum preparation see PROMISE-meso procedures manual. 
Blood samples as defined in Sections 15.2.2. and 15.3.2. 
Blood samples must be stored locally at -80ºC and will be kept at the participating site until 
shipment. Shipments will be arranged centrally once a site has collected all blood samples 
after the inclusion of the last patient. Samples have to be sent to the same address as 
indicated above. 


 
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16. 
Trial procedures 
This section gives an overview of procedures, clinical and laboratory evaluations and 
follow-up investigations. 
16.1. 
Tumour assessment 
Radiological tumour assessment by CT scans of thorax / upper abdomen (from top of thorax 
until adrenal glands and full liver and kidney included) will be done as indicated in section 
13.1. 
16.2. 
Baseline evaluations before randomisation 
The following examinations should be done within 5 weeks (35 days) before randomisation. 
If examinations were done prior to 5 weeks (35 days) before start of randomisation, they 
have to be repeated. 
16.2.1. Written informed consent: 
before any trial specific evaluations or interventions 
16.2.2. Radiological tumour assessment 
by CT scan of thorax / upper abdomen (from top of thorax until adrenal glands and 
full liver and kidney included) 
16.2.3. Medical history: 
including baseline symptoms, smoking history, medications, comorbidities and 
allergies 
16.2.4. Physical examination: 
including, ECOG performance status, blood pressure, heart rate, temperature, body 
weight, height. 
16.2.5. HIV test 
16.2.6. Thyroid function: 
TSH value. In case of abnormal TSH, free T3 and T4 have also to be measured. 
16.2.7. Chemistry: 
serum albumin, glucose, potassium, sodium, calcium, amylase, lipase and LDH 
16.2.8. Haematology:  
haemoglobin, platelet count, white blood cell (WBC) count including differential 
(lymphocytes and absolute neutrophil count).  
16.2.9. Coagulation profile (INR) 
16.2.10. Liver function tests: 
total bilirubin, ALT, AST, ALP, GGT 


 
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16.2.11. Renal function tests: 
urea, uric acid, serum creatinine and and creatinine clearance calculated according 
to Cockroft-Gault. 
16.2.12. Urine analysis: 
specific gravity, pH, proteins, glucose, blood using a dipstick; elements and 
microscopic examination if needed. 
16.2.13. Pregnancy test: 
Women of childbearing potential, including women who had their last menstrual 
period within the last 2 years, must have a negative serum or urine beta-HCG 
pregnancy test within 35 days before randomisation. The test has to be repeated 
within 72 hours before pembrolizumab treatment start and then every 2nd cycle of 
pembrolizumab treatment.  
16.2.14. Pulmonary function: 
FEV1 and FVC (strongly encouraged) 
16.2.15. Biological material (see Section 15.2 and 15.3 for details): 
FFPE material: archival tumour material from primary diagnosis. In addition, a 
fresh biopsy sample taken close to the start of trial treatment (after first-line 
therapy) if available.  
Note: A fresh biopsy sample is mandatory if the archival tumour material from 
diagnosis is fully depleted. 
 
Blood samples: 2 x 2.5 mL whole blood for RNA and DNA analysis and 
5 mL serum samples. 
16.3. 
Evaluations in the experimental arm (pembrolizumab treatment) 
 
At each treatment cycle 
The following evaluations have to be done on day 1 of every treatment cycle (or within 
3 days before these dates): 
16.3.1. Recording of symptoms, adverse events and concomitant medications. 
16.3.2. Physical examination: 
including ECOG performance status, blood pressure, heart rate, temperature, body 
weight. 
16.3.3. Chemistry: 
serum albumin, glucose, potassium, sodium, calcium, amylase, lipase and LDH 


 
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16.3.4. Haematology:  
haemoglobin, platelet count, white blood cell count including differential 
(lymphocytes and absolute neutrophil count).  
16.3.5. Liver function tests: 
total bilirubin, ALT, AST, ALP, GGT 
16.3.6. Renal function tests: 
urea, uric acid, serum creatinine and and creatinine clearance calculated according 
to Cockroft-Gault. 
 
At every 2nd treatment cycle 
The following additional evaluations have to be done on day 1 (or within 3 days before 
these dates) of every other treatment cycle, (i.e. cycle 1, 3, 5, 7, 9, etc): 
16.3.7. Thyroid function: 
TSH value. In case of abnormal TSH, free T3 and T4 have also to be measured. 
16.3.8. Coagulation profile (INR) 
16.3.9. Urine analysis: 
specific gravity, pH, proteins, glucose, blood using a dipstick; elements and 
microscopic examination if needed. 
16.3.10. Pregnancy test: 
Women of childbearing potential, including women who had their last menstrual 
period within the last 2 years, must have a negative serum or urine beta-HCG 
pregnancy test. The test has to be repeated within 72 hours before pembrolizumab 
treatment start and then every 2nd cycle of pembrolizumab treatment. 
 
At treatment cycle 3 
The following additional evaluations have to be done on day 1 of treatment cycle 3 (or 
within 3 days before this date): 
16.3.11. Pulmonary function: 
relative FEV1 and FVC (strongly encouraged) 
16.3.12. Biological material (see Section 15.2 and 15.3 for details): 
Blood samples:  
- 2.5 mL whole blood for RNA analysis 
- 5 mL serum samples. 


 
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16.4. 
Evaluations in the control arm (chemotherapy treatment) 
 
At each treatment cycle 
The following evaluations have to be done within 3 days before day 1 of each chemotherapy 
treatment cycle: 
16.4.1. Recording of symptoms, adverse events and concomitant medications. 
16.4.2. Physical examination: 
ECOG performance status, blood pressure, heart rate, temperature, body weight. 
16.4.3. Chemistry: 
serum albumin, glucose, potassium, sodium, calcium, amylase, lipase and LDH 
16.4.4. Haematology:  
haemoglobin, platelet count, white blood cell count including differential 
(lymphocytes and absolute neutrophil count).  
16.4.5. Liver function tests: 
total bilirubin, ALT, AST, ALP, GGT 
16.4.6. Renal function tests: 
urea, uric acid, serum creatinine and and creatinine clearance calculated according 
to Cockroft-Gault. 
 
At treatment cycle 3 
The following evaluations have to be done on day 1 of treatment cycle 3 (or within 3 days 
before this date): 
16.4.7. Pulmonary function: 
relative FEV1 and FVC (strongly encouraged) 
16.4.8. Biological material (see Section 15.2 and 15.3 for details): 
Blood samples:  
- 2.5 mL whole blood for RNA analysis  
- 5 mL serum samples. 
16.5. 
Evaluations at disease progression 
At progression, the following assessments are required: 
16.5.1. Pulmonary function: 
relative FEV1 and FVC (strongly encouraged) 


 
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16.5.2. Biological material (see Section 15.2 and 15.3 for details): 
FFPE: tumour re-biopsy is strongly encouraged 
Blood samples:  
- 2.5 mL whole blood for RNA analysis  
- 5 mL serum samples. 
16.6. 
Evaluations after cross-over to pembrolizumab treatment 
At documented disease progression according to RECIST 1.1 criteria, patients in the control 
arm are allowed to receive pembrolizumab, if they meet the cross-over criteria (see 
Section 10.3.3). The following evaulations have to be performed during pembrolizumab 
treatment: 
 
At each treatment cycle 
The following evaluations have to be done on day 1 of every pembrolizumab treatment 
cycle (or within 3 days before these dates): 
16.6.1. Recording of symptoms, adverse events and concomitant medications. 
16.6.2. Physical examination: 
including ECOG performance status, blood pressure, heart rate, temperature, body 
weight. 
16.6.3. Chemistry: 
serum albumin, glucose, potassium, sodium, calcium, amylase, lipase and LDH. 
16.6.4. Haematology: 
haemoglobin, platelet count, white blood cell count including differential 
(lymphocytes and absolute neutrophil count). 
16.6.5. Liver function tests: 
total bilirubin, ALT, AST, ALP, GGT. 
16.6.6. Renal function tests: 
urea, uric acid, serum creatinine and and creatinine clearance calculated according 
to Cockroft-Gault. 
 
At first treatment cycle and then every 2nd cycle  
The following evaluations have to be done on day 1 (or within 3 days before these dates) of 
every other pembrolizumab treatment cycle, (i.e. cycle 1, 3, 5, 7, 9, etc): 
16.6.7. Thyroid function: 
TSH value. In case of abnormal TSH, free T3 and T4 have also to be measured. 


 
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16.6.8. Coagulation profile (INR) 
16.6.9. Urine analysis: 
specific gravity, pH, proteins, glucose, blood using a dipstick; elements and 
microscopic examination if needed. 
16.6.10. Pregnancy test: 
Women of childbearing potential, including women who had their last menstrual 
period within the last 2 years, must have a negative serum or urine beta-HCG 
pregnancy test within 35 days before randomisation. The test has to be repeated 
within 72 hours before pembrolizumab treatment start and then every 2nd cycle of 
pembrolizumab treatment. 
 
At treatment cycle 3 
The following evaluations have to be done on day 1 of pembrolizumab treatment cycle 3 (or 
within 3 days before this date): 
16.6.11. Pulmonary function: 
relative FEV1 and FVC (strongly encouraged) 
16.6.12. Biological material (see Section 15.2 and 15.3 for details): 
Blood samples: 
- 2.5 mL whole blood for RNA analysis 
- 5 mL serum samples. 
16.7. 
Evaluations at the 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 decision to 
stop trial treatment. The following procedures should be performed: 
16.7.1. Recording of symptoms, adverse events and concomitant medications. 
16.7.2. Physical examination: 
including ECOG performance status, blood pressure, heart rate, temperature, body 
weight. 
16.7.3. Chemistry: 
serum albumin, glucose, potassium, sodium, calcium, amylase, lipase and LDH. 
16.7.4. Haematology:  
haemoglobin, platelet count, white blood cell count including differential 
(lymphocytes and absolute neutrophil count). 
 


 
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16.7.5. Liver function tests: 
total bilirubin, ALT, AST, ALP, GGT. 
16.7.6. Renal function tests: 
urea, creatinine and uric acid, serum creatinine and creatinine clearance calculated 
according to Cockroft-Gault. 
16.7.7. Pregnancy test (pembrolizumab treatment only). 
16.7.8. Radiological tumour assessment 
by CT scan of thorax / upper abdomen (from top of thorax until adrenal glands and 
full liver and kidney included), if not done within the last 6 weeks. 
 
16.8. 
Evaluations in the follow-up phase (post treatment) before progression 
Patients who completed pembrolizumab treatment (after 2 years, this corresponds to an 
expected maximum of 36 doses) or discontinue trial treatment before progression should 
have the following examinations documented every 12 weeks (2 week) starting from date 
of end of treatment visit/last dose of treatment received up to 2 years after the randomisation 
of the last patient. 
16.8.1. Physical examination: 
including ECOG performance status, blood pressure, heart rate, temperature, 
body weight. 
 
16.9. 
Evaluations in the follow-up phase (post treatment) beyond progression 
Patients with progression will end trial treatment (exceptions see Section 10.2.7) and will be 
followed up every 12 weeks (2 week) starting from date of progression up to 2 years after 
the randomisation of the last patient. 
They should have documented: 
16.9.1. Survival 
16.9.2. Further lines of treatment 
 
 


 
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17. 
Case report forms and documentation 
17.1. 
Case report forms schedule 
eCRFs will only be available on-line at the electronic data capture (EDC) 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 9 Case report forms 
CRF in ETOPdata 
To be completed 
1 - Eligibility Check and 
Randomisation 
Within 35 days of start of baseline evaluations. 
2 - Baseline 
Within 14 days after randomisation. 
3 - Tumour Assessments  
Baseline before randomisation: within 14 days after 
randomisation; 
During trial: within 14 days of date of each imaging; 
After cross-over: within 14 days of date of each imaging; 
At end of treatment visit if not done within the last 6 weeks. 
4 - Concomitant 
Medications 
Continuously from date of randomisation to 30 days after 
end of trial treatment.  
To be updated: 
- 
within 14 days after randomisation; 
- 
within 14 days of start of each Experimental; 
Arm/Control Arm cycle; 
- 
within 14 days of End of Treatment visit; 
- 
within 14 days of Follow-up visits. 
5 - Experimental Arm /  
Control Arm  
Within 14 days of start of each treatment cycle. 
6 - Adverse Events  
Continuously from date of Informed Consent signature until 
30 days after trial treatments discontinuation. 
To be updated:  
- 
within 14 days of randomisation (baseline 
symptoms); 
- 
within 14 days of start of each Experimental 
Arm/Control Arm cycle; 
- 
within 14 days after End of Treatment visit; 
- 
within 14 days of Follow-up visits. 
7 - Serious Adverse Event 
Initial Reports 
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. 


 
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CRF in ETOPdata 
To be completed 
8 - Serious Adverse Event 
Follow-up Reports 
Within 15 days of completion of initial report. 
If event was not resolved after 15 days, submit an additional 
report within 7 days of resolution of event. 
9 - End of Treatment 
Within 14 days after End of Treatment visit (which is to take 
place within 30 days following the decision to stop initial 
trial treatment). 
10 - Cross-Over to 
Pembrolizumab Treatment 
Only for patients in Control Arm 
11 - End of Treatment after 
Cross-Over 
Only for patients in Control Arm after cross-over 
Within 14 days after End of Treatment visit (which is to take 
place within 30 days following the decision to stop trial 
treatment). 
12 - Follow-up  
Follow-up before/after progression: 
Within 14 days of clinical follow-up visits. 
Follow-up on death:  
Within 14 days upon awareness of death. 
13 - Pregnancy  
Within 24h of first documentation of pregnancy; 
Within 14 days of end of pregnancy. 
14 - Biological Material 
Tracking  
This eCRF is to be completed incrementally. 
Entries are to be made: 
- 
within 4 weeks of randomisation: for information 
pertaining to “Tumour material from primary 
diagnosis” (archival) and/or fresh biopsy taken close 
to the start of trial treatment (at randomization, after 
disease progression on first-line therapy); 
- 
immediately after local storage of blood samples (on 
same day): for information pertaining to “Date of 
blood draw”; 
- 
immediately (on same day) after submission of 
material (FFPE and blood) for central biobanking: 
for “Date Sent to Central Laboratory”; 
- 
within 4 weeks of progression: for information 
pertaining to “Tumour material from re-biopsy at 
progression” (after trial treatment, optional). 
15 - WC/LFU 
Within 14 days of awareness of withdrawal of consent or 
loss to follow-up. 


 
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18. 
Statistical considerations 
18.1. 
Primary objective 
This randomised phase III trial will evaluate the potential of pembrolizumab to provide PFS 
benefit (based on independent radiological review) over standard institutional-choice 
chemotherapy (gemcitabine or vinorelbine monotherapy) in patients with advanced pre-
treated malignant mesothelioma. Patients randomised to chemotherapy will be allowed to 
cross over to receive pembrolizumab at progression. 
18.2. 
Sample size determination 
This is a 1:1 randomised phase III trial, designed to detect an increase in median PFS from 
3.5 months in the control arm to 6 months in the experimental arm. This corresponds to a 6-
month PFS of 30% vs 50% for the control and the experimental group respectively 
(HR=0.58). Using 80% power and a one-sided type I error of 2.5%, a total of 110 events 
need to be observed to achieve the trial goal. Assuming an accrual rate of 2 patients per 
month for the first 6 months and 10 patients per month thereafter, a total sample size of 142 
patients accrued over a period of 19 months would be required to observe the above number 
of events with a maximum total trial follow-up of 24 months. 
18.3. 
Trial duration 
Assuming a cumulative drop-out rate of 5%, the total trial duration from randomisation of 
the first patient to the date of the primary analysis is estimated to be 36 months, allowing for 
a start-up period of 6 months. 
All calculations are performed using the EAST package [30]. 
18.4. 
Analysis populations 
18.4.1. Intention-to-treat (ITT) population 
All randomised patients will be analysed in the arm they were allocated by randomisation. 
18.4.2. Censored population 
All randomised patients will be analysed in the arm they were allocated by randomisation 
but in addition, patients in the control arm that will selectively cross over to receive 
pembrolizumab after progression, will be censored at the time point of cross-over when 
evaluating OS. 
18.4.3. Safety population 
All patients who have started trial treatment (at least one dose of the trial drug/s).  
A patient will be considered to be eligible if he/she did not have any major deviation from 
the patient entry criteria listed in section 7 of the protocol. Potential eligibility problems will 
be assessed by the ETOP medical reviewer. 
 


 
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18.5. 
Evaluation of primary and secondary objectives 
18.5.1. Primary analysis 
The analysis of the primary and secondary endpoints will be performed on all randomised 
patients according to the ITT principle. 
Time to event endpoints (PFS, OS, TTF) 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 stratification factors) and multivariate Cox models will be used for 
exploring the association of the primary (investigator assessed PFS) and secondary 
endpoints (irPFS, OS and TTF) with treatment in the presence of prognostic factors. 
Clinical efficacy will be further described by objective response rate (ORR; complete or 
partial response) for all eligible patients according to the treatment assigned at 
randomisation (ITT analysis population). ORR will be compared between the two treatment 
groups by the Fisher's exact test. 
The safety and tolerability of pembrolizumab treatment will be assessed through analysis of 
toxicity, based on the safety population. The worst grade of toxicity/ adverse events 
observed over the whole treatment period according to CTCAE version 4.0 will be 
displayed. No formal statistical analysis will be performed to compare toxicity between the 
two arms. 
18.5.2. Sensitivity analysis 
For the secondary endpoints OS and TTF, censored analysis and the inverse probability 
weighting (IPW) approach will be applied as sensitivity analyses to the ITT approach. These 
methods aim to account for disruptions in randomisation due to selective cross-over at 
progression and will be performed on the censored population. 
Statistical analysis for the primary and secondary endpoints will be described in detail in the 
statistical analysis plan (SAP) document. 
18.6. 
Early safety evaluation 
In order to exclude an exacerbation of adverse events by pembrolizumab treatment, a safety 
evaluation will take place when 33% of the patients will have reached 6 months from 
randomisation. This first safety evaluation will be submitted to the IDMC for advice. 
Recruitment into the trial will continue while safety is evaluated. Safety evaluations will be 
performed at least yearly and submitted to the IDMC at their regular bi-annual meetings. 
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 IMP 
leads to doubt as to the benefit/risk ratio, by decision of ETOP upon recommendation of the 
ETOP 9-15 PROMISE-meso Steering Committee and IDMC. Specific considerations will 
be based on the interim safety and efficacy evaluations. 


 
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The trial can be terminated at any time if the authorization and approval to conduct the trial 
is withdrawn by ethics committee or regulatory authority decision, insufficient accrual, 
emerging new data impacting the scientific value of the trial or ethical grounds. 
19.2. 
Discontinuation of protocol treatment for individual patients  
Protocol treatment should be stopped in the following situations: 
 Disease progression according to RECIST 1.1 criteria.  
 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 malignant 
tumour) does not mandate a stop of trial therapy, patients may continue to receive 
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 transferred to 
the follow-up phase. 
Note: Patients randomised to the control arm who refuse further chemotherapy may 
only cross over to pembrolizumab treatment after progressive disease has been 
diagnosed. 
 If a patient refuses to have the treatments or 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 
individual situation. 
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 time point of withdrawal will 
continue 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 
instructions in the ETOP 9-15 PROMISE-meso 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 
if the patient agrees to this. 
20. 
Ethics aspects, regulatory approval, and patient informed consent 
The investigator will ensure that this trial is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country in 


 
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which the research is conducted, whichever affords the greater protection to the individual. 
The trial must fully adhere to the principles outlined in “Guideline for Good Clinical 
Practice (GCP)” 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 compliance with the EU Clinical Trial Directive (2001/20/EC). 
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 
protocol title and version number), and of the patient informed consent. 
The Ethical Review Board/Institutional Review Board (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 
randomisation 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 
modifications 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 
legislation, the protocol, protocol related documents including patient information and 
informed 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, a 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 randomisation into this trial. 
The “Declaration of Helsinki” recommends that consent be obtained from each potential 
patient 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 physician. 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 


 
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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 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 GCP 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 IRB / local EC 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 chairs and co-chairs, trial statisticians, ETOP officials, representatives 
from participating institutions and a representative from Merck Sharp & Dohme Corp. 
21.3. 
Independent Data Monitoring Committee 
The ETOP IDMC is a standing committee of independent experts. Its role is the systematic 
review of the accumulating data from all ongoing ETOP sponsored trials including accrual, 
safety and efficacy. The primary mandate of the IDMC is to safeguard the interest and 
safety of the patients in the trial and to ensure the scientific integrity of the trial. Details of 
the particular responsibilities and procedures within the ETOP 9-16 PROMISE-meso trial 
are summarised in the ETOP IDMC Guidelines and the trial-specific IDMC charter. 
The trial will be presented for review to the ETOP IDMC at each of their bi-annual meetings. 
Based on this review, the IDMC recommends to the trial Steering Committee whether to 
continue, modify or stop the trial. 
 


 
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21.4. 
Publication 
The results of the trial will be published according to the ETOP publication guidelines 
(appendix 3). 
21.5. 
Clinical trial insurance 
ETOP will contract the appropriate liability insurance for this trial. Patients who suffer 
injuries due to the trial should report them immediately to their physician. The local 
group/institution should report all alleged claims immediately to the ETOP coordinating 
office. 
21.6. 
Quality assurance 
ETOP conducts trials according to the ICH GCP guidelines. The Trial data manager reviews 
each eCRF as it is received. In addition, the ETOP medical reviewer reviews each case at 
specific time points. ETOP conducts periodic audit visits to ensure 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 trial 
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 
documentation 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 EDC 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.  


 
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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 
patient data on-site. ETOP audit or monitoring personnel will also have access to such data 
on-site. 
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. 
 


 
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22. 
References 
1. 
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assessing PD-L1 expression in the KEYNOTE-010 study of pembrolizumab (pembro) 
vs docetaxel (doce) for previously treated advanced NSCLC. J Clin Oncol 2016; 34, 
2016 (suppl; abstr 3030). 
2. 
Hui R, Gandhi L, Carcereny Costa E et al. Long-term OS for patients with advanced 
NSCLC enrolled in the KEYNOTE-001 study of pembrolizumab (pembro). J Clin Oncol 
2016; 34, 2016 (suppl; abstr 9026). 
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Herbst RS, Baas P, Kim DW et al. Pembrolizumab versus docetaxel for previously 
treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a 
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Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet 2005; 366: 397-
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Fennell DA, Gaudino G, O'Byrne KJ et al. Advances in the systemic therapy of 
malignant pleural mesothelioma. Nat Clin Pract Oncol 2008; 5: 136-147. 
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Rake C, Gilham C, Hatch J et al. Occupational, domestic and environmental 
mesothelioma risks in the British population: a case-control study. Br J Cancer 2009; 
100: 1175-1183. 
7. 
Tsiouris A, Walesby RK. Malignant pleural mesothelioma: current concepts in 
treatment. Nat Clin Pract Oncol 2007; 4: 344-352. 
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Vogelzang NJ, Rusthoven JJ, Symanowski J et al. Phase III study of pemetrexed in 
combination with cisplatin versus cisplatin alone in patients with malignant pleural 
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Krug LM, Kindler HL, Calvert H et al. Vorinostat in patients with advanced malignant 
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therapeutic strategy against a deadly disease? Oncoimmunology 2014; 3: e27482. 
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12. Janne PA. Chemotherapy for malignant pleural mesothelioma. Clin Lung Cancer 2003; 
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13. Zucali PA, Ceresoli GL, Garassino I et al. Gemcitabine and vinorelbine in pemetrexed-
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14. Ceresoli GL, Zucali PA. Vinca alkaloids in the therapeutic management of malignant 
pleural mesothelioma. Cancer Treat Rev 2015; 41: 853-858. 
15. Stebbing J, Powles T, McPherson K et al. The efficacy and safety of weekly vinorelbine 
in relapsed malignant pleural mesothelioma. Lung Cancer 2009; 63: 94-97. 
16. Sørensen JB, Langer SW, Urbanska E, Aamdal E. Second-line Oral Vinorelbine 
Following First-Line Platinum and Pemetrexed in Malignant Pleural Mesothelioma. 
European Journal of Clinical and Medical Oncology 2012; 4: 1-7. 
17. Zucali PA, Perrino M, Lorenzi E et al. Vinorelbine in pemetrexed-pretreated patients 
with malignant pleural mesothelioma. Lung Cancer 2014; 84: 265-270. 
18. Zauderer MG, Kass SL, Woo K et al. Vinorelbine and gemcitabine as second- or third-
line therapy for malignant pleural mesothelioma. Lung Cancer 2014; 84: 271-274. 
19. Zauderer MG, Sima CS, Ginsberg MS, Krug LM. Abstract IB.7. Presented at the 11th 
International Mesothelioma Interest Group (IMIG) conference 2012. 
20. Toyokawa G, Takenoyama M, Hirai F et al. Gemcitabine and vinorelbine as second-
line or beyond treatment in patients with malignant pleural mesothelioma pretreated 
with platinum plus pemetrexed chemotherapy. Int J Clin Oncol 2014; 19: 601-606. 


 
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21. Brahmer JR, Pardoll DM. Immune checkpoint inhibitors: making immunotherapy a 
reality for the treatment of lung cancer. Cancer Immunol Res 2013; 1: 85-91. 
22. Mansfield JR. Imaging in cancer immunology:phenotyping immune cell subsets in situ 
in FFPE tissue sections. MLO Med Lab Obs 2014; 46: 12-13. 
23. Dostert C, Petrilli V, Van Bruggen R et al. Innate immune activation through Nalp3 
inflammasome sensing of asbestos and silica. Science 2008; 320: 674-677. 
24. Robert C, Schachter J, Long GV et al. Pembrolizumab versus Ipilimumab in Advanced 
Melanoma. N Engl J Med 2015; 372: 2521-2532. 
25. Manegold C, Symanowski J, Gatzemeier U et al. Second-line (post-study) 
chemotherapy received by patients treated in the phase III trial of pemetrexed plus 
cisplatin versus cisplatin alone in malignant pleural mesothelioma. Ann Oncol 2005; 16: 
923-927. 
26. van Meerbeeck JP, Baas P, Debruyne C et al. A Phase II study of gemcitabine in 
patients with malignant pleural mesothelioma. European Organization for Research 
and Treatment of Cancer Lung Cancer Cooperative Group. Cancer 1999; 85: 2577-
2582. 
27. Kindler HL, Millard F, Herndon JE, 2nd et al. Gemcitabine for malignant mesothelioma: 
A phase II trial by the Cancer and Leukemia Group B. Lung Cancer 2001; 31: 311-317. 
28. Pocock SJ. Allocation of patients to treatment in clinical trials. Biometrics 1979; 35: 
183-197. 
29. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-247. 
30. Corporation CS. EaSt: a software package for the design and interim monitoring of 
group sequential clinical trials. In. Cytel Software Corporation, Cambridge, MA 2011. 
 

SAP_001.pdf: 
Statistical Analysis Plan  
Page 1 of 25 
 
 
PROMISE-meso 
ETOP 9-15 
A multicentre randomized phase III trial comparing pembrolizumab 
versus standard chemotherapy for advanced pre-treated malignant 
pleural mesothelioma 
 
 
 
Statistical Analysis Plan (SAP) 
Final efficacy analysis 
 
 
 
 
A clinical trial of ETOP 
 
 
 
SAP VERSION 
1.1 
SAP DATE 
15.01.2019 
 
 


Statistical Analysis Plan  
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Table of Contents 
INTRODUCTION.................................................................................................................................... 4 
1 
Trial oversight............................................................................................................................... 5 
1.1 
Objectives ............................................................................................................................. 5 
1.2 
Endpoints ............................................................................................................................. 6 
1.3 
Most important eligibility criteria ........................................................................................... 6 
1.4 
Treatment............................................................................................................................. 7 
1.5 
Sample size & power ............................................................................................................. 7 
1.6 
Total trial duration ................................................................................................................ 8 
2 
General considerations ................................................................................................................. 9 
2.1 
Analysis timing ...................................................................................................................... 9 
2.2 
Data Retrieval Information..................................................................................................... 9 
3 
Statistical considerations ............................................................................................................. 10 
3.1 
Study’s endpoints ................................................................................................................ 10 
3.2 
(Serious) Adverse Events...................................................................................................... 12 
Prognostic score ......................................................................................................................... 13 
3.3 
Analysis populations ............................................................................................................ 13 
4 
Study Analysis............................................................................................................................. 15 
4.1 
Patient accrual, balance of stratification factors and baseline characteristics .......................... 15 
4.2 
Treatment administration .................................................................................................... 16 
4.3 
Efficacy analysis .................................................................................................................. 17 
4.3.1 
Primary endpoint:  PFS based on independent radiological review .................................. 17 
4.3.2 
Secondary endpoints: Overall Survival ........................................................................... 18 
4.3.3 
OS analysis taking into account crossover ...................................................................... 19 
4.3.4 
Secondary & exploratory endpoints: Objective Response & Duration of response............ 20 
4.3.5 
Secondary endpoints: Investigator assessed PFS ............................................................ 20 
4.3.6 
Subgroup analysis ........................................................................................................ 20 
4.4 
Safety analysis..................................................................................................................... 21 


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4.5 
Exploratory analysis of the cross-over cohort ........................................................................ 22 
4.6 
Missing Data ....................................................................................................................... 22 
4.7 
Sensitivity analysis............................................................................................................... 23 
5 
TECHNICAL DETAILS .................................................................................................................... 24 
 
 
 
 
 


Statistical Analysis Plan  
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INTRODUCTION 
This is a technical document describing thoroughly and in detail an analysis framework for 
the ETOP 9-15 PROMISE-meso trial.  
A short description of the contents of this statistical analysis planned is provided below: 
1. PROMISE-meso 
trial 
outline/oversight: trial’s schema, eligibility criteria, 
objectives, trial duration, sample size & power, treatment 
2. General considerations: Analysis timing, data retrieval 
3. Statistical considerations: definition of primary and secondary endpoints, (serious) 
adverse events definition, analysis populations 
4. Study Analysis: Baseline characteristics, treatment administration, efficacy analysis, 
safety analysis and exploratory analysis, handling of missing data 
5. Technical issues: Software and testing 
 


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1 
Trial oversight  
This is a randomized phase III multicentre clinical trial aiming to demonstrate superiority of 
pembrolizumab versus standard, institutional-choice chemotherapy (gemcitabine or 
vinorelbine) 
in patients with advanced pre-treated malignant mesothelioma. Patients 
randomized to chemotherapy arm will be allowed to cross-over and receive pembrolizumab 
at progression.  
 
SCHEMA 1. Trial design  
 
1.1 Objectives  
Primary objective 
The primary objective of the study is to investigate whether treatment with pembrolizumab 
improves progression-free survival (PFS), as assessed by independent radiological review, 
compared to standard, institutional choice chemotherapy (gemcitabine/vinorelbine). 
Secondary objectives  
The secondary objectives of the study include: 
- 
To evaluate secondary measures of clinical efficacy including objective response (OR), 
investigator assessed PFS (ia-PFS), overall survival (OS), and time to treatment failure 
(TTF) 
- 
To asses the safety and tolerability of the treatment 


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1.2 Endpoints  
Primary endpoint:  
• PFS according to RECIST 1.1 criteria based on independent radiological review 
Secondary endpoints:  
 
Objective response determined by RECIST 1.1  
 
Overall survival 
 
Time to treatment failure 
 
Investigator assessed PFS determined according to RECIST 1.1  
 
Tolerability assessed by adverse events graded according to CTCAE v4.0 
Correlative endpoints: 
 
Responses according to PD-L1 expression levels, measured by IHC 
 
TILs analysis 
 
Mutation load 
1.3 Most important eligibility criteria  
Inclusion criteria at enrolment:  
 Histologically confirmed malignant pleural mesothelioma (all subtypes are eligible)  
 Progressing after or on previous platinum-based chemotherapy.  
 Availability of tumour tissue for translational research  
 Male and female patients 
 Age 18 years ECOG performance status 0-1  
 Life expectancy of at least 3 months  
 Measurable or evaluable disease according to RECIST 1.1 criteria  
 Adequate hematological, renal, and liver function  
Exclusion criteria at enrolment:  
 Prior therapy with an anti-PD-1, anti-PD-L1/L2, anti-CD137, or anti-CTLA-4 antibody  
 Prior therapy with gemcitabine or vinorelbine  
 Known active central nervous system metastases and/or carcinomatous meningitis.  


Statistical Analysis Plan  
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 Active autoimmune disease that has required systemic treatment in past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).  
1.4 Treatment 
Experimental arm 
Pembrolizumab, 200 mg fixed dose i.v. on day 1 of every 3-week (+/-3 days) cycle until 
progression of disease determined according to RECIST 1.1 criteria or lack of tolerability or 
until further protocol treatment is declined by the patient, for a maximum of 2 years.  
In case of clinical benefit, with physician and patient agreement, pembrolizumab treatment 
can continue beyond documented disease progression according to RECIST 1.1 criteria until a 
maximum of 2 years on pembrolizumab treatment is reached. Patients need to meet the 
following criteria: ECOG performance status 0-1, absence of rapid progression of disease,  
absence of progressive tumour at critical anatomical  
Control arm 
For the control chemotherapy options, the choice of vinorelbine (p.o.) or vinorelbine (i.v.) or 
gemcitabine chemotherapy will be made on a per-patient basis prior to randomisation.  
 Gemcitabine 1000 mg/m2 i.v., day 1 and day 8 of every 3-week (+/-3 days) cycle  
 Vinorelbine i.v. 30 mg/m2 i.v., day 1 and day 8 of every 3-week (+/-3 days) cycle  
 Vinorelbine 60/80 mg/m2 p.o., day 1 and day 8 of every 3-week (+/-3 days) cycle  
 
At documented disease progression according to RECIST 1.1 criteria, patients in the control 
arm are allowed to receive pembrolizumab, if they meet the cross-over criteria:  
ECOG performance status 0-1, absence of progressive tumours at critical anatomical sites (e.g., 
cord compression) requiring urgent alternative medical intervention.  
1.5 Sample size & power 
This is a 1:1 randomized phase III trial (stratified by predominately epitheloid vs. non-
epitheloid histological subtype), designed to detect with 80% power, using a one-sided 
test at significance level of 0.025, an increase of the median PFS from 3.5 months on 
the chemotherapy arm to 6 months on pembrolizumab. This corresponds to a 6-month 
PFS of 30% vs 50% for the chemotherapy and the pembrolizumab group respectively 


Statistical Analysis Plan  
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[hazard ratio (HR)=0.58]. A cumulative drop-out of 5% is assumed. A total of 110 events 
need to be observed to achieve the trial goal.  
The expected accrual rate is 2 patients per month for the first 6 months, increasing to 10 
patients per month thereafter. A total sample size of 142 patients accrued over a period of 
19 months would be required to observe the total number of 110 events with a maximum 
total trial follow-up of 24 months.  
The primary analysis is expected to be available 36 months after the inclusion of the first 
patient. The trial treatment phase will continue for a maximum of 2 years from the inclusion 
of the last patient and the trial is expected to end at all sites approximately 43 months after 
the inclusion of the first patient. 
1.6 Total trial duration 
The trial treatment phase will continue for a maximum of 2 years from the inclusion of the last 
patient and the trial is expected to end at all sites approximately 43 months after the inclusion of 
the first patient. 
 


Statistical Analysis Plan  
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2 
General considerations 
2.1 Analysis timing 
According to the statistical design, the primary analysis is scheduled to be performed when 110 
PFS events have been observed, for a total of 142 patients accrued over a period of 19 months. 
Under the protocol assumptions, this is expected to occur 24 months after the inclusion of the 
first patient.  
2.2 Data Retrieval Information 
The final analysis will be based on the database download that will take place, as soon as the 
total number of 110 PFS events (based on independent radiological review) 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. 
 


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3 
Statistical considerations 
3.1 Study’s endpoints 
Primary endpoint 
The primary endpoint of the trial is PFS, defined as time from randomization until 
documented progression (based on independent radiological review. according to RECIST 
1.1 criteria) or death, whichever occurs first.  
Secondary endpoints  
Secondary endpoints include OR (tumor response based on independent radiological 
review), OS, TTF, investigator assessed PFS (ia-PFS) and adverse events graded according to 
CTCAE V4.0. 
More specifically OR is defined as the best overall response (complete or partial) across all 
assessment time-points according to RECIST Criteria 1.1, during the period from 
randomization to termination of trial treatment. OS is defined as the time from the date of 
randomization until death from any cause. In addition, TTF is defined as time from the date 
of randomization to treatment failure for any reason, including progression of disease, 
treatment toxicity, refusal/withdrawal and death (even after treatment completion). Ia-PFS, 
is defined as the time from randomization to documented progression (investigator 
assessed) or death from any cause. 
More details on the exact definition and calculation of efficacy endpoints is provided in 
Table 1 that follows. 
Finally, a detailed description of AEs and SAEs is provided in the section 3.2.  
Correlative endpoints  
Correlative endpoints of the study include responses according to PD-L1 expression levels, 
measured by IHC (cut-offs considered will be 1% and 50%) as well as TILs analysis and 
mutation load, depending on data availability. 
Exploratory endpoints  
Time to treatment discontinuation (TTD), defined as the time from randomization to 
treatment discontinuation for any reason and Duration of response (DoR), defined as the 
time from documentation of tumor response (either partial or complete based on 
independent radiological review) to disease progression or death, will be explored in 


Statistical Analysis Plan  
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patients with respect to their initial treatment assignment and additionally for patients who 
crossed-over to receive pembrolizumab, after progression under standard institutional 
choice chemotherapy.  
Furthermore, PFS2 defined as time from randomisation to objective tumor progression 
(based either on independent radiological review or investigator assessed) on further line of 
treatment or death from any cause, whichever occurs first, will be also presented. 
 
 
 


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3.2 (Serious) Adverse Events  
Adverse events 
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. 
The CTCAE is available for downloading (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
An adverse event is defined as any untoward medical occurrence that occurs from the first 
dose of study medication until 30 days after the final dose, regardless of whether it is 
considered related to a medication. 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.  
 
 Serious Adverse Events (SAE) 
An SAE is defined in general as any undesirable medical occurrence/adverse drug 
experience that occurs during or within 30 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 
 requires significant medical intervention 
Other significant/important medical events which may jeopardize the patient are also 
considered serious adverse events. 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. 


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 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 subject. 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: 
1=Grade 1 
Mild 
2=Grade 2 
Moderate 
3=Grade 3 
Severe 
4=Grade 4 
Life-threatening 
5=Grade 5 
Fatal 
Prognostic score 
Patients will be categorized in “good” or “poor” prognostic score groups according to the 
EORTC mesothelioma prognostic score (EPS). The formula for the calculation of the EPS is as 
per Curran et al (1998). Here, EPS(0.55)a + (0.60)b + (0.52)c + (0.67)d + (0.60)e  
where a= if the total white blood cell count is more than 8.3 109 /L, b=if the Eastern 
Cooperative Oncology Group (ECOG) performance status is 1 or 2, c=if the histology is 
probable, d= if the histology is sarcomatous, and e=if the sex is male. 
Patients are categorized into “good prognosis” if total score ≤1.27 (corresponding to having 
zero, one, or two poor prognostic factors) and “poor prognosis” if total score >1.27 
(corresponding to having three, four, or five poor prognostic factors). The impact of the EPS 
“good” and “poor” categories will be explored in time-to-event analyses. 
 
3.3 Analysis populations 
Intent-to-Treat Population (ITT): The ITT population will include all patients randomized 
into the trial based on the initial treatment assignment and not on the treatment eventually 


Statistical Analysis Plan  
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received. The ITT population will be used for the assessment of patient baseline 
characteristics and all efficacy endpoints.   
As-treated population (AT): The AT population will include all patients that received at 
least one dose of trial treatment, with treatment assignments designated according to actual 
study treatment received. The AT population will be the primary population for evaluating 
treatment administration/compliance and safety.  
Cross-over cohort (COC): Patients originally randomized in the control arm, that 
progressed and decided to switch to experimental treatment, will encompass the cross-over 
cohort. 
 
 


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4 
Study Analysis 
4.1 Patient accrual, balance of stratification factors and baseline characteristics 
- 
Patient accrual by center will be presented in tabular format. 
- 
In addition, observed vs. expected accrual will be graphically displayed. 
- 
For patients deemed ineligible (patients registered in the online database but 
eventually not randomized) a table summarizing reason for non-randomization will 
be provided. 
- 
Balance of treatment allocation by center and by stratification factor will be 
summarized as well.  
- 
A consort diagram will be created to graphically depict the flow of patients and the 
phases of the trial.  
- 
Patient baseline characteristics (categorical: gender, smoking history, ECOG 
performance status at diagnosis and continuous: age at randomization), will be 
presented overall and separately by treatment arm. 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. Balance of baseline 
characteristics by treatment arm will be assessed via the fisher’s exact test for 
categorical variables and the Mann-Whitney U test for continuous. Also available 
information on prior treatment will be summarised. 
- 
Median follow-up (FU) of the patients (overall and by treatment arm) along with the 
respective interquartile range (IQR) and the number (%) of patients that are still on 
FU, will be summarized in a table. A Kaplan-Meier (K-M) will be also provided for a 
graphical representation of the respective information. 
 
 


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4.2 Treatment administration 
Treatment information will be summarized overall and separately by treatment arm. More 
specifically the following information will be presented: 
- 
Number of patients that started treatment, information on number of cycles (median, 
min-max). For those patients randomized in experimental arm, progressed but with 
physician’s and their own agreement continued receiving treatment, information on 
treatment cycles as well as treatment failure after 1st progression will be additionally 
provided. 
- 
Number of patients that did not receive any dose of trial treatment, along with 
reasons for not doing so 
- 
Number of treatment failures, median TTF (95% CI), rate of TTF events and reasons 
for treatment failure/discontinuation will be presented overall and by treatment 
arm.  The log-rank test will be used to compare TTF between the two treatment arms. 
- 
A Kaplan Meier curve for TTF, overall and by treatment group will be created. In case 
a statistically significant difference between the two treatment arms is found the 
overall line will be displayed only for illustrative purposes and will be light grey and 
dashed. A similar approach will be followed for TTD analysis. 
- 
The number of patients that completed treatment and whether or not they 
experience a PFS thereafter, will be also recorded.  
- 
For those patients that progressed information on further lines of treatment will be 
also provided.  


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4.3 Efficacy analysis 
Efficacy analysis will be performed on all randomized patients, based on their initial 
treatment assignment (ITT cohort).  
4.3.1 Primary endpoint:  PFS based on independent radiological review 
Primary analysis on PFS 
The study is designed to test the hypothesis that treatment of advanced malignant pleural 
mesothelioma with pembrolizumab will lead to an increase in median PFS (based on 
independent radiological review) to 6 months, from 3.5 months under standard institutional 
choice chemotherapy.  This according to the study design, corresponds to a HR of 0.58. Using 
80% power and a one-sided type I error of 2.5%, a total of 110 PFS events are needed to be 
observed in order to achieve the trial goal. 
The total number of PFS events observed, overall and by treatment arm will be presented. In 
addition, 3-month, 6-month PFS estimates, median PFS and respective 95% CIs will be 
provided. To formally compare PFS between the two treatment arms, the stratified log-rank 
test will be used (with histological subtype being the stratification factor).  Unstratified log-
rank will be also calculated. This would be of particular value in case that the we have strata 
levels with very low number of patients. 
To assess treatment effect on PFS, a stratified Cox proportional hazards model will be fitted, 
using histological sub-type as the stratification factor, adjusted for clinicopathological 
variables of interest (gender, age, smoking history, ECOG performance status at diagnosis, 
PD-L1 status, mutation load, TILs (if available, appropriately categorized). The backward 
elimination method, with a removal criterion at 10% will be implemented to conclude on 
the statistically significant variables of the model. The HRs and corresponding 95% CIs for 
all significant PFS predictors will be summarized in a forest plot (final model).  
Graphical representation of PFS, by treatment arm will be performed via a Kaplan-Meir plot 
(in case of statistically significant differences between groups overall lines will be grey and 
dashed). The plot will be produced separately by histological subtype.  
PFS will be analysed separately by subgroups defined by PD-L1 status (1% and 50% cut-off 
levels will be considered), mutation load and TILs. For these subgroups number of PFS 
events, 3-month/6-month PFS estimates, median PFS and corresponding 95% CI overall and 
by treatment arm will be presented. Observed differences in hazard will be assessed via the 


Statistical Analysis Plan  
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log-rank test and will be graphically depicted by Kaplan-Meier plots. In addition, number of 
PFS events, median PFS and unstratified/unadjusted HRs (along with 95% CIs) will be 
summarized for the subgroups defined by treatment arm and the following variables: age 
(appropriately categorized), ECOG performance status, histological subtype, gender, EORTC 
score, PD-L1 status (cut-offs considered 1% & 50%), mutation load (using median value as a 
cut-off) and TILs.  This information will be depicted in a tabular format in the report and a 
forest plot will be created for the presentation/manuscript, if investigators consider it 
interesting. 
Finally, a waterfall plot for each treatment arm will be created to graphically depict the 
percent tumor change and a swimmer plot to illustrate efficacy information by patient 
(time-on-treatment, time to response and progression, follow-up), and spider plots 
generated split by treatment type (chemo vs pembrolizumab) to graphically overview the 
changes in tumour size over time with spider lines coloured by histological type (epithelioid 
vs non-epithelioid). 
4.3.2 Secondary endpoints: Overall Survival 
At the time of final analysis, the OS events will most probably not be sufficient to provide 
enough power for comparison between treatment. An additional OS analysis with longer 
follow-up will be performed at a later time point. The following will be presented at both 
analyses (final and longer follow-up), with the understanding that at the final analysis, 
statistically significant differences will not be expected.  
The number of deaths will be presented overall and by treatment arm. In addition, 3-
month/6-month/1-year OS estimates, median OS and respective 95% CI will be provided. 
OS comparison by treatment arm will be assessed using a stratified log-rank test 
(histological subtype will be the stratification factor, as for PFS the unstratified log-rank will 
be also calculated). OS, by treatment group, will be graphically displayed by Kaplan Meier 
plot (if a statistically significant difference between treatment groups is detected the overall 
line will be grey and dashed).  Similar to PFS, the plot will be produced separately by 
histological subtype. 
Similar to PFS, OS information (number of deaths,  median OS, unstratified/unadjusted HRs 
with  95% CIs) will be summarized by subgroups defined by treatment arm and the 
following variables of interest: age (appropriately categorized), ECOG performance status, 


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histological subtype,  gender, EORTC score , PD-L1 status (cut-off considered 1% & 50%), 
mutation load (cut-off: median value) and TILs. This information will be depicted in a 
tabular 
format 
in 
the 
report 
and 
a 
forest 
plot 
will be created for the 
presentation/manuscript, if investigators consider it interesting. 
In addition, Restricted Mean Survival Time (RMST) will be compared between groups, to 
accommodate a possible delayed survival effect in the treatment group. 
OS will be modelled via stratified Cox proportional hazards model (histological sub-type will 
be the stratification factor), adjusted for clinicopathological variables of interest: gender, 
age, EORTC score, ECOG performance status at diagnosis, PD-L1 status, mutation load, TILs. 
Same with PFS analysis, he backward elimination method, with a removal criterion at 10% 
will be implemented to conclude on the statistically significant variables of the model. The 
HRs and corresponding 95% CIs for all significant OS predictors will be summarized in a 
forest plot.  
4.3.3 OS analysis taking into account crossover 
To circumvent the selective crossover effect, a censored and an inverse probability weighted 
(IPW) analyses will be performed for OS (Robins et al, 2000). In the censored analysis, all 
observation patients who switch to receive experimental treatment at progression, will be 
censored the first day they received active treatment. The IPW approach is based on the idea 
of artificially censoring the follow-up of each patient at the time of crossover. Then, the real 
treatment effect is assessed by recreating the population that would have been observed 
without crossover through statistical modelling and weights assignment. In this way, the 
follow-up of patients whose experience receiving the control treatment could not be 
observed because they selectively switched to experimental treatment, will be replaced by 
the follow-up of patients with similar characteristics (both baseline and post-randomization 
factors) who remain in the control arm at the time of treatment switching. Fundamental to 
the IPW approach is the assumption of no unmeasured confounders, which implies that all 
common predictors are appropriately measured and accounted for in the analysis. Even 
though this assumption cannot be tested based on the observed data, the availability of a 
sufficient number of covariates and the use of both baseline and time-dependent covariates 
that are common predictors of the outcome of interest and artificial censoring limits the risk 
of important omissions. Apart from IPW, Landmark analysis will also be implemented to 
address cross-over. 


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4.3.4 Secondary & exploratory endpoints: Objective Response & Duration of 
response 
Objective response rate (ORR) will be presented overall and separately for the two 
treatment arms, along with a 95% exact binomial CI.  The stratified Miettinen and 
Nurminen’s method (Miettinen O, Nurminen M., 1985) will be used for the comparison of 
ORR between treatment arms. The difference in ORR (with 95% CI), will be estimated using 
the stratification factor applied in randomization. Finally, if the number of responses allows, 
ORR will be presented by PD-L1, mutation load and TILs subgroups, and graphically as 
scatter plots, or waterfall plots.  
Median DOR, along with 95% CI will be presented, for all patients and separately for the two 
treatment groups. Graphical representation of duration of response will be performed via 
swimmer plots. 
Some trials of checkpoint inhibitors have suggested a treatment effect in those with grade 3 
or higher immune-related adverse events. Contingent on numbers of grade 3 or more 
events, exploratory analyses of PFS, OS, TTF, and ORR will be performed in those with grade 
3 or more immune-related adverse events or not. 
4.3.5 Secondary endpoints: Investigator assessed PFS 
A similar approach to the PFS as assessed by independent radiological review will be 
followed for the analysis of investigator assessed PFS.   
4.3.6 Subgroup analysis 
To determine whether the treatment effect is consistent across various subgroups the 
between-group treatment effect for all efficacy endpoints will be estimated within each 
category of the following pre-specified variables. 
Main subgroup analyses:  
- 
Histological subtype 
- 
Gender 
- 
PD-L1 (cut-offs considered: 1%) 
Other pre-planned subgroup analyses: 
- 
EORTC prognostic score 
- 
PD-L1 (cut-offs considered: 50%) 


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- 
Patients with immune related grade ≥3 event vs. not 
- 
Age group 
- 
Mutation load 
- 
TILs 
Note: 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.  
4.4 Safety analysis  
The safety analysis will be performed in the AT population with the following information 
presented: 
- 
Overview of the number of patients who experienced AE/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 and rate of AE/SAE occurrence per month of FU (again 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 CTACE category, overall and separately for the 
two treatment arms. 
- 
Maximum severity of adverse events (AE/SAE) for patients, overall and by treatment 
arm.  
- 
Number and corresponding percentages of treatment related (S)AEs by grade, 
leading either to treatment discontinuation or death will be summarized for the two 
trial arms. Treatment related (S)AEs (of any grade) occurring in more than 15% (or 
any other relevant %) will be presented for the two treatments.  


Statistical Analysis Plan  
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- 
The risk difference, along with corresponding 95% CIs of specific adverse evets (most 
frequent i.e. ≥15%, of any grade and also focusing on grade ≥3), between the two 
treatment arms will be presented. 
- 
For all fatal SAEs, cause of death will be provided. 
Note: In cases where a patient may experience the same event (AE/SAE) more than once, the 
event will be counted only once for the calculation of the total number of events reported for 
the overall safety cohort, using the highest observed grade.  
Finally, adverse events occurring after cross-over, will be analysed separately.   
4.5 Exploratory analysis of the cross-over cohort 
A similar analysis, whenever applicable will be performed (efficacy & safety) for the 
cross-over cohort. 
4.6 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. 
- 
Incomplete tumor assessment information 
In patients who have no on-study assessments: 
- 
If death is recorded prior to the first planned tumor assessment, the death date will 
be considered as the date of the PFS event. 


Statistical Analysis Plan  
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- 
If clinical progression is recorded prior to the first planned tumor assessment, the 
date of the reported clinical progression will be considered as the date of the PFS 
event. 
4.7 Sensitivity analysis 
In a sensitivity analysis framework, the efficacy analysis will be repeated using the AT 
population. 
 
 
 


Statistical Analysis Plan  
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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 analyses, such as the IPW analysis, and 
specific plots.  
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. 
 
 
 


Statistical Analysis Plan  
Page 25 of 25 
References 
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factors in patients with pleural mesothelioma: the European Organization for Research and 
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Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in an 
AIDS Clinical Trial with inverse probability of censoring weighted (IPCW) log-rank tests. 
Biometrics. 2000;56(3):779-788 
Miettinen O, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 1985; 4: 
213–226.