Conditions: Mesothelioma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 248
Healthy volunteers: no

Brief summary:
The main purpose of the 15743 study is to assess efficacy and safety of anetumab ravtansine versus vinorelbine in progression free survival in patients with stage IV mesothelin overexpressing malignant pleural mesothelioma (MPM).

210 eligible patients will be randomized to receive either anetumab ravtansine every three weeks or weekly vinorelbine.

Treatment will continue until centrally confirmed disease progression or until another criterion is met for withdrawal from the study. Patients will enter follow up phase to capture safety and endpoint data as required.

Efficacy will be measured by evaluating progression free survival from randomization. Radiological tumor assessments will be performed at defined time points until the patient's disease progresses.

Blood samples will be collected for safety, pharmacokinetic and biomarker analysis. Archival or fresh biopsy tissue may also be collected for central pathology review and biomarkers.

Detailed description:

Arms:
arm 1: Drug Anetumab ravtansine given Intravenously (IV) arm 2: Drug Vinorelbine given Intravenously

Interventions: intervention 1: Anetumab ravtansine (BAY94-9343) intervention 2: Vinorelbine
Intervention descriptions: intervention 1: Starting dose: 6.5 mg/kg administered as IV infusion over 1 h every 3 weeks until disease progression or treatment withdrawal for any reason. Dose reductions are permitted. intervention 2: Starting dose: 30mg/m\^2 administered as an IV infusion over 6 to 10 min every week until disease progression or treatment withdrawal for any reason. Dose reductions are permitted per standard practise.

Protocol document:
Prot_000.pdf: 
 
Document Type: 
Study Protocol  
Official Title: 
A randomized, open-label, active-controlled, Phase II study of 
intravenous anetumab ravtansine (BAY 94-9343) or vinorelbine in 
patients with advanced or metastatic malignant pleural 
mesothelioma overexpressing mesothelin and progressed on first 
line platinum/pemetrexed-based chemotherapy 
NCT Number: 
NCT02610140 
Document Date: 
27-Mar-2018 
 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  1 of 269
Cover page of the integrated protocol
A randomized, open-label, active-controlled, Phase II study of intravenous anetumab 
ravtansine (BAY 94-9343) or vinorelbine in patients with advanced or metastatic 
malignant pleural mesothelioma overexpressing mesothelin and progressed on first line 
platinum/pemetrexed-based chemotherapy
This protocol version is an integration of the following documents / sections:

Original protocol, Version 1.0, dated 17 AUG 2015

Amendment 02 (global amendment described in Section 15.1)
forming integrated protocol Version 2.0, dated 09 FEB 2016

Amendment 04 (global amendment described in Section 15.2)
forming integrated protocol Version 3.0, dated 11 AUG 2016

Amendment 05 (global amendment described in Section 15.3)
forming integrated protocol Version 4.0, dated 18 APR 2017

Amendment 06 (global amendment described in Section  15.4)
forming integrated protocol Version 5.0, dated 27 MAR 2018
Amendments not included in the consecutive numbering of amendments are 
local amendments not forming part of this integrated global protocol. This currently 
includes:

Amendment 01, dated 04 DEC 2015
(local amendment valid for UK only)

Amendment 03, dated 23 MAY 2016
(local amendment valid for Finland only)


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  2 of 269
1.
Title page
A randomized, open-label, active-controlled, Phase II study of intravenous anetumab 
ravtansine (BAY 94-9343) or vinorelbine in patients with advanced or metastatic 
malignant pleural mesothelioma overexpressing mesothelin and progressed on first line 
platinum/pemetrexed-based chemotherapy
Phase II anetumab ravtansine as 2nd line treatment for malignant pleural mesothelioma 
(MPM)
ARCS-M2L (Anetumab Ravtansine Clinical Studies – Mesothelioma 2nd Line)
Test drug:
BAY 94-9343 / anetumab ravtansine
Study purpose:
Assess the efficacy and safety of anetumab ravtansine as 2nd line 
treatment in MPM
Clinical study phase:
II
Date:
27 MAR 2018
Registration:
EudraCT no.: 2012-003650-88
Version no.:
5.0
Sponsor’s study no.:
15743
Sponsor:
Non-US: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer HealthCare Pharmaceuticals Inc., 
100 Bayer Boulevard, P.O. Box 915, 
Whippany NJ 07981-0915, USA
Sponsor’s medical expert:
Telephone no.:
Mobile: 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation.  Reproduction or disclosure of this document 
- whether in part or in full - to parties not associated with the clinical investigation, or its use 
for any other purpose, without the prior written consent of the sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD
PPD
PPD
PPD
PPD


27MAR2018 
Integrated Clinical Study Protocol 
No. BAY 94-9343 I 15743 
Version 5.0 
Page: 3 of 269 
Signature of the sponsor's medically responsible person 
The signatory agrees to the content of the final integrated clinical study protocol as presented. 
Name: 
 
Role: 
 
Date: 
Signature:
PPD
PPD
PPD


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  4 of 269
Signature of principal investigator
The signatory agrees to the content of the final integrated clinical study protocol as presented.
Name:
Affiliation:
Date:
Signature:
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  5 of 269
2.
Synopsis
Title
A randomized, open-label, active-controlled, Phase II study of intravenous 
anetumab ravtansine (BAY 94-9343) or vinorelbine in patients with 
advanced or metastatic malignant pleural mesothelioma overexpressing 
mesothelin and progressed on first line platinum/pemetrexed-based 
chemotherapy
Short title
Phase II anetumab ravtansine as 2nd line treatment for malignant pleural 
mesothelioma (MPM)
Clinical study phase
II
Study objective(s)
The primary objective of this study is to:

Test the superiority of anetumab ravtansine monotherapy over 
vinorelbine in progression-free survival (PFS)
The secondary objectives of this study are to:

Test overall survival (OS)
Secondary objective related to pulmonary function removed by 
amendment 2

Evaluate patient-reported outcomes (PROs) – symptom burden and 
health-related quality of life (QoL)

Evaluate other indicators of treatment efficacy (indicators of tumor 
response)

Evaluate safety
The other objectives of this study are to evaluate the:

Pharmacokinetics (PK)

Immunogenicity

Biomarkers
Test drug(s)
Anetumab ravtansine
Name of active ingredient
Anetumab ravtansine / BAY 94-9343
Dose(s)
6.5 mg/kg every 3 weeks (Q3W)
Route of administration
Intravenous (IV) infusion over 1 h
Duration of treatment
Patients will continue on treatment until one of the following occurs:

Progressive disease (PD) as defined by modified Response Evaluation 
Criteria in Solid Tumors (mRECIST) for mesothelioma as assessed by 
blinded central radiology review; however, treatment may be 
continued provided that the patient derives clinical benefit as 
determined by the treating physician.

Clinical progression (criteria related to progressive disease and 
clinical progression modified by amendment 2)

Death

Any other criterion for withdrawal from study treatment.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  6 of 269
Reference drug(s)
Vinorelbine
Name of active ingredient
Vinorelbine
Dose(s)
30 mg/m2 once weekly (QW)
Route of administration
IV injection over 6 to 10 min
Duration of treatment
Patients will continue on treatment until one of the following occurs:

PD as defined by mRECIST for mesothelioma as assessed by blinded 
central radiology review; however, treatment may be continued 
provided that the patient derives clinical benefit as determined by the 
treating physician

Clinical progression (criteria related to progressive disease and 
clinical progression modified by amendment 2)

Death

Any other criterion for withdrawal from study treatment.
Indication
Advanced or metastatic MPM overexpressing mesothelin
Diagnosis and main criteria for 
inclusion /exclusion
Male or female patients (≥ 18 years of age) with unresectable locally 
advanced or metastatic MPM overexpressing mesothelin. Patients must 
have Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) of 0 or 1, a life expectancy of at least 3 months and at least 1 
measurable lesion per mRECIST per MPM (i.e. pleural lesion(s) 
measured using mRECIST or extra-pleural lesion(s) measurable per 
RECIST 1.1) as determined by the central reviewer (modified by 
amendment 2). Patients must have received only 1 line of previous 
systemic anti-cancer treatment with platinum-pemetrexed with or without 
bevacizumab and must have no corneal epitheliopathy or any 
predisposing eye disorder.
Study design
A randomized, open-label, active-controlled, 2-arm, multicenter, Phase II 
study.
Approximately 210 patients (changed by amendment 2) who meet the 
eligibility criteria will be randomly assigned in a 2:1 ratio to receive 
anetumab ravtansine or vinorelbine, respectively. Patients will be 
stratified at randomization according to geographic region and per time to 
progression (TTP) on 1st line treatment.
The study is composed of the following periods:

Screening
Note: A prescreening step, including the mesothelin expression level 
testing, can be performed without evidence of disease progression 
after the initial treatment cycles with platinum/pemetrexed (with or 
without bevacizumab) at the investigator’s discretion after signing of 
informed consent.

Treatment

Safety-follow-up: 
Patients who discontinue study treatment for any reason.

Active follow-up (which also includes the safety follow-up period):


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  7 of 269
Patients who discontinue study treatment for any reason other 
than centrally confirmed radiological PD will be followed for 
progression during active follow-up until data maturation for the OS 
final analysis is reached (i.e. completion of number of events required 
for OS analysis), or until centrally confirmed progression, death, 
consent withdrawal or end of study, whichever occurs first (modified 
by amendment 6).

Long-term follow-up: 
All patients who end study treatment for any reason will be followed 
for OS and any new anti-cancer treatment every 3 months until death, 
consent withdrawal, 24 months after the last patient’s last treatment or 
end of study, whichever occurs first (modified by amendment 6).
Methodology
Primary efficacy will be assessed based on radiological tumor evaluation 
by contrast-enhanced computed tomography (CT) or contrast-enhanced 
magnetic resonance imaging (MRI) of chest/abdomen/pelvis. The first 
tumor images will be obtained during full screening and will be sent to 
blinded central review to confirm radiological eligibility prior to 
randomization (modified by amendment 2). During treatment as well as 
active follow-up, tumor imaging will be performed with the same 
modality every 6 weeks during the first 6 months after the start of study 
treatment, every 9 weeks until the end of year 2, and every 12 weeks 
thereafter, until the earlier of centrally confirmed radiological disease 
progression, OS analysis data maturation, or end of study (modified by 
amendment 6). Primary analysis results will be based on central review.
Description of forced vital capacity methodology removed by 
amendment 2
Patients will be contacted to assess survival status every 3 months during 
long-term follow-up. In addition, extra survival sweep contacts will be 
conducted at the time of PFS final analysis and prior to OS final analysis 
to ensure that long-term follow-up data is current.
The effect of treatment on disease-specific symptoms and disease-specific 
health-related QoL will be assessed using the MD Anderson Symptom 
Inventory-Malignant Pleural Mesothelioma (MDASI-MPM) and the Lung 
Cancer Symptom Scale-Mesothelioma (LCSS-Meso), respectively, at full 
screening, at each cycle during treatment, at the safety follow-up visit, and 
during active follow-up (paragraph clarified by amendment 4).
Safety evaluations will be done at full screening, at each clinic visit during 
the treatment, and at the safety follow-up visit. The National Cancer 
Institute’s Common Terminology Criteria for Adverse Events (NCI-
CTCAE) version 4.03 will be used to grade severity of adverse events 
(AEs). In addition, a Bayer grading system will be used to assess corneal 
epitheliopathy (sentence added by amendment 2).
Sparse plasma sampling for PK will be performed on all patients.
Immunogenicity assessment will be performed for patients in the 
anetumab ravtansine arm only.
Obligatory biomarker sampling will be performed on all patients to 
measure mesothelin expression levels in tumor material at prescreening. 
In addition, plasma levels of soluble mesothelin will be studied to 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  8 of 269
evaluate whether plasma mesothelin levels may correlate with response 
rate and be of predictive value. Biomarker plasma will be collected to 
analyze circulating tumor DNA, too. Exploratory biomarker analysis may 
also be performed using additional fresh or archival tumor tissue to 
determine alterations in tumor-associated genes and to perform gene 
expression analysis (modified by amendment 4).
An independent Data Monitoring Committee will periodically monitor 
patient safety (clarification added by amendment 4).
Following OS data maturation, patients remaining on study will continue 
to be followed with reduced mandated assessments and data collection 
(although assessments can continue per investigator’s judgement). Active 
follow-up, efficacy, and some safety assessments will no longer be 
required (paragraph added by amendment 6). 
Type of control
Patients in the comparator arm will receive vinorelbine 30 mg/m2 IV QW. 
Vinorelbine is one of the drugs considered by various guidelines (e.g. 
National Comprehensive Cancer Network [NCCN], European Society of 
Medical Oncology [ESMO]) as a potential option for patients with 
advanced mesothelioma progressed after platinum-pemetrexed. 
Mechanistically, it is a spindle poison, therefore comparable with DM4, 
anetumab ravtansine metabolite.
Data Monitoring Committee
Yes
Number of patients
Approximately 210 patients will be randomized. Approximately 50% rate 
of screening failures is estimated, i.e. approximately 420 patients will be 
prescreened (modified by amendments 2 and 4).
Primary variable
Progression-free survival (PFS), defined as time from randomization until 
disease progression (according to mRECIST for MPM, per blinded central 
radiology review) or death.
Time point/frame of measurement 
for primary variable
Primary analysis will be performed after approximately 117 PFS events 
are observed by central review in the study.
Plan for statistical analysis
The primary analysis set for the efficacy variables is the intent-to-treat set 
(ITT).
The primary variable, PFS based on assessment of central review, will be 
tested using a log-rank test stratified by geographic region and per TTP on 
1st line treatment, with a 1-sided significance level of 0.0125. Kaplan-
Meier survival curves will be plotted. Medians with Brookmeyer-Crowley 
confidence intervals will be calculated. The primary analysis will occur 
after approximately 117 PFS events are observed by central review.
Secondary efficacy variable OS will be tested using a 2-stage group-
sequential testing procedure with an overall 1-sided significance level of 
0.025 and 80% power. Each stage will utilize a 1-sided log-rank test 
stratified by geographic region and per TTP on 1st line treatment. A Lan-
Demets alpha spending function with O’Brien-Fleming boundaries will be 
used. An interim analysis for OS will be performed at the same time as the 
final analysis for PFS, when approximately 80 OS events are expected to 
have been observed. The final analysis for OS will be performed after 
approximately 159 events have been observed (paragraph modified by 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  9 of 269
amendment 2).
Additional secondary variables include objective response rate (ORR), 
disease control rate (DCR), duration of response (DOR), durable response 
rate (DRR) and analysis of the change in physical symptoms of MPM by 
PROs (as measured using the MDASI-MPM and LCSS-Meso) (modified 
by amendment 2). In the event primary PFS and secondary OS hypothesis 
tests succeed, key secondary PRO variables will be tested at 1-sided 
significance level using an alpha-preserving hierarchy. A stratified log-
rank test will be used for time-to-event endpoints, and a Cochran-Mantel-
Haenszel test will be used for rate endpoints (paragraph modified by 
amendment 4).
The 210 randomized patients are estimated to be accrued in approximately 
19.8 months. Data for final PFS analysis are estimated to mature in 
21.2 months. Data for final OS analysis are estimated to mature in 
41.3 months (paragraph modified by amendment 2).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  10 of 269
Table of contents
1.
Title page.............................................................................................................................2
Signature of the sponsor’s medically responsible person......................................................3
Signature of principal investigator..........................................................................................4
2.
Synopsis...............................................................................................................................5
Table of contents .....................................................................................................................10
Table of tables..........................................................................................................................18
Table of figures........................................................................................................................18
List of abbreviations ...............................................................................................................19
3.
Introduction......................................................................................................................24
3.1
Background.....................................................................................................................24
3.1.1
Anetumab ravtansine (BAY 94-9343) ........................................................................26
3.1.2
Clinical experience......................................................................................................26
3.2
Rationale of the study.....................................................................................................30
3.3
Benefit-risk assessment ..................................................................................................30
4.
Study objectives................................................................................................................31
5.
Study design......................................................................................................................32
5.1
Design overview.............................................................................................................32
5.2
Primary variable..............................................................................................................35
5.3
Justification of the design...............................................................................................35
5.4
End of study....................................................................................................................36
5.5
Primary completion ........................................................................................................36
6.
Study population ..............................................................................................................36
6.1
Inclusion criteria.............................................................................................................36
6.1.1
Eligibility criteria for prescreening .............................................................................37
6.1.2
Eligibility criteria for full study...................................................................................38
6.2
Exclusion criteria............................................................................................................40
6.3
Withdrawal of patients from study .................................................................................42
6.3.1
Withdrawal ..................................................................................................................42
6.3.1.1
Screening failure ......................................................................................................42
6.3.1.1.1
Prescreening failure ..............................................................................................42
6.3.1.1.2
Full screening failure ............................................................................................42
6.3.1.1.3
Re-screening .........................................................................................................42
6.3.1.2
Withdrawal criteria ..................................................................................................43
6.3.1.3
General procedures ..................................................................................................46
6.3.2
Replacement ................................................................................................................46
6.4
Patient identification.......................................................................................................46
7.
Treatment(s) .....................................................................................................................47


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  11 of 269
7.1
Treatments to be administered........................................................................................47
7.2
Identity of study treatment..............................................................................................47
7.2.1
Test drug - anetumab ravtansine .................................................................................47
7.2.2
Comparator - vinorelbine ............................................................................................48
7.3
Treatment assignment.....................................................................................................49
7.4
Dosage and administration .............................................................................................49
7.4.1
Treatments to be administered ....................................................................................49
7.4.1.1
Administration of anetumab ravtansine ...................................................................49
7.4.1.2
Administration of vinorelbine..................................................................................49
7.4.2
Dose modification .......................................................................................................50
7.4.2.1
Dose modifications of anetumab ravtansine ............................................................50
7.4.2.1.1
Hematological toxicities .......................................................................................50
7.4.2.1.2
Non-hematological toxicities................................................................................52
7.4.2.1.3
Miscellaneous toxicities........................................................................................53
7.4.2.1.4
Continuation of treatment with anetumab ravtansine...........................................56
7.4.2.1.5
Permanent discontinuation of anetumab ravtansine due to TEAEs......................56
7.4.2.2
Dose modifications of vinorelbine...........................................................................57
7.5
Blinding ..........................................................................................................................58
7.6
Drug logistics and accountability ...................................................................................58
7.7
Treatment compliance ....................................................................................................59
8.
Non-study therapy............................................................................................................59
8.1
Prior and concomitant therapy........................................................................................59
8.2
Post-study therapy ..........................................................................................................63
9.
Procedures and variables ................................................................................................63
9.1
Tabular schedule of evaluations .....................................................................................63
9.2
Visit description..............................................................................................................73
9.2.1
Prescreening ................................................................................................................73
9.2.2
Full screening period...................................................................................................73
9.2.3
Treatment period .........................................................................................................75
9.2.3.1
Treatment – Cycle 1.................................................................................................75
9.2.3.2
Treatment – Cycle 2 and higher – prior to OS maturation.......................................78
9.2.3.3
Treatment post OS maturation – anetumab ravtansine arm - Day 1........................81
9.2.3.4
Treatment post OS maturation – vinorelbine arm – Days 1, 8 and 15.....................82
9.2.4
Efficacy assessments ...................................................................................................82
9.2.5
Follow-up periods........................................................................................................83
9.2.5.1
Safety follow-up prior to OS maturation .................................................................83
9.2.5.2
Safety follow-up post OS maturation.......................................................................84
9.2.5.3
Active follow-up ......................................................................................................85
9.2.5.4
Long-term follow-up................................................................................................85
9.3
Population characteristics...............................................................................................86
9.3.1
Demographic ...............................................................................................................86
9.3.2
Medical history............................................................................................................86
9.3.3
Other baseline characteristics......................................................................................86
9.4
Efficacy...........................................................................................................................87


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  12 of 269
9.4.1
Radiological tumor assessments..................................................................................87
9.4.2
Survival .......................................................................................................................89
9.4.3
Patient-reported outcomes...........................................................................................90
9.4.3.1
MDASI-MPM ..........................................................................................................90
9.4.3.2
LCSS-Meso..............................................................................................................91
9.5
Pharmacokinetics / pharmacodynamics..........................................................................91
9.6
Safety..............................................................................................................................93
9.6.1
Adverse events ............................................................................................................93
9.6.1.1
Definitions................................................................................................................93
9.6.1.2
Classifications for adverse event assessment...........................................................94
9.6.1.2.1
Seriousness ...........................................................................................................94
9.6.1.2.2
Intensity ................................................................................................................94
9.6.1.2.3
Causal relationship................................................................................................95
9.6.1.2.4
Action taken with study treatment........................................................................96
9.6.1.2.5
Other specific treatment(s) of adverse events.......................................................96
9.6.1.2.6
Outcome................................................................................................................96
9.6.1.3
Assessments and documentation of adverse events.................................................97
9.6.1.4
Reporting of serious adverse events.........................................................................97
9.6.1.5
Expected adverse events ..........................................................................................98
9.6.1.6
Adverse events of special safety interest .................................................................98
9.6.2
Pregnancies..................................................................................................................99
9.6.3
Further safety...............................................................................................................99
9.6.3.1
Laboratory evaluations.............................................................................................99
9.6.3.2
Physical examination .............................................................................................100
9.6.3.2.1
Complete physical examination..........................................................................100
9.6.3.2.2
Brief physical examination.................................................................................101
9.6.3.3
ECOG Performance Status.....................................................................................101
9.6.3.4
Vital signs ..............................................................................................................101
9.6.3.5
12-lead ECG...........................................................................................................101
9.6.3.6
Cardiac function.....................................................................................................101
9.6.3.7
Ophthalmologic examinations ...............................................................................102
9.7
Other procedures and variables ....................................................................................102
9.7.1
Biomarkers ................................................................................................................102
9.7.2
Immunogenicity.........................................................................................................103
9.8
Appropriateness of procedures / measurements ...........................................................103
10. Statistical methods and determination of sample size................................................104
10.1
General considerations..................................................................................................104
10.2
Analysis sets .................................................................................................................105
10.3
Variables and planned statistical analyses....................................................................105
10.3.1
Population characteristics..........................................................................................106
10.3.2
Primary efficacy variable ..........................................................................................106
10.3.3
Secondary variables...................................................................................................107
10.3.3.1
Secondary efficacy variables .................................................................................107
10.3.3.2
Other efficacy variables .........................................................................................111


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  13 of 269
10.3.3.3
Safety variables......................................................................................................111
10.3.4
Other variables ..........................................................................................................112
10.3.4.1
Pharmacokinetic variables .....................................................................................112
10.3.4.2
Biomarker variables ...............................................................................................112
10.3.4.3
Immunogenicity variables......................................................................................112
10.4
Determination of sample size .......................................................................................113
10.4.1
Primary endpoint progression-free survival..............................................................113
10.4.2
Secondary endpoint overall survival .........................................................................113
10.5
Planned interim analyses ..............................................................................................114
11. Data handling and quality assurance...........................................................................114
11.1
Data recording ..............................................................................................................114
11.2
Monitoring....................................................................................................................116
11.3
Data processing.............................................................................................................117
11.4
Missing data..................................................................................................................117
11.5
Audit and inspection.....................................................................................................118
11.6
Archiving......................................................................................................................119
12. Premature termination of the study.............................................................................119
13. Ethical and legal aspects................................................................................................120
13.1
Investigator(s) and other study personnel.....................................................................120
13.2
Funding and financial disclosure..................................................................................122
13.3
Ethical and legal conduct of the study..........................................................................122
13.4
Patient information and consent ...................................................................................123
13.5
Publication policy and use of data................................................................................125
13.6
Compensation for health damage of patients / insurance .............................................125
13.7
Confidentiality..............................................................................................................126
14. Reference list ..................................................................................................................127
15. Protocol amendments ....................................................................................................131
15.1
Amendment 2................................................................................................................131
15.1.1
Overview of changes to the study .............................................................................131
15.1.1.1
Modification 1: Change in OS analysis design......................................................131
15.1.1.2
Modification 2: Changes in determination of sample size.....................................131
15.1.1.3
Modification 3: Pulmonary function evaluation removed .....................................131
15.1.1.4
Modification 4: Clarification of progression as withdrawal criterion....................132
15.1.1.5
Modification 5: Definition of corneal epitheliopathy introduced ..........................132
15.1.1.6
Modification 6: Redefinition of mesothelin overexpression..................................132
15.1.1.7
Modification 7: Clarification of start of full study.................................................132
15.1.1.8
Modification 8: Clarification of radiological eligibility ........................................132
15.1.1.9
Modification 9: Clarification of contraception duration and use...........................133
15.1.1.10 Modification 10: Addition of optometrist as an alternative to ophthalmologist....133
15.1.1.11 Modification 11: Clarification of ocular eligibility................................................133
15.1.1.12 Modification 12: Vinorelbine formulation corrected.............................................133
15.1.1.13 Modification 13: Dose modification due to hypersensitivity corrected.................133


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  14 of 269
15.1.1.14 Modification 14: Clarification of reporting of AE of special interest....................133
15.1.1.15 Modification 15: Clarification of blinded central review during screening...........134
15.1.1.16 Modification 16: Clarification of intra-patient dose escalation for study drugs....134
15.1.1.17 Modification 17: Clarification on follow-up of patients who are randomized 
but not treated.........................................................................................................134
15.1.1.18 Modification 18: Additional contact attempt added at the time of each 
survival sweep........................................................................................................134
15.1.1.19 Modification 19: Time window between randomization and treatment start 
added ......................................................................................................................134
15.1.1.20 Modification 20: PROs schedule updated..............................................................135
15.1.1.21 Modification 21: Inconsistency in dose re-escalation clarified .............................135
15.1.1.22 Modification 22: Clarification on start of treatment period...................................135
15.1.1.23 Modification 23: Clarification of the study background with data on 
probability of corneal epitheliopathy versus model-predicted drug exposure.......135
15.1.1.24 Modification 24: Urine dipstick test removed from visit C1D1 ............................135
15.1.1.25 Modification 25: Appendix regarding response assessment updated ....................136
15.1.1.26 Other modifications and corrections......................................................................136
15.1.2
Changes to the protocol text......................................................................................137
15.1.2.1
Section 2 Synopsis .................................................................................................138
15.1.2.2
List of abbreviations...............................................................................................143
15.1.2.3
Section 3.1 Background .........................................................................................143
15.1.2.4
Section 3.1.2 Clinical experience...........................................................................144
15.1.2.5
Section 4 Study objectives .....................................................................................146
15.1.2.6
Section 5.1 Design overview .................................................................................146
15.1.2.7
Section 5.3 Justification of the design ...................................................................150
15.1.2.8
Section 5.5 Primary completion.............................................................................151
15.1.2.9
Section 6.1.1 Eligibility criteria for prescreening..................................................152
15.1.2.10 Section 6.1.2 Eligibility criteria for full study .......................................................152
15.1.2.11 Section 6.2 Exclusion criteria ................................................................................155
15.1.2.12 Section 6.3.1.1.1 Prescreening failure....................................................................155
15.1.2.13 Section 6.3.1.2 Withdrawal criteria .......................................................................156
15.1.2.14 Section 7.2.1 Test drug - anetumab ravtansine ......................................................158
15.1.2.15 Section 7.2.2 Comparator - vinorelbine.................................................................158
15.1.2.16 Section 7.3 Treatment assignment .........................................................................159
15.1.2.17 Section 7.4.2.1 Dose modifications of anetumab ravtansine .................................159
15.1.2.18 Section 7.4.2.1.2 Non-hematological toxicities .....................................................159
15.1.2.19 Section 7.4.2.1.3 Miscellaneous toxicities.............................................................161
15.1.2.20 Section 7.4.2.2 Dose modifications of vinorelbine................................................166
15.1.2.21 Section 8.1 Prior and concomitant therapy ............................................................166
15.1.2.22 Section 9.1 Tabular schedule of evaluations..........................................................167
15.1.2.23 Section 9.2.2 Full screening period........................................................................174
15.1.2.24 Section 9.2.3 Treatment period..............................................................................175
15.1.2.25 Section 9.2.3.1 Treatment – Cycle 1......................................................................175
15.1.2.26 Section 9.2.3.2 Treatment – Cycle 2 and higher....................................................178
15.1.2.27 Section 9.2.4 Efficacy assessments........................................................................181


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  15 of 269
15.1.2.28 Section 9.2.5.1 Safety follow-up............................................................................181
15.1.2.29 Section 9.2.5.2 Active follow-up ...........................................................................182
15.1.2.30 Section 9.4.1 Radiological tumor assessments ......................................................182
15.1.2.31 Section 9.4 Efficacy ...............................................................................................183
15.1.2.32 Section 9.4.2 Survival ............................................................................................184
15.1.2.33 Section 9.4.3 Patient-reported outcomes................................................................184
15.1.2.34 Section 9.5 Pharmacokinetics / pharmacodynamics..............................................185
15.1.2.35 Section 9.6.1.2.2 Intensity......................................................................................186
15.1.2.36 Section 9.6.1.2.4 Action taken with study treatment .............................................186
15.1.2.37 Section 9.6.1.3 Assessments and documentation of adverse events......................187
15.1.2.38 Section 9.6.1.6 Adverse events of special safety interest ......................................187
15.1.2.39 Section 9.6.3.1 Laboratory evaluations..................................................................188
15.1.2.40 Section 9.6.3.7 Ophthalmologic examinations ......................................................188
15.1.2.41 Section 9.7.1 Biomarkers.......................................................................................189
15.1.2.42 Section 9.8 Appropriateness of procedures / measurements..................................190
15.1.2.43 Section 10.2 Analysis sets......................................................................................190
15.1.2.44 Section 10.3.2 Primary efficacy variable...............................................................191
15.1.2.45 Section 10.3.3.1 Secondary efficacy variables ......................................................191
15.1.2.46 Section 10.3.3.3 Safety variables...........................................................................193
15.1.2.47 Section 10.4 Determination of sample size............................................................194
15.1.2.48 Section 10.4.1 Primary endpoint progression-free survival...................................194
15.1.2.49 Section 10.4.2 Secondary endpoint overall survival..............................................195
15.1.2.50 Section 10.5 Planned interim analyses...................................................................196
15.1.2.51 Section 11.4 Missing data ......................................................................................196
15.1.2.52 Section 14 Reference list........................................................................................197
15.1.2.53 Section 16.3 Response assessment.........................................................................198
15.2
Amendment 4................................................................................................................200
15.2.1
Overview of changes to the study .............................................................................200
15.2.1.1
Modification 1: Addition of durable response rate (DRR) as a secondary 
variable...................................................................................................................200
15.2.1.2
Modification 2: Change in the number of patients planned to be prescreened......200
15.2.1.3
Modification 3: Change in inclusion/exclusion criteria: Amendment of time 
window for prior participation in another clinical study........................................200
15.2.1.4
Modification 4: Change in exclusion criteria: Exclusion of prior experimental 
device therapy ........................................................................................................200
15.2.1.5
Modification 5: Change in exclusion criteria: Exclusion of patients with CNS 
metastasis ...............................................................................................................200
15.2.1.6
Modification 6: Clarification on re-screening criteria ...........................................201
15.2.1.7
Modification 7: Removal of details around reconstitution and dilution of 
anetumab ravtansine...............................................................................................201
15.2.1.8
Modification 8: Changes to dose modifications of anetumab ravtansine ..............201
15.2.1.9
Modification 9: Addition of Oxford Schema.........................................................202
15.2.1.10 Modification 10: Corrections to prior and concomitant therapies .........................202
15.2.1.11 Modification 11: Addition of collection of optional archival tumor tissue for 
exploratory analysis ...............................................................................................202


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  16 of 269
15.2.1.12 Modification 12: Clarification regarding central review for determination of 
progressive disease.................................................................................................203
15.2.1.13 Modification 13: Clarification to PK validity criteria............................................203
15.2.1.14 Modification 14: Timing of analysis of DRR, DOR and updated PFS..................203
15.2.1.15 Modification 15: Addition of mention of sensitivity analyses and citations .........203
15.2.1.16 Modification 16: Addition of further details to the analysis of the patient-
reported outcomes..................................................................................................203
15.2.1.17 Modification 17: Clarification of patient-reported outcomes instrument use........204
15.2.1.18 Modification 18: Addition of hypothesis tests and hierarchy for selected 
secondary variables................................................................................................204
15.2.1.19 Other modifications and corrections......................................................................204
15.2.2
Changes to the protocol text......................................................................................206
15.2.2.1
Section 1 Title page................................................................................................207
15.2.2.2
Section 2 Synopsis .................................................................................................208
15.2.2.3
List of abbreviations...............................................................................................210
15.2.2.4
Section 3.2 Rationale of the study .........................................................................210
15.2.2.5
Section 5.1 Design overview .................................................................................210
15.2.2.6
Section 5.3 Justification of the design ...................................................................211
15.2.2.7
Section 6.1.2 Eligibility criteria for full study .......................................................212
15.2.2.8
Section 6.2 Exclusion criteria ................................................................................212
15.2.2.9
Section 6.3.1.1.3 Re-screening...............................................................................213
15.2.2.10 Section 6.3.1.2 Withdrawal criteria .......................................................................214
15.2.2.11 Section 7.2.1 Test drug – anetumab ravtansine .....................................................215
15.2.2.12 Section 7.4.2.1 Dose modifications of anetumab ravtansine .................................217
15.2.2.13 Section 7.4.2.1.1 Hematological toxicities ............................................................217
15.2.2.14 Section 7.4.2.1.2 Non-hematological toxicities .....................................................220
15.2.2.15 Section 7.4.2.1.3 Miscellaneous toxicities.............................................................222
15.2.2.16 Section 7.5 Blinding...............................................................................................223
15.2.2.17 Section 8.1 Prior and concomitant therapy ............................................................223
15.2.2.18 Section 9.1 Tabular schedule of evaluations..........................................................226
15.2.2.19 Section 9.2.2 Full screening period........................................................................230
15.2.2.20 Section 9.2.3.1 Treatment – Cycle 1......................................................................231
15.2.2.21 Section 9.2.3.2 Treatment – Cycle 2 and higher....................................................231
15.2.2.22 Section 9.2.5.2 Active follow-up ...........................................................................232
15.2.2.23 Section 9.4.1 Radiological tumor assessments ......................................................232
15.2.2.24 Section 9.4.3 Patient-reported outcomes................................................................233
15.2.2.25 Section 9.6.2 Pregnancies ......................................................................................234
15.2.2.26 Section 9.6.3.1 Laboratory evaluations..................................................................234
15.2.2.27 Section 9.6.3.6 Cardiac function............................................................................235
15.2.2.28 Section 9.7.1 Biomarkers.......................................................................................235
15.2.2.29 Section 10.2 Analysis sets......................................................................................236
15.2.2.30 Section 10.3.2 Primary efficacy variable...............................................................236
15.2.2.31 Section 10.3.3.1 Secondary efficacy variables ......................................................237
15.2.2.32 Section 10.3.3.3 Safety variables...........................................................................241
15.2.2.33 Section 10.3.4.2 Biomarker variables ....................................................................242


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  17 of 269
15.2.2.34 Section 10.4.1 Primary endpoint progression-free survival...................................242
15.2.2.35 Section 11.1 Data recording...................................................................................243
15.2.2.36 Section 11.4 Missing data ......................................................................................243
15.2.2.37 Section 13.1 Investigator(s) and other study personnel .........................................244
15.2.2.38 Section 14 Reference list........................................................................................244
15.2.2.39 Section 16.9 Grading staining: Oxford Schema (new addition) ............................245
15.3
Amendment 5................................................................................................................246
15.3.1
Overview of changes to the study .............................................................................246
15.3.1.1
Modification 1: Addition of dextrose as alternative diluent for anetumab 
ravtansine ...............................................................................................................246
15.3.1.2
Modification 2: Clarification regarding the definition of mesothelin 
overexpression .......................................................................................................246
15.3.1.3
Modification 3: Clarification regarding continued treatment after centrally 
confirmed progression and tumor assessment requirements..................................246
15.3.1.4
Modification 4: Addition of parameter for pharmacokinetics samples .................246
15.3.1.5
Modification 5: Clarification regarding criteria on continuation of treatment 
with anetumab ravtansine.......................................................................................246
15.3.1.6
Modification 6: Clarification regarding anetumab ravtansine infusion 
duration ..................................................................................................................247
15.3.1.7
Other modifications and corrections......................................................................247
15.3.2
Changes to the protocol text......................................................................................247
15.3.2.1
List of abbreviations...............................................................................................248
15.3.2.2
Section 5.1 Design overview .................................................................................248
15.3.2.3
Section 5.3 Justification of the design ...................................................................248
15.3.2.4
Section 6.1.1 Eligibility criteria for prescreening..................................................249
15.3.2.5
Section 6.1.2 Eligibility criteria for full study .......................................................249
15.3.2.6
Section 6.3.1.1.1 Prescreening failure....................................................................249
15.3.2.7
Section 7.2.1 Test drug - anetumab ravtansine ......................................................250
15.3.2.8
Section 7.4.1.1 Administration of anetumab ravtansine ........................................250
15.3.2.9
Section 7.4.2.1.4 Continuation of treatment with anetumab ravtansine ................251
15.3.2.10 Section 9.2.3 Treatment period..............................................................................251
15.3.2.11 Section 9.4.1 Radiological tumor assessments ......................................................251
15.3.2.12 Section 9.5 Pharmacokinetics / pharmacodynamics..............................................252
15.3.2.13 Section 9.7.1 Biomarkers.......................................................................................253
15.3.2.14 Section 13.1 Investigator(s) and other study personnel .........................................254
15.4
Amendment 6................................................................................................................255
15.4.1
Overview of changes to the study .............................................................................255
15.4.1.1
Modification 1: Evaluations and data collection reduced for patients ongoing 
on treatment post OS maturation ...........................................................................255
15.4.1.2
Modification 2: Continuation of collection of survival data post OS 
maturation ..............................................................................................................255
15.4.1.3
Modification 3: Clarification of end of study definition........................................255
15.4.1.4
Modification 4: Modification of withdrawal criteria .............................................256
15.4.1.5
Modification 5: Addition of reference to the investigator’s brochure to 
Clinical experience section ....................................................................................256


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  18 of 269
15.4.2
Changes to the protocol text......................................................................................256
16. Appendices......................................................................................................................257
16.1
ECOG Performance Status ...........................................................................................257
16.2
New York Heart Association (NYHA) functional classification .................................257
16.3
Response assessment ....................................................................................................258
16.4
National Cancer Institute’s Common Terminology Criteria for Adverse Events, 
version 4.03...................................................................................................................259
16.5
Patient-reported outcomes ............................................................................................260
16.5.1
MDASI-MPM ...........................................................................................................260
16.5.2
LCSS-Meso ...............................................................................................................262
16.6
CYP3A4 inhibitors and inducers..................................................................................264
16.7
Calculation of glomerular filtration rate by the Modification of Diet in Renal 
Disease formula ............................................................................................................264
16.8
Mosteller Equation for calculation of body surface area (BSA) ..................................264
16.9
Grading staining: Oxford Schema ................................................................................265
Table of tables
Table 7–1 Identity of anetumab ravtansine.............................................................................48
Table 7–2 Dose levels of anetumab ravtansine.......................................................................50
Table 7–3 Dose modifications for anetumab ravtansine in response to hematological 
toxicities a for neutrophil and platelet nadir b counts – table added.......................51
Table 7–4 Dose adjustments in response to non-hematologic toxicities - amended...............53
Table 7–5 Bayer classification and management of corneal epitheliopathy - amended .........54
Table 7–6 Bayer classification of visual acuity changes.........................................................56
Table 7–7 Dose adjustments based on neutrophil granulocyte counts....................................57
Table 7–8 Modifications based on total bilirubin ...................................................................58
Table 8–1 Prohibited prior and concomitant therapies - amended..........................................60
Table 8–2 Permitted concomitant therapies - amended ..........................................................62
Table 9–1 Study flow chart – prior to OS maturation – amended ..........................................64
Table 9–2 Study flow chart – anetumab ravtansine arm patients ongoing on treatment post 
OS maturation – added...........................................................................................69
Table 9–3 Study flow chart – vinorelbine arm patients ongoing on treatment post OS 
maturation – added.................................................................................................71
Table of figures
Figure 3–1 Probability of corneal epitheliopathy versus model-predicted drug exposure – 
figure added by amendment 2 ................................................................................29
Figure 5–1 Study periods..........................................................................................................32
Figure 5–2 Overall study design - amended.............................................................................33
Figure 6–1 Withdrawal criteria - amended...............................................................................45


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  19 of 269
List of abbreviations
List of abbreviations was updated by amendments 2, 4 and 5.
5-HT3
5-hydroxytryptamine (serotonin)
AAG
Alpha-1 acid glycoprotein
ADA
Anti-drug antibody
ADC
Antibody-drug conjugate
AE
Adverse event
AG
Joint stock company, Aktiengesellschaft
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
ARDS
Acute respiratory distress syndrome
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
AUC
Area under the curve
BCVA
Best corrected visual acuity
β-HCG
β subunit of human chorionic gonadotropin
BIC
Best investigator choice
BIO
Biomarker set
BM
Biomarker
BP
Blood pressure
BSA
Body surface area
BUN
Blood urea nitrogen
°C
Celcius degree(s)
C
Cycle
CBC
Complete blood count
Cmax
Maximum drug concentration
CNS
Central nervous system
COA
Clinical Outcomes Assessment
CR
Complete response
CRF
Case report form
CRO
Contract research organization
CSF
Colony stimulating factor
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group
CYP2D6
Cytochrome P450, family 2, subfamily D, polypeptide 6
CYP3A4
Cytochrome P450, family 3, subfamily A, polypeptide 4
D
Day
DCR
Disease control rate
DICOM
Digital Imaging and Communications in Medicine
dL
Deciliter
DM4
Derivatives of maytansine 4
DM4-Me
Methyl-DM4
DMC
Data Monitoring Committee


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  20 of 269
DNA
Deoxyribonucleic acid
DOR
Duration of response
DRR
Durable response rate
ECG
Electrocardiogram
EchoCG
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
ECOG PS
Eastern Cooperative Oncology Group Performance Status
EDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
ENR
Enrolled set
ESMO
European Society of Medical Oncology
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
EudraCT
EU data repository for clinical trials
°F
Fahrenheit degree(s)
FDA
Food and Drug Administration
FFPE
Formalin-fixed, paraffin-embedded
FiH
First in Human
FSH
Follicle stimulating hormone
g
Gram(s)
GCL
Global Clinical Leader
GCP
Good Clinical Practice
G-CSF
Granulocyte-colony stimulating factor
GFR
Glomerular filtration rate
GGT
Gamma-glutamyl transferase
GMP
Good Manufacturing Practice
GPV
Global Pharmacovigilance
h
Hour(s)
H0
Null hypothesis
HA
Alternative hypothesis
Hb
Hemoglobin
HDAC
Histone deacetylase
HIV
Human immunodeficiency virus
HR
Heart rate
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonization
IEC
Independent Ethics Committee
IFCT
French Cooperative Thoracic Intergroup
IgG1
Immunoglobulin G subclass 1
IHC
Immunohistochemistry
ILD
Interstitial lung disease
IM
Immunogenicity
IMP
Investigational medicinal product
INR
International normalized ratio
IOP
Intraocular pressure
IRB
Institutional Review Board
IRC
Image Review Charter


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  21 of 269
ITT
Intent-to-treat (set)
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IxRS
Interactive Voice / Web Response System
kg
Kilogram(s)
LCSS
Lung Cancer Symptom Scale
LCSS-Meso
Lung Cancer Symptom Scale-Mesothelioma
LDH
Lactic dehydrogenase 
LLN
Lower limit of normal
LPLV
Last patient last visit
LVEF
Left ventricular ejection fraction
m2
Square meter(s)
MAPS
Mesothelioma Avastin Plus Pemetrexed-cisplatin Study
MD
Doctor of Medicine
MDACC
MD Anderson Cancer Center
MDASI
MD Anderson Symptom Inventory
MDASI-LC
MD Anderson Symptom Inventory-Lung Cancer
MDASI-MPM
MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram(s)
MHRA
Medicines and Healthcare Products Regulatory Agency
Min
Minute(s)
miRNA
Micro ribonucleic acid
mL
Milliliter(s) 
mm3
Cubic millimeter(s)
mmHg
Millimeter of mercury
MoA
Mechanism of action
MPM
Malignant pleural mesothelioma
mRECIST
Modified Response Evaluation Criteria in Solid Tumors
MRI
Magnetic resonance imaging
M&S
Modelling and Simulation
MTD
Maximum tolerated dose
MUGA
Multiple gated acquisition
N
Number of patients
n
Number of non-missing values
N HCl
Normal hydrochloric acid
NAB
Neutralizing anti-drug antibody
NC
No change
NCCN
National Comprehensive Cancer Network
NCI-CTCAE
National Cancer Institute’s Common Terminology Criteria for Adverse 
Events
NE
Not evaluated
NGS
Next generation sequencing
NYHA
New York Heart Association
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  22 of 269
PDX
Patient-derived xenograft
PET
Positron emission tomography
PFS
Progression-free survival
P-gp
Permeability glycoprotein
PGt
Pharmacogenetic
PhD
Doctor of Philosophy
PI
Patient information
PK(s)
Pharmacokinetic(s)
PopPBPK
Population, physiologically-based pharmacokinetic
PR
Partial response
PRO
Patient-reported outcome
PT
Prothrombin time
PTT
Partial thromboplastin time
Q3W
Every 3 weeks
QA
Quality assurance
QoL
Quality of life
QOL
Quality of life set
QW
Once weekly
RBC
Red blood cell count
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RoW
Rest of the world
RPIID
Recommended Phase II dose
RR
Respiratory rate
RT
Radiotherapy
SAE
Serious adverse event
SAF
Safety set
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
SC
Steering Committee
SD
Stable disease
SmPC
Summary of product characteristics
SoC
Standard of care
SPDB
N-succinimidyl 4-(2-pyridyldithio)butyrate (reducible disulfide linker)
SPK
Superficial punctate keratitis
SQR RT
Square root (√)
SUSAR
Suspected, unexpected, serious adverse reaction
T1
Tumor invades lamina propria
Ta
Non-invasive tumor
TEAE
Treatment-emergent adverse event
Temp
Body temperature
Tis
Carcinoma in situ
TMF
Trial master file
TTP
Time to progression
UK
United Kingdom
ULN
Upper limit of normal
US(A)
United States of America
VAS
Visual analogue scale


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  23 of 269
WBC
White blood cell count
WOCBP
Women of childbearing potential


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  24 of 269
3.
Introduction
3.1
Background
Malignant pleural mesothelioma (MPM) is a locally invasive, usually fatal neoplasm arising 
from the mesothelial surfaces of the pleural cavity. The exact prevalence is unknown but it is 
estimated that mesotheliomas represent less than 1% of all cancers (1). A rare condition 
before 1950, its incidence rose following the increased use of asbestos with an expected peak 
in the next 10-20 years (2). Approximately 2500 new cases are recorded per year in the US 
(3) and the incidence of MPM shows marked variations from one country to another. 
Incidence is increasing in Russia, Western Europe (1.25/100000 per year in Great Britain, 
1.1/100000 per year in Germany (4)), China and India. Mortality is highest in the UK, 
Netherlands, Australia; and is increasing in Japan, Argentina and Brazil (3). The link between 
occupational or environmental asbestos exposure and MPM was recognized in the early 1960s 
(5, 6). Since 1980 the use of asbestos was widely abandoned in the Western countries, but the 
incidence of MPM will continue to rise until approximately year 2020 (7) due to the long 
latency between asbestos exposure and development of MPM (8). Russia, China, Brazil and 
Canada are currently the top producers of asbestos (3).
Life expectancy in MPM is poor, with a median survival of approximately 1 year following 
diagnosis, also depending on the histological subtype (epithelioid and biphasic or mixed 
having a better prognosis than sarcomatoid), tumor stage and some patient-derived factors 
(general condition, age, weight loss, pain, platelets and asbestos exposure) (9). Typical 
presenting features of MPM are chest pain and dyspnea. Most people with MPM have pleural 
effusion evident on examination. Fatigue, profuse sweating, weight loss, anorexia and 
difficulty in swallowing become common as the disease progresses. The most suggestive 
computed tomography (CT) findings indicating malignant pleural disease are 1) a 
circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 
4) mediastinal pleural involvement (10). Presentation and diagnosis often occur at an 
advanced stage and the prognosis for most patients is extremely poor (11).
Treatment of MPM
Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate 
management of disease, using a framework of radiotherapy, chemotherapy, surgery and 
symptom palliation with terminal care. However, few patients qualify for curative surgery, 
and the efficacy of radiotherapy is limited, hence the high need for effective systemic 
treatments. The combination of cisplatin and the antifolate pemetrexed proved superior to 
single cisplatin, respectively, in terms of overall survival (OS) (12.1 vs. 9.3 months), 
progression-free survival (PFS) (5.7 vs. 3.9 months), and response rate (41.3% vs. 16.7%) 
(12). The combination of cisplatin and pemetrexed is the worldwide current standard of care 
(SoC) for chemotherapy-naive patients (3). Data from the phase III, randomized, multicenter 
Mesothelioma Avastin Plus Pemetrexed-cisplatin Study (MAPS) (13) by the French 
Cooperative Thoracic Intergroup (IFCT) have been recently presented by Dr. Zalcman at 
2015 ASCO annual meeting; this study was conducted to determine if the addition of 
bevacizumab 15 mg/kg every 3 weeks (Q3W) to standard cisplatin plus pemetrexed 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  25 of 269
chemotherapy would affect OS in patients with MPM. A total of 448 patients were enrolled, 
with 225 patients receiving SoC and 223 patients receiving bevacizumab plus SoC. In the 
intent-to-treat (ITT) population, the median OS in the bevacizumab arm was 18.8 months 
compared with 16.1 months in the SoC arm. Median PFS was 9.6 months in the bevacizumab 
arm compared with 7.5 months in the standard chemotherapy arm, also in the ITT population. 
Significantly more patients in the bevacizumab arm experienced Grade 3/4 events (71.2%) 
compared with standard chemotherapy arm (62.1%). In addition, significantly more Grade 3/4 
hypertension (23.0% vs. 0%) and arterial and venous thrombotic events (5.8% vs. 0.9%) were 
reported in the bevacizumab arm. The overall conclusion was that the addition of 
bevacizumab to cisplatin and pemetrexed led to longer survival with acceptable toxicity in 
patients with MPM. However, discussant Dr. Nowak noted that whether the bevacizumab, 
cisplatin and pemetrexed triplet is widely adopted as a new SoC in this patient population will 
depend on several factors, particularly cost-effectiveness and reimbursement decisions made 
by health care systems in different parts of the world (paragraph updated by amendment 2, 
see section 15.1.1.3).
There is no SoC for patients who relapse following a platinum-based treatment, as no single 
agent or combination has been shown to prolong survival. The largest study in relapsed 
patients with mesothelioma tested histone deacetylase (HDAC) inhibitor vorinostat against 
placebo (14). This Phase III study was conducted in 660 patients who had progressed after 
1 or 2 systemic therapies, including cisplatin and pemetrexed. All patients received best 
supportive care, and were randomized to receive placebo or vorinostat 300 mg orally twice 
daily for 3 days each week of a 21-day cycle. There was no significant difference in median 
OS between the vorinostat and placebo groups (30.7 vs 27.1 weeks; hazard ratio 0.98; 
P = .858). Median PFS was comparable (6.3 vs. 6.1 weeks). Recently, another Phase III trial 
(NGR015) of NGR-hTNF plus best investigator choice (BIC) versus placebo plus BIC failed 
to meet the primary endpoint in 400 subjects enrolled: no OS benefit was found in previously 
treated patients in the experimental arm (median 8.4 vs 7.9 months) (15). Pemetrexed (if not 
given in 1st line), can be used in a 2nd line setting with median PFS and median OS of 3.6 and 
8.4 months, respectively (16). Among other drugs used as single agents or in combination in 
MPM are vinorelbine and gemcitabine. The Phase II study to assess the safety and efficacy of 
weekly vinorelbine (30 mg/m2 for 6 weeks) in 63 pre-treated patients showed an objective 
response rate (ORR) of 16% and an OS of 9.6 months (95% confidence interval: 7.3 -
 11.8 months) (17). The main Grade 3/4 toxicity observed was neutropenia. Toxicity was 
similar to weekly vinorelbine when used in the 1st line setting. The authors concluded that 
weekly vinorelbine appeared to have a reasonable response rate with an acceptable toxicity 
profile in the 2nd line treatment of MPM (17). A Phase II study of gemcitabine monotherapy 
for 10 cycles (a 30-minute intravenous [IV] administration of 1250 mg/m2 on Days 1, 8, and 
15 of a 28-day cycle) involved 27 chemotherapy-naive patients (18). Neutropenia of 
≥ Grade 3 occurred in 30% of patients, without episodes of febrile neutropenia. One case of 
hemolytic-uremic syndrome, most likely related to gemcitabine use, was observed. Overall, 
2 objective responses were observed (ORR of 7%; 95% confidence interval: 1 - 24%) and the 
median OS was 8 months. The authors concluded that gemcitabine has limited activity in 
MPM.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  26 of 269
3.1.1
Anetumab ravtansine (BAY 94-9343)
Anetumab ravtansine (BAY 94-9343) is an antibody-drug conjugate (ADC) targeting 
mesothelin, a protein normally present on mesothelial cells and overexpressed in the majority 
of mesotheliomas (both epithelioid and mixed histology for MPM), ductal pancreatic 
adenocarcinomas and adenocarcinomas of the ovary. The expression profile as well as the fact 
that mesothelin is an internalizing antigen suggest mesothelin as an adequate target for 
antibody-mediated delivery of cytotoxics. The biological function of mesothelin is unknown; 
mesothelin-deficient mice do not display a specific phenotype (19).
Anetumab ravtansine is composed of the human anti-mesothelin-monoclonal antibody 
BAY 86-1903 and the maytansinoid DM4 (BAY 100-6640), conjugated by a disulfide linker 
moiety to lysine residues of the antibody. DM4 is a spindle poison, and its mechanism of 
action (MoA) is inhibition of microtubule assembly (similar to that of vinca alkaloids).
In vivo, anetumab ravtansine showed potent inhibition of the growth of the human 
mesothelioma NCI-H226 cells (20). In a mouse xenograft model (subcutaneous NCI-H226), 
2 cycles of triple IV inoculations of 0.2 mg/kg anetumab ravtansine (related to the 
concentration of DM4) significantly reduced tumor growth compared with the vehicle control 
(94%, P < 0.001) and achieved a 63% response rate (partial response [PR] in 5 out of 8 mice). 
In contrast, treatment with free active methyl-DM4 (DM4-Me) did not affect tumor growth 
significantly. Direct comparison of anetumab ravtansine at 0.2 mg/kg with cisplatin plus 
pemetrexed revealed a significantly higher efficacy of anetumab ravtansine, as cisplatin alone 
and in combination with pemetrexed resulted in 70% reduction of tumor growth (P < 0.01). 
The treatment groups were also compared by measuring the tumor weight at the end of the 
study: treatment with anetumab ravtansine resulted in a 14-fold lower tumor weight as 
compared with the combination of cisplatin and pemetrexed (P < 0.05).
Anetumab ravtansine has convincingly demonstrated monotherapy anti-tumor efficacy also in 
preclinical patient-derived xenograft (PDX) MPM tumor models (20). Evaluation of 
anetumab ravtansine in PDX models demonstrated tumor shrinkage and regression superior to 
several chemotherapies currently being used for the treatment of MPM in humans. Only 
3 administrations of anetumab ravtansine at 0.2 mg/kg resulted in at least partial tumor 
regression in all mice using a Meso7212 PDX mesothelioma model (P < 0.001). Comparison 
with SoC revealed that the anti-tumor efficacy of anetumab ravtansine was more pronounced 
than cisplatin (P < 0.05) and pemetrexed (P < 0.001). The difference between the effects of a 
microtubule-targeting drug vinorelbine and anetumab ravtansine was not significant.
Further details can be found in the latest available version of the investigator's brochure (IB), 
which contains comprehensive information on the study drug.
3.1.2
Clinical experience
As of 18 JAN 2014, a total of 77 patients with advanced refractory solid tumors expressing 
mesothelin have been treated with the anti-mesothelin ADC anetumab ravtansine given as a 
single agent by 1-hour IV infusion in the Phase I First in Human (FiH) 15051 study with a 
Q3W schedule. Additional cohorts of patients have been enrolled in the 1.8 mg/kg or 
2.2 mg/kg once weekly (QW) regimen.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  27 of 269
The dose-escalation part of the FiH study 15051 was completed in FEB 2013 with 45 patients 
evaluated in 10 cohorts spanning the dose range from 0.15 mg/kg to 7.5 mg/kg given by 1-
hour IV infusion Q3W. The maximum tolerated dose (MTD) was defined as 6.5 mg/kg Q3W. 
Subsequently 2 expansion cohorts (n=32) were treated at 6.5 mg/kg Q3W.
A total of 32 males and 45 females were treated, with a mean age of 61.4 years. Within the 
escalation cohorts (total 45 patients) the most common cancers were mesothelioma (n=21), 
pancreatic (n=9), breast (n=5), and ovarian cancer (n=4) whilst in the 6.5 mg/kg Q3W 
expansion cohorts (total 32 patients) patients had ovarian cancer (n=20) or mesothelioma 
(n=12).
Following IV administration, maximum ADC concentrations were typically observed around 
the end of infusion or within 1 h after the end of infusion. The pharmacokinetics (PK) 
parameters of interest, maximum drug concentration (Cmax) and area under the curve (AUC) 
of the ADC, generally increased in a dose proportional manner in the 0.15 mg/kg to 
7.5 mg/kg dose range studied. At the MTD, average half-life values of the ADC, total 
antibody and DM4-Me were approximately 5 to 6 days, and approximately 3 days for DM4, 
generally consistent with the range of half-life values reported for biologics and with no 
accumulation expected after Q3W dosing.
20 (53%) of 38 patients who started treatment at the MTD of 6.5 mg/kg Q3W had at least 
1 dose modification due to a treatment-emergent adverse event (TEAE) deemed by the 
investigator to be causally related to anetumab ravtansine; 8 (40%) had the first dose 
modification in response to drug-related corneal morphology changes, and 7 (35%) had the 
first dose reduction due to drug-related peripheral neuropathy or symptoms commonly 
associated with it. 18 (90%) of 20 patients had a dose reduction to 5.5 mg/kg Q3W, and 
5 (28%) of these 18 had another dose reduction to 4.5 mg/kg Q3W; both dose reductions were 
caused by a drug-related TEAE. It should be noted that none of the drug-related TEAEs that 
led to dose delay/interruption or dose reduction have been life-threatening or incapacitating, 
and all have been either fully reversible or resolved to a less severe grade upon interruption; 
very few drug-related TEAEs required permanent discontinuation of treatment. Nevertheless, 
only 3 (9%) of 35 patients who started treatment at doses ≤ 6.5 mg/kg Q3W had a dose 
modification due to a drug-related TEAE, and none of those required a dose reduction.
A significantly higher incidence of dose modifications due to drug-related TEAEs at the MTD 
of 6.5 mg/kg Q3W could be at least in part explained by the much longer drug exposure 
(duration of time on treatment) in patients who start treatment at this dose. The ORR, as 
determined by the incidence of PR, was notably better in patients who started at 6.5 mg/kg 
Q3W. 7 (18%) of 38 patients who started at 6.5 mg/kg Q3W had a long-lasting PR; these 
included 2 (10%) of 21 patients with ovarian cancer and 5 (31%) of 16 patients with 
mesothelioma (4 with pleural and 1 with peritoneal epithelial mesothelioma). 11 of the 
16 patients with mesothelioma (8 with pleural mesothelioma and 3 with peritoneal 
mesothelioma) had received only 1 previous line of systemic cytotoxic chemotherapy before 
enrolling in the study. 5 of 11 patients in this group (45%) had a confirmed PR (4 PRs in 
pleural mesothelioma patients and 1 PR in peritoneal mesothelioma patients), which lasted for 
11 months in 1 patient and ≥ 20 months in the other 4 patients.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  28 of 269
Objective tumor responses persisted in 6 of 7 patients with PR in whom the starting dose of 
6.5 mg/kg Q3W had to be reduced to 5.5 mg/kg Q3W due to a drug-related TEAE, and even 
in 2 of 4 patients who required a second dose reduction to 4.5 mg/kg Q3W due to another 
related TEAE. In contrast, none of the 35 patients who started at doses < 6.5 mg/kg Q3W had 
a PR, and only 1 of 9 patients who started at 5.5 mg/kg Q3W had an unconfirmed PR. If 
patients were to start treatment at doses < 6.5 mg/kg Q3W, the potential for clinical benefit 
could be reduced despite the lower risk of dose modification due to a drug-related TEAE.
Objective responses or prolonged SD occurred only in patients with strong mesothelin 
expression (e.g. MPM of epithelioid and mixed histology).
Data from 15051 study indicate an overall acceptable and manageable safety profile. At the 
MTD of 6.5 mg/kg Q3W, the most common TEAEs that were assessed to be related to 
anetumab ravtansine were corneal epitheliopathy, peripheral neuropathy, myalgia, weakness, 
fatigue, anorexia, nausea, vomiting and diarrhea. The incidence of treatment-emergent serious 
adverse events (SAEs) that were considered to be related to anetumab ravtansine was low in 
all patients. There were no drug-related deaths throughout the study.
The safety finding of particular interest at the 6.5 mg/kg Q3W dose has been the corneal 
epitheliopathy and keratitis with and without blurred vision probably related to anetumab 
ravtansine: 11 of 38 patients (29%) developed corneal adverse events (AEs). None of these 
events affected the deep corneal stroma or were considered serious or led to drug 
discontinuation and all events were reversible.
Furthermore, population, physiologically-based pharmacokinetic (PopPBPK) modeling of 
preliminary data from the FiH study 15051, combined with a probabilistic regression analysis 
provided evidence that the area under the ADC plasma concentration-time curve at steady 
state, AUC(ADC), is a descriptor for the occurrence of corneal epitheliopathy, as shown in 
Figure 3–1. Based on the on average linear PK of anetumab ravtansine (see above in this 
section), it can be assumed that dose reduction will lead to a reduced total drug exposure, i.e. 
AUC(ADC), and thus, also to a reduced probability of corneal epitheliopathy (see Figure 3–1) 
(paragraph and Figure 3-1 added by amendment 2, see section 15.1.1.23).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  29 of 269
Figure 3–1
Probability of corneal epitheliopathy versus model-predicted drug exposure – 
figure added by amendment 2
5000
10000
15000
20000
25000
30000
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
AUC(ADC) [mgh/L]
Probability for corneal toxicity
ADC = Antibody-drug conjugate; AUC = Area under the curve; N = Number of patients; PopPBPK = Population, physiologically-
based pharmacokinetic; Q3W = Every 3 weeks
Drug exposure versus the probability of corneal toxicity relationship with AUC(ADC) equals the PopPBPK model-predicted area 
under the anetumab ravtansine plasma concentration-time curve at steady state.
The solid line indicates the median estimate and the thin lines represent the 90% confidence interval; data used for logistic 
regression model development are shown as diamonds. 
The box plots represent simulated AUC(ADC) distributions in a virtual population of N=1000 subjects receiving either 4.5 mg/kg 
(dotted box), 5.5 mg/kg (dashed box) or 6.5 mg/kg (solid box) anetumab ravtansine given Q3W.
The other identified risks so far include peripheral neuropathy, liver function test increases 
and hypersensitivity reaction. In the Q3W MTD dose level, 16 of 38 patients (42%) 
experienced peripheral neuropathy and associated disorders (muscle spasms and cramps, gait 
disorder etc.); all but 1 case were Common Terminology Criteria for Adverse Events 
(CTCAE) Grade 1 or 2, 1 patient developed a Grade 3 event. It commonly led to dose 
interruption and reduction but it did not cause treatment discontinuation. The elevation on 
liver function test values was observed in patients treated at 6.5 mg/kg Q3W: aspartate 
aminotransferase (AST) increase in 7 patients (18%, with only 1 Grade 3, 3%), alanine 
aminotransferase (ALT) increase in 5 patients (13%, with no Grade 3), alkaline phosphatase 
(ALP) increase in 4 patients (10%, with only 1 Grade 3), and total bilirubin increase in 
1 patient (3%, with no Grade 3). Only 1 patient required dose reduction due to drug-related 
Grade 3 AST increase. Finally, only 1 patient was reported with an infusion-related reaction 
(Grade 2) at the Q3W 6.5 mg/kg dose level.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  30 of 269
In summary, anetumab ravtansine has demonstrated durable ORR when given at the MTD of 
6.5 mg/kg Q3W in refractory metastatic mesothelioma. This preliminary potential for clinical 
benefit in an unmet medical need indication and overall safety profile lead to the selection of 
6.5 mg/kg Q3W as the starting dose for anetumab ravtansine in the 2nd line treatment of 
patients with unresectable or metastatic pleural mesothelioma in this study.
No results are available from human interaction studies between anetumab ravtansine and 
other chemotherapies. No data are available to evaluate the potential interaction between 
anetumab ravtansine and radiation treatment.
Updated information on the safety profile including results from this study are available in the 
latest available version of the investigator's brochure (IB), which contains comprehensive 
information on the study drug (sentence added by amendment 6, see section 15.4.1.5).
3.2
Rationale of the study
At the MTD of 6.5 mg/kg Q3W, anetumab ravtansine has demonstrated very strong efficacy 
in advanced, unresectable or metastatic epithelial mesothelioma (best objective response 31% 
overall or 45% in the 2nd line setting, with very durable responses) in a Phase I expansion 
cohort. Such high response rate and long lasting responses, if repeatable, would translate to 
the potential for anetumab ravtansine to impart large clinical benefit as the 2nd line treatment 
for advanced mesothelioma, which represents an indication of high unmet medical need for 
effective treatment options, as currently no approved SoC exists (paragraph clarified by 
amendment 4, see section 15.2.1.19).
3.3
Benefit-risk assessment
Preliminary results from the ongoing 15051 FiH study demonstrated anti-tumor efficacy of 
anetumab ravtansine monotherapy in patients with MPM previously treated with platinum-
based chemotherapy. Of the 38 patients treated at the MTD dose level of 6.5 mg/kg Q3W, 
16 patients had mesothelioma, including 11 patients (8 with pleural mesothelioma and 3 with 
peritoneal mesothelioma) who received anetumab ravtansine as 2nd line treatment. Of these, 
5 patients obtained PR as best objective response (4 PRs in pleural mesothelioma patients and 
1 PR in peritoneal mesothelioma patients). 4 patients with objective responses and SD cases 
showed long response durations (> 20 months on study and ongoing).
Data from the ongoing 15051 FiH study indicate an overall acceptable and manageable safety 
profile. Drug-related TEAEs requiring dose reduction and/or interruption have been reported 
in approximately half of the patients treated at the MTD of 6.5 mg/kg Q3W (1 patient in 
cohort 9 and 16 patients in the expansion 6.5 mg/kg Q3W cohort). Treatment discontinuations 
due to drug-related TEAEs were rare. At the dose of 6.5 mg/kg Q3W, the safety finding of 
particular interest has been the corneal epitheliopathy in 11 patients; however, none of these 
events affected the deep corneal stroma or were considered serious or led to drug 
discontinuation and all events were fully reversible. An action plan has been developed for 
corneal epitheliopathy early detection and monitoring; prophylactic measures have been 
implemented (e.g. entry criteria, ocular lubricants, steroid eye drops) and a management 
algorithm including effective eye treatment and anetumab ravtansine dose adjustments has 
been set up in close collaboration with Bayer ophthalmologists (see Table 7–5). The other 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  31 of 269
TEAEs that would require diligent monitoring and management are hypersensitivity reaction, 
liver function abnormalities and peripheral neuropathy; however, these disorders were not 
either life-threatening and have been manageable and fully reversible and responded to dose 
reduction and/or symptomatic therapy.
In summary, a strong potential efficacy signal was obtained in the Phase I study (15051) in 
patients with mesothelioma treated with Q3W 6.5 mg/kg anetumab ravtansine. No approved 
SoC exists for 2nd line MPM, and drugs currently being used show a very limited response 
rate (16%) and a median PFS limited to 3.6 months (16). At the current state, 2nd line 
malignant mesothelioma is an indication of high unmet medical need for effective treatment 
options. Based on the available preclinical and clinical data, anetumab ravtansine has the 
potential to become the SoC in the 2nd line mesothelioma indication by significantly 
prolonging PFS and OS.
The overall safety profile of anetumab ravtansine is consistent with the employed class of 
toxophores and the underlying MoA. Most, if not all, reported AEs were manageable with 
short delays in drug administration and dose reductions. Therefore, the expected improvement 
in PFS, as seen in the Phase I FiH study, represents an important benefit that exceeds the risk 
from observed treatment-emergent adverse reactions.
The present study is acceptable after considering the risks and benefits associated with it.
4.
Study objectives
The primary objective of this study is to:

Test the superiority of anetumab ravtansine monotherapy over vinorelbine in 
progression-free survival (PFS)
The secondary objectives of this study are to:

Test overall survival (OS)
Secondary objective related to pulmonary function removed by amendment 2

Evaluate patient-reported outcomes (PROs) – symptom burden and health-related 
quality of life (QoL)

Evaluate other indicators of treatment efficacy (indicators of tumor response)

Evaluate safety
The other objectives of this study are to evaluate the:

Pharmacokinetics (PK)

Immunogenicity

Biomarkers
o
Further biomarkers to investigate the drug (i.e. mode-of-action-related effect 
and / or safety) and / or the pathomechanism of the disease (exploratory).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  32 of 269
5.
Study design
5.1
Design overview
This is a randomized, open-label, active-controlled, 2-arm, multicenter, Phase II trial to 
evaluate the safety and efficacy of anetumab ravtansine as a single agent administered as an 
IV infusion Q3W in comparison to IV vinorelbine given according to the usual QW schedule.
At the time of the start of study treatment, the patients will have advanced or metastatic MPM 
recurrent/relapsing after a 1st line treatment with platinum in combination with pemetrexed 
with or without bevacizumab, and overexpressing mesothelin as determined by 
immunohistochemistry (IHC). Only patients who demonstrate mesothelin overexpression at 
the moderate and stronger membrane staining level by IHC in at least 30% of viable tumor 
cells can be randomized into the study (modified by amendments 2 and 5, see section 15.1.1.6 
and 15.3.1.2).
A prescreening step, including the mesothelin expression level testing, can be performed 
without evidence of disease progression after the initial treatment cycles with 
platinum/pemetrexed (with or without bevacizumab) at the investigator’s discretion.
The overview of study periods is presented in Figure 5–1.
Figure 5–1
Study periods
On study
Off study
Pre-
screening
Full 
screening
Treatment
Safety follow-up / 
Active follow-upa
Long-term 
follow-up
Informed 
consent for 
pre-
screening
Informed 
consent 
for full 
study
First dose of 
study drug
Last dose of 
study drug
Last protocol-
stipulated 
procedure
a
If applicable.
The start of the study is defined by signing of the informed consent form (ICF) for 
prescreening. After meeting the eligibility criteria for prescreening and signing the ICF for 
full study (see Sections 6.1 and 6.2), approximately 210 patients who meet all of the inclusion 
and none of the exclusion criteria will be randomly assigned in a 2:1 ratio to receive anetumab 
ravtansine or vinorelbine, respectively. The anetumab ravtansine arm will consist of 
approximately 140 patients and the vinorelbine comparator arm of approximately 70 patients. 
Patients will be stratified at randomization according to geographic region (Rest of the world 
[RoW] versus Asia) and per time to progression (TTP) on 1st line treatment (≥ 6 months 
versus < 6 months). An approximately 50% screen fail rate is anticipated (25% at 
prescreening and a subsequent 33% among biomarker expressers). Approximately 
420 patients are estimated to be required for prescreening to yield approximately 
263 biomarker-positive patients, resulting in 210 randomized eligible patients (paragraph 
modified by amendments 2 and 4, see section 15.1.1.2, 15.1.1.7 and 15.2.1.2).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  33 of 269
A graphical presentation of the overall study design is shown in Figure 5–2 (figure modified 
by amendment 2, see section 15.1.1.2).
Figure 5–2
Overall study design - amended
Stratification 
 Geographic 
region (RoW 
vs. Asia) 
 TTP on 1st line 
treatment        
(≥ 6 months vs.    
< 6 months)
Randomization
2:1
(N=210)
Anetumab 
ravtansine 
6.5 mg/kg Q3W 
Day 1 
of each 21-day Cycle
Vinorelbine 
30 mg/m2 QW
 Days 1, 8 and 15      
of each 21-day Cycle
Disease 
progression
Blinded central 
radiology review
Long-term
 follow-up
Active 
follow-up
N = Number of patients; Q3W = Every 3 weeks; QW = Once weekly; RoW = Rest of the world, TTP = Time to progression
The start of the treatment period is defined for efficacy purposes by randomization to study 
drug (anetumab ravtansine or vinorelbine), and for safety purposes by first administration of 
study drug. Start of treatment has to be within 24 hours after the randomization call. Patients 
in the anetumab ravtansine arm will receive anetumab ravtansine IV infusion at a dose of 
6.5 mg/kg (recommended Phase II dose [RPIID]) on Day 1 of a 21-day cycle. Patients in the 
comparator arm will receive vinorelbine 30 mg/m2 IV on Days 1, 8 and 15 of a 21-day cycle. 
Treatment will be continued until death or occurrence of PD as defined by Modified Response 
Evaluation Criteria in Solid Tumors (mRECIST) for mesothelioma (21) and assessed by 
blinded central radiology review, or clinical progression, or until another criterion for 
withdrawal from the study is met. In case of radiological progression, however, treatment may 
be continued provided that the patient derives clinical benefit as determined by the treating 
physician (paragraph modified by amendment 2, see section 15.1.1.4, 15.1.1.19 and 
15.1.1.22).
All patients who discontinue study treatment for any reason will enter the safety follow-up 
period. Safety follow-up visit will be performed 30 (+7) days after the last administration of 
study treatment.
Patients who discontinue study treatment for any reason other than centrally confirmed 
radiological PD will be followed for progression during active follow-up (which includes the 
safety follow-up period) until data maturation for the OS final analysis is reached (i.e. 
completion of number of events required for OS analysis), or until centrally confirmed 
progression, death, consent withdrawal or end of study, whichever occurs first (modified by 
amendment 6, see section 15.4.1.1).
All patients who end study treatment for any reason will be followed for OS and any new 
anti-cancer treatment every 3 months during the long-term follow-up period until death, 
consent withdrawal, 24 months after the last patient’s last treatment or end of study, 
whichever occurs first (modified by amendment 6, see section 15.4.1.2).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  34 of 269
Primary efficacy will be assessed based on radiological tumor evaluation by contrast-
enhanced CT or contrast-enhanced magnetic resonance imaging (MRI) of 
chest/abdomen/pelvis (see Section 9.4.1). The first tumor images will be obtained during full 
screening and will be sent to blinded central review to confirm radiological eligibility prior to 
randomization (modified by amendment 2, see section 15.1.1.15). During treatment as well as 
active follow-up, tumor imaging will be performed with the same modality every 6 weeks 
during the first 6 months after the start of study treatment, every 9 weeks until the end of 
year 2, and every 12 weeks thereafter, until the earlier of centrally confirmed radiological 
disease progression, OS analysis data maturation, or end of study (modified by amendment 6, 
see section 15.4.1.1). Primary analysis results will be based on central review.
Description of forced vital capacity removed by amendment 2
Patients will be contacted to assess survival status every 3 months during long-term follow-up 
(see Section 9.4.2). In addition, extra survival sweep contacts will be conducted at the time of 
PFS final analysis and prior to OS final analysis to ensure that long-term follow-up data is 
current.
The effect of treatment on disease-specific symptoms and disease-specific health-related QoL 
will be assessed using the MD Anderson Symptom Inventory-Malignant Pleural 
Mesothelioma (MDASI-MPM) and the Lung Cancer Symptom Scale-Mesothelioma (LCSS-
Meso), respectively, at full screening, at each cycle during treatment, at the safety follow-up 
visit, and during active follow-up as per Section 9.4.3 (clarified by amendment 4, see section 
15.2.1.17).
Safety evaluations will be done at full screening, at each clinic visit during the treatment, and 
at the safety follow-up visit as described in Section 9.6. The National Cancer Institute’s 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 will be used 
to grade severity of AEs. In addition, a Bayer grading system (see Table 7–5 and Table 7–6) 
will be used to assess corneal epitheliopathy (sentence added by amendment 2, see section 
15.1.1.26).
Sparse plasma sampling for PK will be performed on all patients as outlined in Section 9.5.
Immunogenicity assessment will be performed for patients in the anetumab ravtansine arm 
only as outlined in Section 9.7.2.
Obligatory biomarker sampling (see Section 9.7.1) will be performed on all patients to 
measure mesothelin expression levels in tumor material at prescreening. In addition, plasma 
levels of soluble mesothelin will be studied to evaluate whether plasma mesothelin levels may 
correlate with response rate and be of predictive value. Biomarker plasma will be collected to 
analyze circulating tumor DNA, too. Exploratory biomarker analysis may also be performed 
using additional fresh or archival tumor tissue to determine alterations in tumor-associated 
genes and to perform gene expression analysis (modified by amendment 4, see section 
15.2.1.11).
Following OS data maturation, patients remaining on study will continue to be followed with 
reduced mandated assessments and data collection (although assessments can continue per 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  35 of 269
investigator’s judgement). Active follow-up, efficacy, and some safety assessments will no 
longer be required (paragraph added by amendment 6, see section 15.4.1.1).
5.2
Primary variable
The primary variable of this study is progression-free survival (PFS) defined as time from 
randomization until disease progression (according to mRECIST for MPM, per blinded 
central radiology review) or death (for full definition, see Section 10.3.2 and Statistical 
Analysis Plan [SAP]).
5.3
Justification of the design
Level of blinding. This Phase II study will be open-label (see Section 7.5), because a double-
blind, active-controlled study is not feasible due to different administration schedules, Q3W 
for anetumab ravtansine and QW for vinorelbine, and different safety profiles (e.g. corneal 
epitheliopathy (modified by amendment 2, see section 15.1.1.5) for the anetumab ravtansine 
arm and neutropenia for the comparator [vinorelbine] arm). The independent and central 
radiological review for the assessment of disease progression and other radiological imaging-
based endpoints will be conducted in a blinded fashion. In addition, an independent PRO 
review committee of PRO, statistical, and psychometric experts, will conduct analyses in a 
blinded fashion to support validation of the MDASI-MPM instrument and determine endpoint 
definitional details (sentence added by amendment 4, see section 15.2.1.16).
Dosage. At the RPIID of 6.5 mg/kg Q3W, anetumab ravtansine has demonstrated very strong 
efficacy in advanced, unresectable or metastatic epithelial mesothelioma (best objective 
response 31% overall or 45% in the 2nd line setting, with very durable responses) (see 
Section 3.1.2). Moreover, no drug-related deaths, only 5 drug-related SAEs and a low rate of 
drug-related Grade 3/4 AEs were reported from clinical experience with anetumab ravtansine 
at the RPIID. Based on the drug exposure corneal epitheliopathy relationship (see 
Section 3.1.2 and Figure 3–1) and the average linear PK of anetumab ravtansine, it can be 
assumed that dose reduction planned in this Phase II study will lead to a reduced total drug 
exposure, and thus, to a reduced probability of corneal epitheliopathy (sentence modified by 
amendment 2, see section 15.1.1.5 and 15.1.1.23).
Comparator. Vinorelbine (see Section 7.2.2) is one of the drugs considered by various 
guidelines (e.g. National Comprehensive Cancer Network [NCCN], European Society of 
Medical Oncology [ESMO]) as a potential option for patients with advanced mesothelioma 
progressed after treatment with platinum and pemetrexed. Mechanistically, it is a spindle 
poison, therefore comparable with DM4.
Study population. Objective responses or prolonged SD cases in the 15051 study of 
anetumab ravtansine occurred in patients who demonstrated mesothelin overexpression at the 
moderate and stronger membrane staining level by IHC in at least 30% of viable tumor cells 
(modified by amendments 2 and 5, see section 15.1.1.6 and 15.3.1.2). Because of the 
treatment’s surface mesothelin targeting MoA, no clinical efficacy is expected in MPM 
patients with little or no mesothelin cell surface expression. Patients with a sarcomatoid 
histology are not expected to have mesothelin overexpression and should not enter 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  36 of 269
prescreening. Therefore, pre-selection based on mesothelin expression (see Section 6.1.1) is 
intended during recruitment of this study.
Regimen/schedule of administration. The choice of schedule (see Section 7.4.1.1) is based 
on exposure-response analysis based on clinical PK, efficacy and safety results from the 
77 patients treated with anetumab ravtansine on the Q3W schedule in the study 15051 and, 
moreover, from the 38 patients treated with the MTD in the 6.5 mg/kg Q3W escalation cohort 
9 (n=6) and the RPIID of 6.5 mg/kg Q3W expansion cohort (n=32).
Randomization. A 2:1 randomization ratio is used to provide an adequate safety database for 
evaluating anetumab ravtansine safety. This ratio also encourages study participation by 
providing an elevated probability of receiving experimental treatment. The sample size is 
adequate for efficacy, and the safety of vinorelbine is well-studied. The sample size includes a 
dropout rate of 3.4%/month (15.7% as of planned primary analysis) to address the possibility 
of dropouts (see Section 11.4) (paragraph modified by amendment 2, see section 15.1.1.2).
For justification of study endpoints and measurements, see Section 9.8 (cross-reference added 
by amendment 2, see section 15.1.1.26).
For strategies to limit the amount and impact of missing data, see Section 11.4.
5.4
End of study
Section modified by amendment 6, see section 15.4.1.3.
For each participating EU country, the end of the study according to the EU Clinical Trial 
Directive will be reached when the last visit of the last patient for all centers in the respective 
country has occurred within this study.
As for this study, important data will be collected after LPLV, the end of the study as a whole 
will be the date when the final clean database is available.
If the trial is stopped but benefits are observed for individual subjects and/or follow up of 
subjects is needed; treatment and/or follow up may be continued in a separate program upon 
agreement among the investigators, the sponsor, and appropriate regulatory authorities. 
Survival follow-up offered in a separate program will be offered to all surviving consenting 
patients.
5.5
Primary completion
Primary analysis will be performed after approximately 117 PFS events are observed by 
central review in the study (clarified by amendment 2, see section 15.1.1.26).
The primary completion date for this study according to the FDA Amendment Act is specified 
in a separate document (not part of this study protocol).
6.
Study population
6.1
Inclusion criteria
Patients eligible for inclusion into the study must meet the following inclusion criteria.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  37 of 269
6.1.1
Eligibility criteria for prescreening
Overexpression of mesothelin at the moderate and stronger membrane staining level in at least 
30% of viable tumor cells is a prerequisite to be eligible for this study (modified by 
amendments 2 and 5, see section 15.1.1.6 and 15.3.1.2). Patients can only be randomized and 
start treatment in the study when there is a progression after 1st line treatment of 
platinum/pemetrexed (with or without bevacizumab). However, as part of prescreening, 
mesothelin expression level testing can be performed at the investigator’s discretion as soon 
as the initial 1st line treatment cycles with platinum/pemetrexed (with or without 
bevacizumab) are administered, even without evidence of disease progression. Also if patients 
have ended this 1st line treatment and have not progressed yet, the mesothelin expression level 
test can be performed. The following criteria must be met at the time of prescreening.
1.
Written informed consent for prescreening.
2.
Unresectable locally advanced or metastatic MPM, confirmed by histology.
3.
Availability of archival or fresh tissue for testing of mesothelin expression level.
Note: Archival tissue is preferred and fresh biopsy should only be obtained if no 
archival tissue is available and if in the investigator’s judgement, there is no additional 
risk for the patient’s safety. Patients with a sarcomatoid histology are not expected to 
have mesothelin overexpression and should not enter prescreening.
4.
Age ≥ 18 years (age limit may be higher if legally required in a country, e.g. in Japan 
adult age is considered ≥ 20 years).
5.
Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 
(specified in Appendix 16.1).
6.
Life expectancy of at least 3 months.
7.
No prior treatment with anetumab ravtansine (or any other mesothelin-based therapy) or 
vinorelbine (or any other vinca-containing compound or spindle poison).
8.
No prior use of targeted agents, experimental therapy or systemic anti-cancer treatment 
other than ongoing or completed 1st line platinum/pemetrexed (with or without 
bevacizumab).
Besides these basic criteria, any criterion as outlined below under inclusion eligibility 
criteria for full study and exclusion criteria already known to prohibiting the patient’s 
participation in the study should be considered. No study-related procedures should be 
performed which are not covered by the prescreening ICF.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  38 of 269
6.1.2
Eligibility criteria for full study
The following inclusion criteria must be met at the time of randomization call and on C1D1 
unless otherwise specified (this sentence was clarified by amendment 2, see section 15.1.1.19 
and 15.1.1.26).
1.
Written informed consent for full study.
2.
Histological documentation of MPM overexpressing mesothelin at the moderate and 
stronger membrane staining level in at least 30% of viable tumor cells as determined by 
centrally performed IHC (modified by amendments 2 and 5, see section 15.1.1.6 and 
15.3.1.2).
3.
Unresectable locally advanced or metastatic MPM after locally confirmed unequivocal 
progression on 1st line treatment with platinum (both cis- or carbo-platinum) in 
combination with pemetrexed. Last dose of previous therapy must be at least 28 days 
before the start of study treatment (modified by amendment 4, see section 15.2.1.3).
Note: Patients progressed on 1st line treatment with platinum plus pemetrexed in 
combination bevacizumab are allowed (13).
4.
Patients must have at least 1 measurable lesion according to mRECIST for 
mesothelioma (specified in Appendix 16.3) i.e. pleural lesion(s) measured using 
mRECIST or extra-pleural lesion(s) measurable per RECIST 1.1. This will be 
confirmed by central review of images before the patient can be randomized into the 
study.
Note: In case the only site of disease was previously treated with radiotherapy, there 
should be evidence of unequivocal PD in this site: measurable pleural disease should be 
assessed on a contrast enhanced CT/MRI done at the minimum 4 weeks after the end of 
radiotherapy and compared with previous imaging; unequivocal progression should be 
judged by the investigator as per mRECIST per MPM (criterion 4 modified by 
amendment 2, see section 15.1.1.8 and 15.1.1.26).
5.
ECOG PS of 0 or 1 (specified in Appendix 16.1).
6.
Life expectancy of at least 3 months.
7.
Women of childbearing potential (WOCBP) and fertile men must agree to use adequate 
contraception when sexually active from signing of the ICF for full study until at least 4 
months after the last study drug administration. Men being treated with vinorelbine are 
advised not to father a child during and up to 6 months after treatment; for all male 
patients, prior to treatment with either study drug, advice should be sought for 
conserving sperm due to the chance of irreversible infertility as a consequence of 
treatment (22). The investigator or a designated associate is requested to advise the 
patient how to achieve highly effective birth control. Highly effective (failure rate of 
less than 1% per year) contraception methods (23) include:

Combined (estrogen and progesteron containing: oral, intravaginal, transdermal) 
and progesteron-only (oral, injectable, implantable) hormonal contraception 
associated with inhibition of ovulation.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  39 of 269

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion or vasectomized partner (provided that partner is the sole 
sexual partner and has received medical assessment of the surgical success).

Sexual abstinence (reliability to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient).
Male patients with a female partner of childbearing potential must use a condom and 
ensure that an additional form of contraception is also used during treatment and until 4 
months after last study drug administration.
Note: a woman is considered WOCBP, i.e. fertile, following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include but are not limited to hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. A postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy. A man is considered 
fertile after puberty unless permanently sterile by bilateral orchiectomy (criterion 7 
modified by amendment 2, see section 15.1.1.9).
8.
Adequate bone marrow, liver and renal function as assessed by the following laboratory 
requirements conducted within 7 days before starting study treatment:

Total bilirubin ≤ 1.5 x the upper limit of normal (ULN). Documented Gilbert 
syndrome is allowed if total bilirubin is mildly elevated (< 6 mg/dL).

ALT and AST ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement of their 
cancer).

ALP limit ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement of their 
cancer).

Amylase and lipase ≤ 1.5 x ULN.

Serum creatinine ≤ 1.5 x ULN.

Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according to the 
Modification of Diet in Renal Disease (MDRD) abbreviated formula (see 
Appendix 16.7).

Adequate coagulation, as assessed by the following laboratory test results:
o
International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN 
(CTCAE Grade ≤ 1).
o
Partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN 
(CTCAE Grade ≤ 1).
Note: Patients on stable dose of anti-coagulation therapy will be allowed to 
participate if they have no sign of bleeding or clotting and INR / PT and 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  40 of 269
PTT / aPTT test results are compatible with the acceptable benefit-risk ratio 
at the investigator’s discretion (see Section 8.1).

Platelet count ≥ 100000/mm3, without platelet transfusion within 3 weeks before 
the start of study treatment (see Section 8.1).

Hemoglobin (Hb) ≥ 9 g/dL, without blood transfusion or erythropoietin within 
6 weeks before the start of study treatment (see Section 8.1).
Note: Patients receiving chronic low-dose erythropoietin for chronic renal failure 
are allowed provided no dose adjustment is undertaken within 6 weeks before 
signing consent for full study and until safety follow-up visit and provided that 
they fulfill conditions of eligibility criteria (see also exclusion criterion 
number 18).

Absolute neutrophil count (ANC) ≥ 1500/mm3, without biologic response 
modifiers, such as G-CSF, within 6 weeks before the start of study treatment (see 
Section 8.1).
9.
Left ventricular ejection fraction (LVEF) ≥ 50% or the lower limit of normal (LLN) 
according to local institution ranges of normality.
6.2
Exclusion criteria
Patients who meet the following criteria at the time of randomization call and on C1D1 will 
be excluded (this sentence was modified by amendment 2, see section 15.1.1.19 and 
15.1.1.26):
1.
Previous assignment to treatment during this study. Patients permanently withdrawn 
from study participation will not be allowed to re-enter the study.
2.
Previous (within 5 drug half-lives – if drug half-life in subjects is known - or 28 days, 
whichever is shorter, before the start of study treatment) or concomitant participation in 
another clinical study with investigational medicinal product(s) (IMP[s]).
3.
Close affiliation with the investigational site; e.g. a close relative of the investigator, 
dependent person (e.g. employee or student of the investigational site).
4.
More than 1 previous systemic anti-cancer therapy line for MPM (even if therapy used 
as neoadjuvant or adjuvant treatment) (clarified by amendment 4, see section 15.2.1.19).
Note: Patients pre-treated with systemic therapy other than platinum, pemetrexed, 
bevacizumab (13) (e.g. other cytotoxic drugs, immunotherapy, targeted therapy, 
hormonal therapy, or any other experimental or approved therapy or device) are not to 
be enrolled (modified by amendment 4, see section 15.2.1.4).
5.
Patients with corneal epitheliopathy or any eye disorder that may predispose the patients 
to this condition at the discretion of the investigator in consultation with the 
ophthalmologist/optometrist (modified by amendment 2, see section 15.1.1.10).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  41 of 269
Note: Low grades of superficial punctate keratitis, within the range seen in the normal 
population, should not lead to the exclusion of the patient (note added by amendment 2, 
see section 15.1.1.11).
6.
Previous or concurrent cancer that is distinct in primary site or histology from 
mesothelioma within 5 years before randomization. 
Exceptions: curatively treated

Cervical cancer in situ.

Non-melanoma skin cancer.

Superficial bladder tumors (Non-invasive tumor [Ta], Carcinoma in situ [Tis] and 
Tumor invades lamina propria [T1]).
7.
Major surgery, open biopsy or significant traumatic injury within 28 days before the 
start of study treatment.
8.
Pregnant or breast-feeding patients. WOCBP must have a serum pregnancy test 
performed a maximum of 7 days before the start of study treatment, and a negative 
result must be documented before the start of study treatment.
9.
Pre-existing cardiac conditions as outlined below:

Congestive heart failure ≥ New York Heart Association (NYHA) class 2 (specified 
in Appendix 16.2).

Unstable angina (angina symptoms at rest), new-onset angina (begun within the 
last 3 months). Myocardial infarction less than 6 months before the start of study 
treatment.

Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin 
are permitted).
10.
Clinically significant uncontrolled hypertension (systolic blood pressure > 150 mmHg 
or diastolic pressure > 90 mmHg despite optimal medical management).
11.
Arterial thrombotic or embolic events such as cerebrovascular accident (including 
transient ischemic attacks), or venous pulmonary embolism within 6 months before the 
start of study treatment; venous thrombotic events such as deep vein thrombosis within 
3 months before the start of study treatment.
12.
Ongoing or active infection (bacterial, fungal, or viral) of NCI-CTCAE version 4.03 
Grade > 2.
13.
Known history of human immunodeficiency virus (HIV) infection.
14.
Known history of chronic hepatitis B or C.
15.
Patients with seizure disorder requiring medication.
16.
Brain metastases or meningeal tumors or other metastases in the central nervous system 
(CNS). Patients with neurological symptoms must undergo a contrast CT scan or MRI 
of the brain and/or other areas of the CNS as applicable within 28 days before the start 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  42 of 269
of study treatment to exclude metastastic disease in the CNS (criterion modified by 
amendment 4, see section 15.2.1.5).
17.
History of organ allograft, stem cells or bone marrow transplant.
18.
Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding 
event ≥ CTCAE Grade 3 within 4 weeks before the start of study treatment.
19.
Non-healing wound, ulcer, or bone fracture.
20.
Renal failure requiring peritoneal or hemodialysis.
21.
Known hypersensitivity to anetumab ravtansine or vinorelbine, study drug classes or 
excipients in the formulation.
22.
Any illness or medical conditions that are unstable or could jeopardize the safety of the 
patient and his/her compliance in the study.
23.
Unresolved toxicity higher than NCI-CTCAE version 4.03 Grade 1 attributed to any 
prior therapy/procedure excluding anemia Grade 2 (see Section 6.1.2, inclusion 
criterion 8) and alopecia of any Grade.
24.
Any prohibited prior or concomitant therapy (see Table 8–1 in Section 8.1).
6.3
Withdrawal of patients from study
6.3.1
Withdrawal
6.3.1.1
Screening failure
6.3.1.1.1
Prescreening failure
A patient whose tumor tissue is centrally tested by IHC for mesothelin overexpression and 
whose result is not moderate and stronger membrane staining for mesothelin overexpression 
in at least 30% of viable tumor cells, or who fails to meet any of the other eligibility criteria 
for prescreening, is regarded as a “prescreening failure” (modified by amendments 2 and 5, 
see section 15.1.1.6 and 15.3.1.2). These patients should not undergo any further screening 
procedures.
6.3.1.1.2
Full screening failure
A patient who passes the prescreening, including the mesothelin overexpression testing, but 
for any other reason (e.g. failure to satisfy the remaining selection criteria) terminates the 
study before randomization is regarded as a “full screening failure”.
See Section 11.1 for data to be collected for screening failures.
6.3.1.1.3
Re-screening
The following text was modified and changed to appear as a separate subsection by 
amendment 4, see section 15.2.1.6.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  43 of 269
Re-screening is defined as re-starting the defined set of screening procedures following 
“screening failure” to allow a patient to participate at a later time point. This is not allowed 
except in the following circumstances:

Equivocal screening test results that require repeat or further testing for clarification, 
which cannot for logistical reasons be performed within the screening period.

Initial screening occurred too early to complete the required washout period after prior 
therapy.

The in- / exclusion criteria preventing the patient’s initial attempt to participate have 
been changed (via protocol amendment).

The patient had successfully passed the screening procedures, but could not be 
randomized on schedule and the allocated time window for these tests has expired.
During re-screening, all expired tests must be repeated to fall within the protocol-defined time 
window.
The investigator has to ensure that the repeated screening procedures do not expose the 
patient to an unjustifiable health risk. Also, for re-screening, the patient has to re-sign the ICF, 
even if it was not changed after the patient’s previous screening and a new patient 
identification number has to be requested via Interactive Voice / Web Response System 
(IxRS).
A patient can only be re-screened once and for all re-screening requests, the sponsor needs to 
be contacted to discuss before re-screening the patient.
Re-testing for mesothelin expression after obtaining an initial negative result is not allowed.
6.3.1.2
Withdrawal criteria
All patients who enter the study should complete all phases of the study:
1. Prescreening
2. Full screening
3. Randomization
4. Treatment
5. Safety follow-up
6. Active follow-up
7. Long-term follow-up
Study treatment discontinuation (i.e. discontinuation during the treatment period) does not 
constitute withdrawal from the study.
Every effort should be made to retain patients who discontinue the treatment period for any 
reason. These patients are to be encouraged to remain on the study for follow-up of primary, 
secondary and other objectives (i.e. continue in the safety follow-up, active follow-up and/or 
long-term follow-up periods).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  44 of 269
Patients are expected to participate in the follow-up unless they explicitly object. Withdrawal 
of consent to treatment should be documented in the patient’s medical record. If the patient 
does not wish to be followed up further, this additional consent withdrawal for follow up 
would have to be documented, too.
Withdrawal from study treatment, active follow-up and long-term follow-up
Patients withdrawn from the study treatment phase of the study should be followed for 
primary, secondary and other objectives (i.e. continue in the safety follow-up, active follow-
up and/or long-term follow-up periods) (see Figure 6–1 for withdrawal criteria).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  45 of 269
Figure 6–1
Withdrawal criteria - amended
PATIENTS MUST BE WITHDRAWN FROM THE STUDY TREATMENT IF ANY OF THE FOLLOWING 
OCCURS:

At their own request or at the request of their legally acceptable representative. At any time during the study and 
without giving reasons, a patient may decline to participate further. The patient will not suffer any disadvantage 
as a result.

If, in the investigator's opinion, continuation of the study treatment would be harmful to the patient's well-being.

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious non-compliance, safety 
concerns).

Centrally confirmed radiological PD as per mRECIST criteria; however, treatment may be continued provided 
that the patient derives clinical benefit as determined by the treating physician. Post OS maturation, central 
confirmation of radiological PD is no longer required; local assessment of radiological PD only is sufficient.  

Clinical progression. 

Occurrence of unacceptable toxicity to anetumab ravtansine or vinorelbine (see also Section 7.4.2).

CTCAE Grade ≥ 3 hypersensitivity and acute infusion reaction.

An adverse reaction deemed sufficiently serious to warrant discontinuation of treatment by the investigator or his 
designated associate(s). 

Development of a secondary malignancy.

Patient starts treatment with any other anti-cancer therapy or any other prohibited medication as per Section 8.1.

Positive serum β-HCG test consistent with pregnancy. Pregnancy should be reported along the same timelines 
as an SAE. 

Use of illicit drugs or other substances that may, in the opinion of the investigator or his designated associate(s), 
have a reasonable chance of contributing to toxicity or otherwise confound the results. 

Development of any intercurrent illness or situation which may, in the judgment of the investigator, affect 
assessments of clinical status and study endpoints to a relevant degree.

Lost to follow-up.

Death.
Patients must be withdrawn from treatment with anetumab ravtansine if any of the following occurs:

Bayer Grade 4 corneal epitheliopathy (see Table 7–5).

CTCAE Grade 4 non-hematological AE (see Table 7–4).

If any type of TEAE requiring dose modification does not resolve to Grade ≤ 2(or Hb ≥ 9 g/dL in case of anemia) 
within 12 weeks after the last dose of anetumab ravtansine.

Delay in anetumab ravtansine administration of 9 weeks (max. 12 weeks between 2 infusions of study drug).

TEAE requiring dose reduction when already at the 4.5 mg/kg Q3W dose level (minimum dose).

More than 2 dose reductions required due to a TEAE.
Patients must be withdrawn from treatment with vinorelbine if any of the following occurs:

Development of CTCAE Grade ≥ 2 neurotoxicity.

Confirmed interstitial pneumonitis or acute respiratory distress syndrome (ARDS).

If 3 consecutive weekly doses are held because neutrophil granulocytes count is < 1,000 cells/mm3 in 
hematologic toxicity (27).
SAFETY FOLLOW-UP VISIT
All patients who discontinue study treatment must perform this visit, 30+7 days after the last administration of study 
treatment.
Patients ending treatment without centrally confirmed 
radiological PD as per mRECIST criteria
Patients ending treatment with centrally confirmed 
radiological PD as per mRECIST criteria OR
All patients ending treatment post OS maturation
ACTIVE FOLLOW-UP
Imaging and QoL assessment will continue until centrally 
confirmed PD is observed or they withdraw consent to 
active follow-up, are lost to follow-up or due to death or 
until data maturation for the OS analysis is reached.
LONG-TERM FOLLOW-UP
Patients in long-term follow-up will have information on 
survival and new anti-cancer treatment collected.  
Patients must be withdrawn if they withdraw consent to 
long term follow-up, are lost to follow-up or due to death 
or at 24 months after the last patient’s last treatment.
AE = Adverse event; ARDS = Acute respiratory distress syndrome; β-HCG = β subunit of human chorionic gonadotropin; 
CTCAE = Common Terminology Criteria for Adverse Events; Hb = Hemoglobin; mRECIST = Modified Response 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  46 of 269
Evaluation Criteria in Solid Tumors; OS = Overall survival; PD = Progressive disease; Q3W = Every 3 weeks; 
QoL = Quality of life; SAE = Serious adverse event; TEAE = Treatment-emergent adverse event
Figure modified by amendment 2 (see section 15.1.1.3, 15.1.1.4, 15.1.1.5 and 15.1.1.26), amendment  4 (see 
section 15.2.1.8), and amendment 6 (see section 15.4.1.1, 15.4.1.2 and 15.4.1.4).
Patients randomized but not treated
In the event a patient is randomized but never treated, a withdrawal from treatment CRF 
should be filled out for the patient articulating the date of and reason for not treating the 
patient. The patient should receive efficacy follow-up, active follow-up if feasible, otherwise 
long-term follow-up. No safety follow-up is required (section added by amendment 2, see 
section 15.1.1.17).
Lost to follow-up patients
When a patient is lost to follow-up at any stage of the study, the site should try to contact the 
patient, the patient’s relatives, or another doctor treating the patient, unless prohibited by local 
regulations. All attempts to contact the patient or relatives should be documented and sites are 
expected to perform at least 5 attempts to contact the patient over the course of 3 months. An 
additional contact attempt should be made at the time of each survival sweep (sentence added 
by amendment 2, see section 15.1.1.18).
6.3.1.3
General procedures
In all cases, the reason for withdrawal must be recorded in the CRF and in the patient's 
medical records.
The patient may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12.
6.3.2
Replacement
No replacement of randomized patients will be allowed during this study.
6.4
Patient identification
After a patient has signed the prescreening ICF, the patient identification number will be 
provided to the investigators through an IxRS. Patients will be identified by a 9-digit patient 
identification number consisting of:
Digits 1 to 5 
=  Unique center number
Digits 6 to 9 
=  Current patient number within the center
When the patient is found eligible, a randomization contact to IxRS will be performed and the 
patient will be given a unique randomization number.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  47 of 269
7.
Treatment(s)
7.1
Treatments to be administered
All patients who meet the entry criteria will receive the test drug anetumab ravtansine 
considered to be an IMP, or vinorelbine.
The following treatment groups are defined for this study:

Anetumab ravtansine arm: anetumab ravtansine 6.5 mg/kg IV Q3W

Comparator arm: vinorelbine 30 mg/m2 IV QW
7.2
Identity of study treatment
All study drugs will be labeled according to the requirements of local law and legislation. 
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.
Both anetumab ravtansine and vinorelbine will receive study-specific labeling and will be 
provided by the sponsor.
For all study drugs, a system of numbering in accordance with all requirements of GMP will 
be used, ensuring that each dose of study drug can be traced back to the respective bulk batch 
of the ingredients. Lists linking all numbering levels will be maintained by the sponsor’s 
clinical supplies quality assurance (QA) group.
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor’s study file.
7.2.1
Test drug - anetumab ravtansine
Anetumab ravtansine is an ADC consisting of a fully human IgG1 antibody (MF T, BAY 86-
1903) directed at the mesothelin antigen and conjugated to a synthetic maytansine derivative 
as toxophore (DM4, BAY 100-6640) through a reducible disulfide linker (SPDB linker).
The details of the investigational drug are given in Table 7–1.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  48 of 269
Table 7–1
Identity of anetumab ravtansine
Chemical name
Mesothelin antibody-drug conjugate:
Immunoglobulin G1, anti-(human mesothelin) human 
monoclonal MF-T-IgG1 heavy chain, disulfide with 
human monoclonal MF-T-IgG1 -chain, dimer, triamide 
with N2´-[4-[(3-carboxypropyl) dithio]-4-methyl-1-
oxopentyl]-N2´-deacetylmaytasine
Substance code number(s)
BAY 94-9343
Appearance 
Freeze-dried drug product
White to off-white lyophilized cake or powder
Reconstituted solution
Clear or slightly opalescent solution
Formulation
Freeze-dried product in a 30 mL injection vial, 
containing 5 mg/mL of active ingredient after 
reconstitution
Composition
Anetumab ravtansine / BAY 94-9343 / L-histidine / 
glycine / sucrose / polysorbate 80 / 1 N HCl
Type of packaging and content
30 mL injection vial
IgG1 = Immunoglobulin G subclass 1; N HCl = Normal hydrochloric acid
The drug product is available as a lyophilizate. Each vial contains 62.5 mg of anetumab 
ravtansine; the amount available for administration, based on retractable volume of 
reconstituted solution, is 60 mg of anetumab ravtansine. It should be reconstituted in water for 
injection and diluted in 0.9% sodium chloride solution (normal saline) or dextrose 5% 
solution prior to administration as IV infusion (modified by amendment 5, see 
section 15.3.1.1).
The drug product is to be stored at 2°C to 8°C (36°F to 46°F).
The reconstitution and dilution of the anetumab ravtansine solution and the associated 
stability information is described in detail in a separate manual “15743 Anetumab ravtansine 
storage and handling instructions” that will be maintained in the trial master file (TMF) and in 
each center’s investigator site file (paragraph added to replace the sections of reconstitution 
and dilution of the anetumab ravtansine solution and the associated stability information by 
amendment 4).
Refer to IB for anetumab ravtansine for details regarding drug properties and formulation.
7.2.2
Comparator - vinorelbine
Vinorelbine formulation is a concentrate for infusion solution. It is available as concentrate 
with 10 mg/mL or 50 mg/5 mL vinorelbine (as tartrate) (concentration corrected by 
amendment 2).
Vinorelbine should be prepared according to the manufacturer’s instructions.
The participating investigators are required to consult the SmPC/desk reference of 
vinorelbine, which contains details regarding drug properties, formulation, handling, 
reconstitution, contraindications, precautions and administration.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  49 of 269
7.3
Treatment assignment
Patients with obtained written informed consents, who satisfy all eligibility criteria, will be 
stratified and randomized following a 2:1 ratio to either anetumab ravtansine or comparator 
(vinorelbine) arm.
Patients will be stratified according to geographic region (RoW versus Asia) and per TTP on 
1st line treatment (≥ 6 months versus < 6 months). To accomplish random assignment, a 
computer-generated randomization list will be prepared by the sponsor and provided to an 
IxRS. Patients will be randomized using permuted-block randomization. The IxRS will assign 
each eligible patient to a treatment arm based on the stratification factors and randomization 
list and will provide a randomization number. The IxRS procedure is described in detail in a 
separate IxRS instruction manual that will be maintained in the TMF and in each center’s 
investigator site file.
Confirmation of adequate level of mesothelin overexpression will be obtained from the 
central lab. Confirmation of radiological eligibility will be obtained from central radiological 
review (modified by amendment 2, see section 15.1.1.15). Confirmation of other inclusion and 
exclusion requirements will be obtained from the investigator. After confirmation of patient 
eligibility in IxRS, a randomization code will be assigned.
7.4
Dosage and administration
7.4.1
Treatments to be administered
7.4.1.1
Administration of anetumab ravtansine
After reconstitution and dilution (as described in Section 7.2.1), anetumab ravtansine will be 
administered as a 1-hour IV infusion every 3 weeks on Day 1 of each 21-day cycle until 
centrally confirmed radiological PD or any other criteria for withdrawal of treatment.
The individual dose will be 6.5 mg/kg per infusion from Cycle 1 onwards (see Section 5.3). In 
obese patients, anetumab ravtansine dose should be calculated considering a maximum weight 
of 100 kg.
Strict IV administration has to be ensured to avoid local intolerance reactions. After 
completion of the 1-hour anetumab ravtansine infusion, the infusion line will be rinsed with 
≥ 100 mL of 0.9% saline solution to be administered as a short infusion.
See Section 9.1 for details on scheduled administrations.
Anetumab ravtansine infusion longer than 1 hour is permitted if following the dose 
modification guidelines. See Section 7.4.2.1 for details on dose modifications of anetumab 
ravtansine (paragraph added by amendment 5, see section 15.3.1.6).
7.4.1.2
Administration of vinorelbine
Vinorelbine will be administered as IV injection over 6 to 10 min; the dose will be 30 mg/m2 
to a maximum dose of 60 mg (17, 24, 25) weekly (i.e. on Days 1, 8 and 15 of each 21-day 
cycle) until centrally confirmed radiological PD or any other criteria for withdrawal of 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  50 of 269
treatment. Calculation of body surface area (BSA) will be done within the IxRS and the 
Mosteller equation will be used (see Appendix 16.8).
The participating investigators are required to consult the SmPC/desk reference of 
vinorelbine, which contains more details regarding drug contraindications, precautions and 
administration, the latter should be done according to local standards (see Section 7.2.2).
See Section 9.1 for details on scheduled administrations.
7.4.2
Dose modification
7.4.2.1
Dose modifications of anetumab ravtansine
The NCI-CTCAE v4.03 will be used to assess toxicities; in addition, a Bayer grading system 
(see Table 7–5 and Table 7–6) will be used to assess corneal epitheliopathy (modified by 
amendment 2, see section 15.1.1.5).
TEAE requiring dose modification (dose omission, infusion interruption, change in infusion 
rate, dose delay, dose reduction, or permanent discontinuation of study drug) will be defined 
as any of the events described below that is possibly, probably, or definitely related to 
anetumab ravtansine and occurs anytime during the study (not only in Cycle 1) (clarified by 
amendment 4, see section 15.2.1.19).
The dose reduction levels of anetumab ravtansine will follow pre-defined dose levels shown 
in Table 7–2.
Table 7–2
Dose levels of anetumab ravtansine
Dose level 1 (starting dose):
6.5 mg/kg Q3W
Dose level -1:
5.5 mg/kg Q3W
Dose level -2:
4.5 mg/kg Q3W
Q3W = Every 3 weeks
7.4.2.1.1
Hematological toxicities
Dose modifications for hematological toxicity

If treatment modification is required due to a hematological TEAE, and the 
continuation of treatment is appropriate, the anetumab ravtansine dose will be adjusted 
as described in Table 7–3 below (cross-reference to Table 7-4 removed by 
amendment 4).

G-CSF and other hematopoietic growth factors may be used during the study in the 
management of acute toxicity such as febrile neutropenia when clinically indicated per 
ASCO Recommendations for Therapeutic Use of CSF (26) or at the discretion of the 
investigator; however they may not be substituted for a required dose reduction.

Blood transfusions and therapy with IV or subcutaneous erythropoietin-stimulating 
agents (epoetin alpha, darbepoetin alpha) are allowed per institution guidelines but 
may not be used as substitute for a required dose reduction (see also Table 8–1).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  51 of 269

Platelet transfusion may be used during the study in the management of acute toxicity 
such as hemorrhage or bleeding events, however they may not be used as substitute for 
a required dose reduction.
Table 7–3
Dose modifications for anetumab ravtansine in response to hematological 
toxicities a for neutrophil and platelet nadir b counts – table added
Dose modifications
Blood count
Start new cycle only if 
platelet count is
≥ 75,000 (Grade ≤ 1) (pre-infusion)
< 25,000 (Grade 4) for ≥ 7 days (nadir b)
Platelet 
count
(/mm3)
Dose reduce by 1 dose 
level c
< 50,000 (Grade 3) for ≥ 7 days with bleeding d 
(nadir b)
Start new cycle only if 
ANC is
≥ 1000 (Grade ≤ 2) (pre-infusion)
< 500 (Grade 4) for 7 days (nadir b)
Absolute 
neutrophil 
count
(/mm3)
Dose reduce by 1 dose 
level c
Febrile neutropenia (Grade 3) e (during previous 
cycle)
Start new cycle only if 
hemoglobin is
Hb ≥ 8 (pre-infusion)
Hemoglobin 
(g/dL)
Re-start at the same dose 
or dose reduce by 1 dose 
level c (at investigator’s 
discretion)
< 8 (nadir b)
Any
Discontinue
Grade 3 or 4 toxicity after 2 dose reductions
ANC = Absolute neutrophil count; C = Cycle; CBC = Complete blood count; D = Day; Hb = Hemoglobin; 
Q3W = Every 3 weeks
a
For any toxicity ≤ Grade 2 assessed as related to study drug(s) by the investigator, dose modification 
may be considered if investigator feels this is in the patients best interest. Such toxicities might be 
≤ Grade 2 toxicities which interfere with the activities of daily life.
b
Nadir: lowest value measured in previous cycle or pre-infusion. Site visits and blood test for CBC on D8 
and D15 are mandatory for C1, C2 and C3 only. From C4 onwards, visits and procedures on D8 and D15 
are no longer required.
c
Dose reduction by 1 dose level translates to a change from 6.5 mg/kg Q3W to 5.5 mg/kg Q3W, or from 
5.5 mg/kg Q3W to 4.5 mg/kg Q3W. Not more than 2 dose reductions from the starting dose level are 
permitted.
d
Clinically significant bleeding, i.e. bleeding requiring platelet transfusion.
e
Febrile neutropenia is defined as ANC < 1000/mm3 and fever (a single body temperature reading of 
> 38.3°C [101°F] or a sustained body temperature of ≥ 38°C [100.4°F] for more than 1 hour).
Table 7-3 was added to combine the previous Tables 7-3 and 7-4 by amendment 4, see section 15.2.1.8. 
Consequently, the numbering of the subsequent tables in this section changed accordingly.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  52 of 269
7.4.2.1.2
Non-hematological toxicities
Non-hematological toxicities requiring dose modification
This subsection was modified by amendments 2 and 4, see section 15.1.1.5, 15.1.1.13, 
15.1.1.26 and 15.2.1.8.

CTCAE Grade 2 anetumab ravtansine infusion-related reaction or other CTCAE 
Grade 2 hypersensitivity events (see Section 7.4.2.1.3)

AST and/or ALT increase  3.0 x ULN (CTCAE Grade  2) with concomitant 
increase in total bilirubin  1.5 x ULN (CTCAE Grade  2)

Bayer Grade ≥ 3 corneal epitheliopathy (see below and Table 7–5)

Any other Grade ≥ 3 non-hematological toxicity that, in the investigator’s opinion, 
warrants treatment modification (see Table 7–4), excluding the following:
o
Nausea, vomiting, or diarrhea if manageable with anti-emetics or anti-
diarrheals within 7 days
o
Fatigue lasting ≤ 72 h

Any other toxicity irrespective of the type or severity that represents a clinically 
significant risk to patient in the investigator’s opinion.
Dose modifications for non-hematological toxicity
If treatment modification is required due to Grade ≥ 3 non-hematological TEAE, other than 
corneal epitheliopathy and infusion-related reaction/hypersensitivity events, and the 
continuation of treatment is appropriate, the anetumab ravtansine dose will be either reduced 
or maintained as is at investigator’s discretion (modified by amendment 2, see section 15.1.1.5 
and 15.1.1.13) (see Table 7–4).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  53 of 269
Table 7–4
Dose adjustments in response to non-hematologic toxicities - amended
CTCAE v4.03 
grade
Anetumab ravtansine dose 
delay / interruption
Anetumab ravtansine dose 
modification
Grade 1 – 2 a
Treat on time
No change required
Grade 3 
1st appearance: Delay/Interruption 
until Grade ≤ 2 b
2nd appearance: 
Delay/Interruption until Grade ≤ 2b
3rd appearance: Permanently 
discontinue
Re-start at the same dose or 
decrease by 1 dose level c (at 
investigator’s discretion)
Decrease by 1 more dose level c
Grade 4
Permanently discontinue
ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; CTCAE = Common Terminology 
Criteria for Adverse Events; Q3W = Every 3 weeks; TEAE = Treatment-emergent adverse event
a
AST and/or ALT increase of CTCAE Grade 2 with concomitant increase in total bilirubin of CTCAE 
Grade 2 will be treated as a CTCAE Grade 3 event.
b
Treatment will be discontinued if the TEAE fails to resolve to Grade ≤ 2 within 12 weeks after the 
last dose of anetumab ravtansine (clarified by amendment 4, see section 15.2.1.8, and modified by 
amendment 6, see section 15.4.1.4).
c
Dose reduction by 1 dose level translates to a change from 6.5 mg/kg Q3W to 5.5 mg/kg Q3W, or 
from 5.5 mg/kg Q3W to 4.5 mg/kg Q3W. Not more than 2 dose reductions from the starting dose 
level are permitted.
The anetumab ravtansine dose reduction due to non-hematological TEAE will be done as 
described below:

If the patient experienced a TEAE requiring dose reduction at the 6.5 mg/kg Q3W 
dose level, the subsequent anetumab ravtansine dose should be reduced to 5.5 mg/kg 
Q3W.

If the patient experienced a TEAE requiring dose reduction at the 5.5 mg/kg Q3W 
dose level, the subsequent anetumab ravtansine dose should be reduced to 4.5 mg/kg 
Q3W.
After dose reduction for TEAE, there could be no intra-patient dose re-escalation irrespective 
of the type of TEAE that has led to dose reduction in this patient with the exception of grade 3 
corneal epitheliopathy as per Table 7–5 (sentence clarified by amendment 2, see section 
15.1.1.16 and 15.1.1.21).
7.4.2.1.3
Miscellaneous toxicities
IV infusion-related reaction and other hypersensitivity events (modified by amendment 2)
Subsection modified by amendments 2 and 4, see section 15.1.1.13 and 15.2.1.8.
If a patient experiences a CTCAE Grade 2 anetumab ravtansine infusion-related reaction or 
other CTCAE Grade 2 hypersensitivity event deemed at least possibly related to anetumab 
ravtansine, the infusion of anetumab ravtansine will be interrupted.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  54 of 269
If treatment interruption is caused by a CTCAE Grade 2 anetumab ravtansine infusion-
related reaction or other CTCAE Grade 2 hypersensitivity event deemed at least possibly 
related to anetumab ravtansine, treatment may be re-started at the time determined at the 
investigator’s discretion. Re-treatment should be at the infusion rate reduced by 50%, along 
with anti-allergic prophylaxis (e.g. anti-histamines, paracetamol, acetaminophen, and/or 
corticosteroids) chosen at the investigator’s discretion or according to the institutional 
guidelines.
In case of a CTCAE Grade ≥ 3 hypersensitivity and acute infusion reaction, treatment must be 
permanently withdrawn.
Miscellaneous toxicities requiring dose modification
For any toxicity ≤ Grade 2 assessed as related to anetumab ravtansine by the investigator, 
dose modification should be considered. Such toxicities might be ≤ Grade 2 toxicities which 
interfere with the activities of daily life, such as long lasting fatigue, or anorexia, or corneal 
epitheliopathy with vision impairment etc. (modified by amendment 2, see section 15.1.1.5). A 
dose change might be necessary in order to ensure the patient’s compliance. These toxicities 
may be declared “TEAE requiring treatment modification” after consultation between the 
investigator and the sponsor.
Dose modifications for corneal epitheliopathy (modified by amendment 2)
For the TEAE of corneal epitheliopathy and the best corrected visual acuity (BCVA) changes 
(blurred vision), the Bayer severity grading system (see Table 7–5 and Table 7–6) will be 
used to assess the severity of TEAEs requiring modification of anetumab ravtansine treatment 
(modified by amendment 2, see section 15.1.1.5).
TEAE of corneal epitheliopathy deemed to be at least possibly related to anetumab ravtansine 
would require modification of anetumab ravtansine treatment (dose reduction or permanent 
discontinuation of treatment) according to the following principles (modified by amendment 2, 
see section 15.1.1.5) (see Table 7–5).
Table 7–5
Bayer classification and management of corneal epitheliopathy - amended
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Corneal 
morphology
No pathologic 
changes
Any stage of 
superficial 
punctate 
keratitis a
Epithelial 
opacities
Corneal ulcer 
without risk of 
acute rupture
Corneal ulcer more 
severe than Grade 3
Micro-cysts
Micro-deposits
Corneal erosion
Stromal opacity: 
non-central
Stromal opacity: 
central


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  55 of 269
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Eye 
treatment b
Ocular 
lubricants at the 
discretion of 
investigator in 
consultation 
with 
ophthalmologist
/ optometrist
Ocular 
lubricants; 
add topical 
steroids if 
superficial 
punctate 
keratitis 
shows 
treatment-
emergent 
progression 
by ≥ 2 SPK 
Grades
Intensive 
treatment with 
ocular lubricants 
enhanced with 
ointments; topical 
steroids; 
therapeutic 
contact lens may 
be considered at 
the discretion of 
investigator in 
consultation with 
ophthalmologist/ 
optometrist
Intensive therapy 
with ointments; 
topical steroids; 
therapeutic contact 
lens or occlusion 
recommended at 
the discretion of 
investigator in 
consultation with 
ophthalmologist/ 
optometrist
Intensive therapy with 
lubricants, ointments, 
topical steroids and 
antibiotics as needed; 
occlusion or 
therapeutic contact 
lens recommended; 
amniotic membrane 
transplant and other 
locally approved 
therapies to be 
considered at the 
discretion of 
investigator in 
consultation with 
ophthalmologist/ 
optometrist
Anetumab 
ravtansine c
No change
No change
Keep treatment 
dose level and 
schedule if the 
ophthalmological 
exam can be 
performed as 
needed; 
otherwise 
consider dose 
reduction by 
-1 dose level 
without dose 
schedule change 
at the discretion 
of investigator in 
consultation with 
ophthalmologist/ 
optometrist
1) Decrease dose 
to -1 dose level (or 
-2 dose level if 
event does not 
resolve to Grade 
≤ 2 at the -1 dose 
level within 
3 weeks) 
2) Re-start at the 
original dose level if 
the first Grade 3 
event resolves to 
Grade ≤ 2 within 
3 weeks and does 
not recur
3) If not resolved 
within 3 weeks 
continue at reduced 
-1 dose level (or 
-2 dose level)
Discontinue treatment
SPK = Superficial punctate keratitis
a
Oxford Schema must be used for grading SPK from stage 0 to VI (see Section 16.9) (cross-reference 
added by amendment 4).
b
Other remedial therapies for corneal epitheliopathy may be added or substituted at investigator's discretion 
or according to the institutional standards.
c
Treatment decisions are based on corneal epitheliopathy only, not on visual acuity changes (modified by 
amendment 2, see section 15.1.1.5).
Clarified that the ophthalmologist/optometrist will be consulted by the investigator by amendment 2
Optometrist added as an alternative to ophthalmologist by amendment 2


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  56 of 269
Table 7–6
Bayer classification of visual acuity changes
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Visual 
acuity
No 
findings, no 
reporting 
from the 
patient
Symptomatic 
visual acuity 
loss < 3 lines 
(ETDRS 
equivalent a)
Visual acuity 
loss ≥ 3 lines, 
but < 6 lines 
(ETDRS 
equivalent a)
Visual acuity loss 
≥ 6 lines (ETDRS 
equivalent a
Visual acuity loss 
≥ 6 lines (ETDRS 
equivalent a) leading to 
blindness
ETDRS = Early Treatment Diabetic Retinopathy Study
a
In the ETDRS chart, each loss of 3 lines corresponds to halving the visual acuity. In other charts, an 
equivalent amount of visual acuity loss must be reached in order to meet this threshold.
Recommended measures in case of eye dryness and ocular hypertension
Changes in tear production as evaluated by the Schirmer test and in intraocular pressure (IOP) 
are not expected to occur as a direct consequence of anetumab ravtansine therapy. However, 
IOP may increase in some patients as a consequence of the therapy with topical steroid eye-
drops. Since these drugs may be required to manage the corneal epitheliopathy syndrome, IOP 
will be monitored during this study for patients receiving topical steroid eye drops.
Changes in IOP should be managed by an ophthalmologist/optometrist (modified by 
amendment 2, see section 15.1.1.10). The remedial therapy should be chosen at investigator’s 
discretion or according to the institutional standards; therapeutic measures can include 
modification of the type or posology of topical steroid eye drop, initiation of topical IOP 
lowering drugs and any other therapeutic options according to the local SoC. 
Ophthalmological monitoring should be maintained until the IOP has returned to normal 
values.
Reductions in tear production evaluated by the Schirmer test, while not being a part of the 
corneal epitheliopathy syndrome, are a risk factor for developing ocular surface disease 
including corneal epithelial defects. Therefore, the tear production will be evaluated in this 
study to determine if changes in this parameter may be helpful to identify patients at higher 
risk of developing the corneal epitheliopathy syndrome. Abnormal values in the Schirmer test 
should be evaluated and managed by an ophthalmologist/optometrist to provide adequate 
protection to the corneal epithelium (modified by amendment 2, see section 15.1.1.10). The 
remedial therapy for the treatment-emergent changes in the Schirmer test (dry eye) should be 
chosen at investigator’s discretion or according to the institutional standards. These measures 
may include topical lubricants such as eye drops and ointments, punctual occlusion, use of 
therapeutic contact lenses and any other treatment approaches according to the local SoC.
7.4.2.1.4
Continuation of treatment with anetumab ravtansine
Treatment with anetumab ravtansine could be re-started at the appropriate dose if the TEAE 
requiring dose modification has resolved to Grade ≤ 2 within 6 weeks after the last dose of 
anetumab ravtansine (clarified by amendment 5, see section 15.3.1.5).
7.4.2.1.5
Permanent discontinuation of anetumab ravtansine due to TEAEs
See Section 6.3.1.2 for withdrawal criteria.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  57 of 269
7.4.2.2
Dose modifications of vinorelbine
The following dose modifications for vinorelbine, based on the US label guidance (27), are 
provided below as a general recommendation. After dose reduction for TEAE, there could be 
no intra-patient dose re-escalation irrespective of the type of TEAE that has led to dose 
reduction in this patient (clarified by amendment 2, see section 15.1.1.16 and 15.1.1.21). All 
label specific instructions for treatment with vinorelbine will apply. Please refer to the local 
full prescribing information for further guidance. 
Dose modifications for hematological toxicity
Neutrophil granulocyte counts should be ≥ 1,000 cells/mm3 prior to the administration of 
vinorelbine. Some local prescribing information could require a treatment delay until recovery 
and observation of the patient if the neutrophil count is <1,500/mm3 (22). Adjustments in the 
dosage of vinorelbine should be based on neutrophil granulocyte counts obtained on the day 
of treatment (or 1 day before) according to Table 7–7. G-CSF and other hematopoietic growth 
factors may be used during the study in the management of acute toxicity such as febrile 
neutropenia when clinically indicated per ASCO Recommendations for Therapeutic Use of 
CSF (26) or at the discretion of the investigator or according to local label guidance (if 
medically necessary, growth factors may be administered at recommended doses no earlier 
than 24 h after and not in the 24 h before vinorelbine administration; see also (27); however 
they may not be substituted for a required dose reduction).
Table 7–7
Dose adjustments based on neutrophil granulocyte counts
Neutrophil granulocytes on day 
of treatment (cells/mm3)
Percentage of starting dose of vinorelbine
≥ 1500
100%
1000-1499
50%
< 1000
Do not administer. Repeat neutrophil granulocyte count 
in 1 week. If 3 consecutive weekly doses are held 
because granulocyte count is < 1,000 cells/mm3, 
discontinue.
Note: For patients who, during treatment with vinorelbine, experienced fever and/or sepsis 
while granulocytopenic (< 1500) or had 2 consecutive weekly doses held due to 
granulocytopenia, subsequent doses of vinorelbine should be:
≥ 1500
75%
1000-1499
37.5%
< 1000
See above
According to local prescribing information, treatment should be delayed until recovery and 
the patient should be observed if the thrombocyte count is below 100,000/mm3 (or, in some 
countries, below 75,000/mm3) (22). Platelet transfusion may be used during the study in the 
management of acute toxicity such as hemorrhage or bleeding events, however they may not 
be used as substitute for a required dose reduction (see also Table 8–1).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  58 of 269
Dose modifications for hepatic insufficiency
Vinorelbine should be administered with caution to patients with hepatic insufficiency. In 
patients who develop hyperbilirubinemia during treatment with vinorelbine, the dose should 
be adjusted for total bilirubin according to Table 7–8.
Table 7–8
Modifications based on total bilirubin
Total bilirubin (mg/dL)
Percentage of starting dose of vinorelbine
≤ 2.0
100%
2.1 - 3.0
50%
> 3
25%
According to local prescribing information, in some countries, a reduced dose of 20 mg/m2 is 
recommended in patients with severe liver impairment (22).
Dose modifications for concurrent hematological toxicity and hepatic insufficiency
In patients with both hematological toxicity and hepatic insufficiency, the lower of the doses 
based on the corresponding starting dose of vinorelbine determined from Table 7–7 and Table 
7–8 should be administered.
Dose modifications for renal insufficiency 
No dose adjustments for vinorelbine are required for renal insufficiency.
Dose modifications for neurotoxicity
If Grade ≥ 2 neurotoxicity develops, vinorelbine should be discontinued.
For further information on dose modifications for vinorelbine, see (27).
7.5
Blinding
This is an open-label study except for: 

The independent and central radiological review for the assessment of disease 
progression and other radiological imaging based endpoints, which will be conducted 
in a blinded fashion.

The independent blinded PRO review committee which will conduct analyses to 
support validation of the MDASI-MPM instrument and determine endpoint 
definitional details (bullet point added by amendment 4, see section 15.2.1.16).
7.6
Drug logistics and accountability
All study drugs will be stored at the investigational site in accordance with GCP and GMP 
requirements and the instructions given by the clinical supplies department of the sponsor, 
and will be inaccessible to unauthorized personnel. Special storage conditions and a complete 
record of batch numbers and expiry dates can be found in the sponsor’s study file; the site-
relevant elements of this information will be available in the investigator site file. On the day 
of receipt, the responsible site personnel will confirm receipt of study drug via IxRS. The 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  59 of 269
personnel will use the study drug only within the framework of this clinical study and in 
accordance with this protocol. Receipt, distribution, return and destruction (if any) of the 
study drug must be properly documented according to the sponsor’s agreed and specified 
procedures.
Both for anetumab ravtansine and vinorelbine, the vials will all have a 2-panel standard label 
or booklet label affixed. 1 panel will be permanently attached to the vial while the second 
panel will be a tear-off section that will be appended to the dispensing documentation.
The number of vials used will be recorded on the appropriate treatment dispensing form. 
Reasons for dose delay and reduction will be recorded in the source documents and on the 
CRF.
Treatment accountability on patient level must be verified at every cycle, starting on C1D1. 
The monitor will review overall drug accountability and destruction per the site 
documentation only.
Written instructions on medication destruction will be made available to affected parties as 
applicable.
7.7
Treatment compliance
The administration of anetumab ravtansine or vinorelbine will be performed in the clinic on 
Day 1 of each 21-day cycle for anetumab ravtansine and on a weekly basis (Day 1, 8 and 15 
of a 21-day cycle) for vinorelbine. Each administration must be recorded on the CRF and 
Drug Dispensing / Accountability Form.
Reasons for dose delay, reduction, or omission will also be recorded in the source documents 
and on the CRF.
An adequate record of receipt, distribution, and return of all study drugs must be kept in the 
form of a Drug Accountability Form.
The preparation and administration of anetumab ravtansine and vinorelbine will be performed 
by members of the investigator team during hospitalization and site visits. These persons will 
ascertain and document that the patient receives all treatments as planned.
Patient compliance with the treatment and protocol includes willingness to comply with all 
aspects of the protocol, and to have blood collected for all safety evaluations. At the discretion 
of the principal investigator or sponsor, a patient may be discontinued from the study 
treatment for non-compliance with visits or study drug.
8.
Non-study therapy
8.1
Prior and concomitant therapy
Any medication which is considered necessary for the patient’s welfare, and which is not 
expected to interfere with the evaluation of the study treatment, may be given at the discretion 
of the investigator. In general, patients should be closely monitored for side effects of all 
concomitant medications regardless of elimination path, especially those with narrow 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  60 of 269
therapeutic indices, such as warfarin, phenytoin, quinidine, carbamazepine, phenobarbital, 
cyclosporine and digoxin. From signing of ICF for full study to safety follow-up visit, all 
concomitant medications (including start/stop dates, dose, frequency, route of administration 
and indication) must be recorded in the patient’s source documentation, as well as on the 
appropriate pages of the CRF. At prescreening and active follow-up period, only concomitant 
medications that are administered to treat AEs related to study-specific procedures are 
mandatory to be reported. Administration of contrast media for protocol-specified radiological 
procedures (CT scan or MRI) does not need to be reported on the concomitant medication 
CRF page, unless there is an AE related to the contrast medium injection (e.g. allergic 
reaction).
Post OS maturation, only concomitant medication related to SAEs is required to be 
reported (sentence added by amendment 6, see section 15.4.1.1). 
Prohibited prior and concomitant therapies and permitted concomitant therapies are listed in 
Table 8–1 and Table 8–2, respectively.
Table 8–1
Prohibited prior and concomitant therapies - amended
Prohibited prior and 
concomitant therapy 
(see also Section 6.2)
Time period when 
prohibited
Comments
Prohibited for all patients
Anetumab ravtansine (or any 
other mesothelin-based 
therapy)
Prior to study treatment
Vinorelbine (or any other 
vinca-containing compound)
Prior to study treatment
Platinum/pemetrexed/ 
bevacizumab
Within 28 days before the 
start of study treatment 
until safety follow-up visit
(modified by amendment 
4, see section 15.2.1.3)
Other systemic anticancer 
treatment (except study 
treatment) (cytotoxic therapy, 
targeted therapies, 
immunotherapy, hormonal 
therapy, or any other 
experimental or approved 
therapy) 
Prior to study treatment 
until safety follow-up visit
Use of biologic response 
modifiers, such as G-CSF
Within 6 weeks before 
the start of study 
treatment
G-CSF and other hematopoietic growth factors may 
be used during the study in the management of 
acute toxicity such as febrile neutropenia when 
clinically indicated per ASCO Recommendations for 
Therapeutic Use of CSF (26) or at the discretion of 
the investigator or according to local label guidance 
(if medically necessary, growth factors may be 
administered at recommended doses no earlier than 
24 h after and not in the 24 h before vinorelbine 
administration; see also (27); however they may not 
be substituted for a required dose reduction).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  61 of 269
Prohibited prior and 
concomitant therapy 
(see also Section 6.2)
Time period when 
prohibited
Comments
Blood transfusions and 
chronic therapy with IV or 
subcutaneous erythropoietin-
stimulating agents (epoetin 
alpha, darbepoetin alpha) 
Within 6 weeks before 
the start of study 
treatment. Thereafter, 
they are allowed per 
institution guidelines but 
may not be used as 
substitute for a required 
dose reduction.
Patients receiving chronic low-dose erythropoietin for 
chronic renal failure are allowed provided no dose 
adjustment is undertaken within 6 weeks before 
signing consent for full study and until safety follow-
up visit and provided that they fulfill conditions of 
inclusion criterion number 8 (Section 6.1.2) and 
exclusion criterion number 20.
Platelet transfusions
Within 3 weeks before 
the start of study 
treatment. Thereafter, 
they may not be used as 
substitute for a required 
dose reduction.
Anti-arrhythmic therapy other 
than beta blockers or digoxin
Radiotherapy
Within 4 weeks before 
the start of screening for 
full study
Except for pain control, see below in Table 8–2. 
Patients must have recovered from all therapy-
related toxicities. The site of previous radiotherapy 
should have evidence of PD if this is the only site of 
disease: measurable pleural disease should be 
assessed on a contrast enhanced CT/MRI done at 
the minimum 4 weeks after the end of RT and 
compared with previous imaging; unequivocal 
progression should be judged by the investigator as 
per mRECIST per MPM.
Drugs with known bone 
marrow toxicity
Strong inhibitors and strong 
inducers of CYP3A4 (listed 
in Appendix 16.6), including:
- Herbal preparations 
containing CYP3A4 inducers 
(e.g. St John’s Wort)
- Grapefruit and grapefruit 
juice (CYP3A4 inhibitor)
Within 2 weeks before 
the start of study 
treatment until the safety 
follow-up visit
DM4 and vinorelbine are substrates of CYP3A4.
During study treatment, moderate and weak CYP3A4 
inducers should be used with caution as decrease in 
plasma concentrations of DM4 cannot be ruled out.
Concomitant live attenuated 
virus vaccines (e.g. yellow 
fever) 
Within 2 weeks before 
the start of study 
treatment (for all patients, 
during screening, then 
from C1D1 until the 
safety follow-up visit for 
patients in vinorelbine 
arm only) (modified by 
amendment 4, see 
section15.2.1.10)
Contraindicated due to risk of generalized vaccine 
disease, possibly fatal
ASCO = American Society of Clinical Oncology; C=Cycle; CSF = Colony stimulating factor; CT = Computed 
tomography; CYP3A4 = Cytochrome P450, family 3, subfamily A, polypeptide 4; D=Day; 
DM4 = Derivatives of maytansine 4; G-CSF = Granulocyte-colony stimulating factor; IV = Intravenous; 
MPM = Malignant pleural mesothelioma; mRECIST = Modified Response Evaluation Criteria in Solid 
Tumors; MRI = Magnetic resonance imaging; PD = Progressive disease; RT = Radiotherapy
Acute steroid therapy or taper was removed by amendment 4. Concomitant live attenuated virus vaccines was 
transferred to under “prohibited for all patients” part of the table by amendment 4.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  62 of 269
Table 8–2
Permitted concomitant therapies - amended
Permitted concomitant therapies
Comments
Permitted for all patients
Oral and parenteral anti-coagulant agents, e.g. 
heparin, enoxaparin, warfarin, rivaroxaban, 
dabigatran, apixaban or aspirin at a dose 
≤ 100 mg
Allowed if continued maintenance therapy is necessary at the 
investigator’s discretion and provided that they fulfill conditions 
of inclusion criterion number 8 (Section 6.1.2).
Institutional standards for the management of 
infusion-related reactions or other 
hypersensitivity events (modified by 
amendment 2, see section 15.1.1.13)
May be utilized at the discretion of the investigator.
Chronic steroid therapy
Permitted provided that the dose is stable for one month prior to 
start of study drug.
Palliative radiotherapy for pain control
Allowed provided that:
- In the opinion of the investigator, the patient does not have 
PD,
- No more than 10% of the patient’s bone marrow is irradiated,
- The radiation field does not encompass a non-pleural target 
lesion or a pleural measurable lesion,
- The radiation field does not encompass a lung field (to reduce 
the risk for interstitial lung disease [ILD] caused by irradiation 
pneumonitis), and
- Vinorelbine and anetumab ravtansine administration is 
interrupted during radiotherapy. Study treatment can be 
restarted after end of radiotherapy, provided all requirements 
outlined in Section 7.4 of this protocol are taken into account. 
The maximum interruption period for both drugs should not be 
exceeded.
Vinorelbine may result in radiosensitizing effects with prior or 
concomitant radiation therapy (27).
Standard therapies for concurrent medical 
conditions
Prophylactic standard anti-emetics
May be administered according to standard practice: 
dexamethasone plus 5-HT3 blockers, such as granisetron, 
ondansetron, or an equivalent agent, are allowed on “as 
needed” basis.
Treatment with non-conventional therapies (for 
example herbs, except St John’s Wort, or 
acupuncture), and vitamin/mineral 
supplements
Acceptable provided that they do not interfere with the study 
endpoints, in the opinion of the investigator.
Bisphosphonates or denosumab, with 
supplement of calcium and vitamin D
Palliative (e.g. analgesics) and supportive care 
(e.g. nutritional therapy) for other disease-
related symptoms and for toxicity associated 
with treatment
Strong P-gp inhibitors (e.g. amiodarone, 
azithromycin, captopril, carvedilol, 
clarithromycin, conivaptan, cyclosporine, 
diltiazem, dronedarone, 
erythromycin,felodipine, itraconazole, 
ketoconazole, lopinavir and ritonavir, 
quercetin, quinidine, ranolazine, ticagrelor, 
verapamil)
DM4-Me (metabolite of DM4) and vinorelbine are P-gp 
substrates. 
Caution should be exercised with concomitant administration of 
strong P-gp inhibitors. If anetumab ravtansine or vinorelbine 
must be co-administered with a strong P-gp inhibitor, then the 
patient should be carefully monitored or the strong P-gp inhibitor 
replaced at investigator’s discretion.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  63 of 269
Narrow therapeutic index medications 
Patients taking narrow therapeutic index medications should be 
monitored proactively, if these medications cannot be avoided.
Beta blockers or digoxin 
Permitted for patients with cardiac arrhythmias requiring therapy
5-HT3 = 5-hydroxytryptamine (serotonin); DM4 = Derivatives of maytansine 4; DM4-Me = Methyl-DM4; 
ILD = Interstitial lung disease; PD = Progressive disease; P-gp = Permeability glycoprotein
Chronic steroid therapy was added by amendment 4.
All prior anti-cancer therapies, and all concomitant therapies including ophthalmological 
therapies as of full screening will be recorded on the CRF. At prescreening and active follow-
up period, only concomitant medications that are administered to treat AEs related to study-
specific procedures are mandatory to be reported.
8.2
Post-study therapy
At the end of study treatment, further therapy is at the discretion of the investigator.
No results are available from human interaction studies between anetumab ravtansine and 
other chemotherapies. No data are available to evaluate the potential interaction between 
anetumab ravtansine and radiation treatment. Therefore, when administering these agents 
after study treatment is withdrawn, it should be taken into consideration that anetumab 
ravtansine, DM4 or DM4-Me levels may be detectable for several weeks and could interact 
with chemotherapy and radiotherapy including palliative radiotherapy as outlined in Table 8–
2 following discontinuation of anetumab ravtansine.
Once the expected final number of events is reached and results are available, the remaining 
patients on anetumab ravtansine treatment, who are considered by the investigator to benefit 
from continued anetumab ravtansine treatment, can be continued in the trial until disease 
progression. Patients still benefiting from vinorelbine treatment, in the investigator’s opinion, 
should be transferred to commercial medication supply if available. There will be no cross-
over between treatment arms.
9.
Procedures and variables
9.1
Tabular schedule of evaluations
Schedule of procedures prior to OS maturation (i.e. prior to completion of number of events 
required for OS analysis) is presented in Table 9–1. Schedule of procedures following OS 
maturation is presented in Table 9–2 for anetumab ravtansine arm patients ongoing on 
treatment post OS maturation and in Table 9–3 for vinorelbine arm patients ongoing on 
treatment post OS maturation (paragraph modified by amendment 6, see section 15.4.1.1).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  64 of 269
Table 9–1
Study flow chart – prior to OS maturation – amended
Treatment
Pre-
screening
Full screening
(maximum days 
before C1D1)
Cycle 1
Cycle 2 and higher
Safety follow-up 
period / visit
Active 
follow-up a
Long-term 
follow-up a
Days
-28
-21
- 7
D1
D8 
D15 
D1
D8 b
D15 b
+30 (after last 
dose)
Every 3 
months
Acceptable time window (in days)
(unless otherwise specified)
+/-1
+/-1
+/-1
+/-1
+/-1
+7
±14
Screening and enrollment
Written informed consent for 
prescreening c
X
Written informed consent for full 
study c
X
Demographics
X
Study disease characteristics d
X
X
Medical history d
X
Check eligibility criteria
X
X
X z
IxRS transaction e
X
X
X z
X
X
X
X
X
X
Safety
Toxicity / AE assessment f 
X f
X
X
X z
X
X
X
X
X
X
X f
Concomitant medication
X f
X
X z
X
X
X
X
X
X
X f
Complete physical examination
X
Brief physical examination g
X z
X
X
X
X g
X g
X
Vital signs (BP, HR, RR, Temp)
X
X z
X
X
X
X
X
X
Weight/height h
X h
X z
X
X
X
X
X
X
12-Lead ECG i
X
X i
X i
X
ECOG PS assessment
X
X
X z
X
X
EchoCG or MUGA scan j
X
X j
Ophthalmologic examination k
X
X 
X
Complete blood count
X
X
X
X
X
X
X
Electrolyte and chemistry panel
X
X l
X l
X aa
X l
X l
X
eGFR
X
X
X
Coagulation panel
X
X
X
Urine dipstick m
X
X


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  65 of 269
Treatment
Pre-
screening
Full screening
(maximum days 
before C1D1)
Cycle 1
Cycle 2 and higher
Safety follow-up 
period / visit
Active 
follow-up a
Long-term 
follow-up a
Days
-28
-21
- 7
D1
D8 
D15 
D1
D8 b
D15 b
+30 (after last 
dose)
Every 3 
months
Acceptable time window (in days)
(unless otherwise specified)
+/-1
+/-1
+/-1
+/-1
+/-1
+7
±14
Serum pregnancy test (if applicable)
X n
X
Efficacy
Radiological tumor evaluation with 
contrast-enhanced CT/MRI o
X bb
Every 6 weeks (first 6 months), every 9 
weeks (until end of year 2), every 12 
weeks thereafter o
X o
Disease and survival status p
X
Pharmacokinetic sampling q
In anetumab ravtansine arm
X r
X
X r
X r
X r
In comparator (vinorelbine) arm
X s
PGt blood for CYP2D6 analysis 
(in anetumab ravtansine arm only)
X
IM sampling (in anetumab ravtansine 
arm only) t
X
X t
Biomarker sampling
BM archival or fresh biopsy tissue u
X v
X u
BM plasma for soluble mesothelin x
X
BM plasma for exploratory analysis x
X
X x
X
Patient-reported outcomes
LCSS-Meso y
X
X
X
X y
MDASI-MPM y
X
X
X
Xy
X y
X y
X
X y
Study drug IV infusion
Anetumab ravtansine arm
X
X
Comparator (vinorelbine) arm
X
X
X
X
X
X
New anti-cancer treatment
X
X
AE = Adverse event; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; BP = Blood pressure; BM = Biomarker; C = Cycle; CT = Computed 
tomography; CYP2D6 = Cytochrome P450, family 2, subfamily D, polypeptide 6; D = Day; ECG = Electrocardiogram; EchoCG = Echocardiogram; ECOG PS 
= Eastern Cooperative Oncology Group Performance Status; eGFR = Estimated glomerular filtration rate; HR = Heart rate; IHC = Immunohistochemistry; IM 
= Immunogenicity; IOP = Intraocular pressure; IV = Intravenous; IxRS = Interactive Voice / Web Response System; LCSS-Meso = Lung Cancer Symptom 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  66 of 269
Scale-Mesothelioma; MDASI-MPM = MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma; mRECIST = Modified Response Evaluation Criteria 
in Solid Tumors; MRI = Magnetic resonance imaging; MUGA = Multiple gated acquisition; OS = Overall survival; PD = Progressive disease; 
PFS = Progression-free survival; PGt = Pharmacogenetic; PK = Pharmacokinetic(s); PR = Partial response; RR = Respiratory rate; SAE = Serious adverse 
event; Temp = Body temperature.
a
Patients who discontinue study treatment due to any reason other than centrally confirmed radiological PD will enter active follow-up period. 
Patients who discontinue study treatment due to centrally confirmed PD will enter the long-term follow-up period immediately after the safety 
follow-up (safety follow-up visit). During active follow-up period, all assessments will be performed in parallel with CT/MRI.
b
Patients in the anetumab ravtansine arm: Site visits on D8 and D15 will be performed only on C1, C2 and C3. From Cycle 4 onwards, visits 
on D8 and D15 are no longer required. Patients in the comparator arm: Site visits will be performed on D1, D8 and D15 of each cycle.
c
Written patient informed consent must be obtained before any study-specific procedures.
d
At prescreening, study disease characteristics and prior therapies for the study indication are collected (see Section 9.3.3). At full screening, 
study disease characteristics and prior therapies for the study indication are updated, and medical history (see Section 9.3.2) and non-study-
indication-related medications collected (see Section 9.3.3).
e
IxRS transaction to register the patient in the system will be done at prescreening. IxRS transaction to randomize the patient will take place 
maximum 24 hours before the administration of first dose of study drug and can only be done after all inclusion and exclusion criteria are 
checked and eligibility is confirmed (modified by amendment 2, see section 15.1.1.19; IxRS transaction added also in the table at full 
screening -28 days by amendment 2). IxRS transactions for medication dispensing will be done on Day 1 of each cycle for the anetumab 
ravtansine arm and on Day 1, Day 8, and Day 15 for the comparator arm. IxRS transaction to register the end of treatment will be done at the 
safety follow-up visit.
f
Any new finding or worsening of any ongoing medical history condition after the patient has signed the informed consent for full study must 
be recorded as an AE. At prescreening and active follow-up period, only AEs and SAEs related to study-specific procedures and concomitant 
medications that are administered to treat AEs related to study-specific procedures are mandatory to be reported. However, at the 
investigator’s discretion, SAEs may be reported if considered potentially relevant. In such cases, the SAEs will be processed by the sponsor 
according to all applicable regulations.
g
After C1, brief physical exams are only mandatory on D1 of each cycle and are optional as per local practice at D8 and D15 visits.
h
Height is measured only at full screening.
i
12-Lead ECGs will be done during full screening, 30 min post-dose C1D1, pre-dose C2D1, pre-dose C3D1, pre-dose C4D1, pre-dose C5D1, 
pre-dose C6D1, and at safety follow-up visit.
j
Cardiac function test is required during full screening and pre-dose C2D1, pre-dose C4D1, and afterwards at the investigator’s discretion 
based on clinical need. During treatment, cardiac function test can be done up to 7 days before study drug administration. EchoCG shall be 
performed instead of MUGA when local regulations do not permit the use of MUGA as requested per protocol schedule (footnote modified by 
amendment 4, see section 15.2.1.19).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  67 of 269
k
A detailed ophthalmologic examination (visual acuity, IOP, Schirmer test and slit lamp) will be done for all patients during full screening within 
3 weeks before the start of study treatment. For patients treated in the anetumab ravtansine arm visual acuity and slit lamp exam will be 
repeated before infusion in every cycle except C1D1, and at safety follow-up visit, or more frequently at investigator’s and 
ophthalmologist/optometrist’s discretion (important to refer to Table 7–5 and Table 7–6) (modified by amendment 2, see section 15.1.1.10). 
IOP measurement is to be repeated during anetumab ravtansine therapy if the patient receives steroid eye drops as treatment for corneal 
epitheliopathy; dry eye (Schirmer) test may be repeated during treatment at investigator’s discretion (e.g. in case of eye dryness during 
anetumab ravtansine therapy) (modified by amendment 2, see section 15.1.1.5). During treatment period, ophthalmologic examination can be 
done up to 7 days before anetumab ravtansine infusion.
l
Only AST, ALT and bilirubin will be measured.
m
During the study, complete urinalysis should be done when dipstick results are indicative or clinically indicated (urine dipstick was removed 
from the table at visit C1D1 by amendment 2).
n
Serum pregnancy test should be repeated at least every 4 weeks until safety follow-up visit; only for women of childbearing potential.
o
Pre-study CT/MRI may be acceptable as a baseline scan if done within 28 days before randomization, if centrally evaluable for mRECIST 
and if performed according to the Imaging Acquisition Guidance provided in the Imaging Manual. During treatment period as well as active 
follow-up period, tumor scans (contrast-enhanced CT/MRI of chest/abdomen/pelvis) will be performed with the same modality every 6 weeks 
during the first 6 months (24 weeks) after the start of study treatment, every 9 weeks until the end of year 2 (105 weeks), and every 12 weeks 
thereafter, until the earlier of centrally confirmed radiological disease progression, OS analysis data maturation, or end of study (modified by 
amendment 6, see section 15.4.1.1). MRI shall be performed instead of CT when local regulations do not permit the use of CT as requested 
per protocol schedule. Visit window of +/- 7 days is allowed.
p
Including survival status, date of death, and date of locally confirmed progression (only if no centrally confirmed PD was documented before 
starting long-term follow-up). Survival data will also be collected through survival sweep contact at the time of PFS final analysis and prior to 
OS final analysis.
q
Time points of sampling are specified in Section 9.5.
r
PK sampling will be performed for patients in the anetumab ravtansine arm on C1D1, C1D8, C2D1, C3D1, C3D8, C3D15, C4D1, C6D1, 
C9D1 and on Day 1 of every 3 cycles thereafter. Unscheduled PK samples are requested at the next clinic visit after the initial onset of 
corneal epitheliopathy and after the radiological assessment of the first PR (for details see Section 9.5) (modified by amendment 2, see 
section 15.1.1.5).
s
PK sampling will be performed for patients in the comparator arm on C1D1 and C1D2 (approximately 24 h after the start of C1D1 infusion) 
(for details see Section 9.5).
t
Serum samples for immunogenicity assessment should be collected for patients in the anetumab ravtansine arm only and should always be 
collected before infusion. Sampling should be performed on C1D1, C2D1, C3D1, C6D1, C9D1 and on Day 1 of every 3 cycles thereafter.
u
If additional archival tissue is available, optional archival tissue should be collected for patients who consent and sent when possible after 
C1D1. Fresh tumor tissue collection is optional after a local assessment of partial or complete response (footnote modified and added to 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  68 of 269
C1D1 by amendment 4, see section 15.2.1.11).
v
Archival tumor tissue should be used, fresh tissue should only be obtained when no archival tissue is available and when there is no 
additional risk for the patient in the investigator’s judgement. Tissue will be used for central mesothelin expression testing via IHC.
x
Biomarker plasma collection for soluble mesothelin will be done on C1D1 pre-dose. Biomarker plasma for exploratory analysis will be 
collected on C1D1 pre-dose, on C6D1, and at safety follow-up visit.
y
MDASI-MPM and LCSS-Meso are to be completed before the patient meets with a clinician and before any examination or test is performed 
on that day. MDASI-MPM and LCSS-Meso are to be completed at full screening, on C2D1 and on Day 1 of every cycle thereafter (e.g. C3D1, 
C4D1 etc.), at safety follow-up visit, and during active follow-up period. During active follow-up period, MDASI-MPM and LCSS-Meso are to 
be taken in parallel with CT/MRI. In addition, the MDASI-MPM only is performed on Day 8 and Day 15 during Cycles 1, 2 and 3 (footnote 
modified by amendment 2, see section 15.1.1.20).
z
Eligibility criteria check, IxRS transaction to randomize the patient, toxicity / AE assessment, concomitant medication review, brief physical 
examination, vital signs and weight measurement, and ECOG PS assessment can be done within 24 hours before administration of the first 
dose of study drug. Eligibility must be confirmed prior to randomizing the patient in IxRS (footnote added by amendment 2).
aa Lipase testing on Cycle 2 and higher Day 1 can be performed within 8 days before administration of the study treatment (footnote added by 
amendment 4, see section 15.2.1.19).
bb Patients with neurological symptoms at screening must undergo a contrast CT or MRI scan of the brain and/or other areas of the CNS as 
applicable within 28 days before the start of study treatment to exclude metastastic disease in the CNS (footnote added by amendment 4, 
see Section 15.2.1.5).
Forced vital capacity measurement was removed by amendment 2
A column for -21 days ophthalmologic examination was added by amendment 4
Vital signs was removed from the -28 day by amendment 4


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  69 of 269
Table 9–2
Study flow chart – anetumab ravtansine arm patients ongoing on treatment post OS maturation – added
Treatment
Safety follow-up period / 
visit
Long-term follow-up 
Every cycle
Every 2 
cycles
Every 3 
cycles
Days
D1
D1
D1
+30 (after last dose)
Every 3 months
Acceptable time window (in days)
(unless otherwise specified)
-1 / +7
-1 / +7
-1 / +7
+7
± 14
Safety
Toxicity / AE assessmenta 
X 
X
Concomitant medication (only report those related to SAEs)
X 
X
Brief physical examination 
X 
X
Weight
X 
X
Ophthalmologic examinationb 
X
X
Complete blood count
X
X
AST/ALT/total bilirubin/creatinine
Xc
X
Urine dipstickd
X
Serum pregnancy test (if applicable)e
X
X
Efficacy
Survival status and new anti-cancer treatmentf
X
Biomarker/Pharmacokinetic sampling
BM plasma for exploratory analysis
X
IM sampling (pre-dose)
X
PK sampling (pre-dose)
X
Study drug IV infusion
Anetumab ravtansine arm
X
IxRS transactiong 
X 
X
AE = Adverse event; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; BM = Biomarker; D = Day; IM = Immunogenicity; IOP = Intraocular 
pressure; IV = Intravenous; IxRS = Interactive Voice / Web Response System; OS = Overall survival; PK = Pharmacokinetic(s); SAE = Serious adverse 
event.
a
New finding or worsening of any ongoing medical history condition after the patient has signed the informed consent for full study must be 
recorded as an AE.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  70 of 269
b
Patients treated in the anetumab ravtansine arm: visual acuity and slit lamp exam will be repeated before infusion in every other cycle or 
more frequently at investigator’s and ophthalmologist/optometrist’s discretion (e.g. for patients with corneal epitheliopathy ≥ Grade 2, 
ophthalmologic examination will occur at least at every cycle until resolution of corneal epitheliopathy to Grades 0 or 1; important to refer to 
Table 7–5 and Table 7–6) and at safety follow-up. IOP measurement is to be repeated during anetumab ravtansine therapy if the patient 
receives steroid eye drops as treatment for corneal epitheliopathy; dry eye (Schirmer) test may be repeated during treatment at investigator’s 
discretion (e.g. in case of eye dryness during anetumab ravtansine therapy). During treatment period, ophthalmologic examination can be 
done up to 7 days before anetumab ravtansine infusion.
c
Day 1 of every cycle: AST/ALT/total bilirubin/creatinine–other chemistry laboratory parameters can be performed at the investigator’s 
discretion but do not need to be reported unless related to an SAE or a drug-related AE of Grade ≥ 3.
d
During the study, complete urinalysis should be done when dipstick results are indicative or clinically indicated.
e
Serum pregnancy test should be repeated at least every 4 weeks until the safety follow-up visit; only for women of childbearing potential.
f
Including survival status and date of death.
g
IxRS transactions for medication dispensing will be done on Day 1 of each cycle for the anetumab ravtansine arm. IxRS transaction to 
register the end of treatment will be done at the safety follow-up visit.
Table added by amendment 6, see section 15.4.1.1.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  71 of 269
Table 9–3
Study flow chart – vinorelbine arm patients ongoing on treatment post OS maturation – added
Treatment - Every cycle
Safety follow-up period / 
visit
Long-term follow-up
Days
D1
D8 
D15 
+30 (after last dose)
Every 3 months
Acceptable time window (in days)
(unless otherwise specified)
+/-1
+/-1
+/-1
+7
± 14 days
Safety
Toxicity / AE assessmenta 
X 
X
X
X
Concomitant medication (only report those related to SAEs)
X 
X
X
X
Brief physical examination
X 
X
X
X
Weight
X 
X
X
X
Complete blood count
X
X
X
X
AST/ALT/total bilirubin/creatinine
Xb
Xb 
Xb 
X
Urine dipstickc
X
Serum pregnancy test (if applicable)d
X
X
Efficacy
Survival status and new anti-cancer treatmente
X
Study drug IV infusion
Comparator (vinorelbine) arm
X
X
X
IxRS transactionf
X 
X
X
X
AE = Adverse event; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; D = Day; IV = Intravenous; IxRS = Interactive Voice / Web Response 
System; OS = Overall survival; SAE = Serious adverse event.
a
New finding or worsening of any ongoing medical history condition after the patient has signed the informed consent for full study must be 
recorded as an AE.
b
Day 1, 8 and 15 of every cycle: AST/ALT/total bilirubin/creatinine – other chemistry laboratory parameters can be performed at the 
investigator’s discretion but do not need to be reported unless related to an SAE or a drug-related AE of Grade ≥ 3.
c
During the study, complete urinalysis should be done when dipstick results are indicative or clinically indicated.
d
Serum pregnancy test should be repeated at least every 4 weeks until the safety follow-up visit; only for women of childbearing potential.
e
Including survival status and date of death.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  72 of 269
f
IxRS transactions for medication dispensing will be done on Day 1, Day 8, and Day 15 of each cycle for the comparator arm. IxRS 
transaction to register the end of treatment will be done at the safety follow-up visit.
Table added by amendment 6, see section 15.4.1.1.  


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  73 of 269
9.2
 Visit description
If not stated otherwise, the measurements listed in the following sections will be performed 
by or under the supervision of an investigator or a delegate.
9.2.1
Prescreening
A prescreening step, including mesothelin expression level testing, can be performed without 
evidence of disease progression after the initial treatment cycles with platinum/pemetrexed 
(with or without bevacizumab) at the investigator’s discretion. Written patient informed 
consent for prescreening must be obtained before any prescreening or study-specific 
procedures. Enrollment in the study is defined as the signing of the ICF.

Written informed consent for prescreening.

Demographics (see Section 9.3.1).

Study disease characteristics and prior therapies for the study indication (see 
Section 9.3.3).

Check eligibility criteria for prescreening (see Section 6.1.1).

IxRS transaction to register the patient (see Section 6.4)

Toxicity/AE assessment (see Section 9.6.1). At prescreening, only AEs and SAEs that 
are related to study-specific procedures are mandatory to be reported.

Concomitant medication review (see Section 8.1). At prescreening, only concomitant 
medications that are administered to treat AEs related to study-specific procedures are 
mandatory to be reported.

ECOG PS assessment (see Section 9.6.3.3).

Mandatory biomarker archival or fresh biopsy tissue (see Section 9.7.1).
All patients enrolled into the study will be listed on a patient enrollment log provided by the 
sponsor representatives.
9.2.2
Full screening period
Written patient informed consent for full study must be obtained before any study-specific 
procedures. The maximum interval allowed between signature of informed consent and the 
start of study treatment is 28 days. Certain results from diagnostic testing prior to the 
informed consent date and time may be used to fulfill screening criteria.
Within 28 days before the start of study treatment: 

Written informed consent for full study.

IxRS transaction to register the patient’s full screening (see Section 6.4) (clarified by 
amendment 2, see section 15.1.1.26)


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  74 of 269

Updates of study disease characteristics and prior therapies for the study indication 
(see Section 9.3.3).

Medical history (see Section 9.3.2) and non-study-indication-related medications (see 
Section 9.3.3).

Check eligibility criteria for full study, and exclusion criteria (see Section 6.1.2 and 
6.2, respectively).

Radiological tumor evaluation with contrast-enhanced CT/MRI of 
chest/abdomen/pelvis (see Section 9.4.1). Pre-study CT/MRI may be acceptable as a 
baseline scan if done within 28 days before start of study drug, if centrally evaluable 
for mRECIST and if performed according to the Imaging Acquisition Guidance 
provided in the Imaging Manual. Patients with neurological symptoms at screening 
must undergo a contrast CT or MRI scan within 28 days before the start of study 
treatment to exclude brain metastases (bullet point modified by amendments 2 and 4, 
see section 15.1.1.19 and 15.2.1.5).
Forced vital capacity measurement removed by amendment 2

Toxicity/AE assessment: any new finding or worsening of any ongoing medical 
history condition after the patient has signed the full study ICF must be recorded as an 
AE (see Section 9.6.1).

Concomitant medication review (see Section 8.1).

Complete physical examination (see Section 9.6.3.2.1).
Vital signs removed by amendment 4

Weight and height.

12-lead electrocardiogram (ECG) (see Section 9.6.3.5).

ECOG PS assessment (see Section 9.6.3.3).

Echocardiogram (EchoCG) or multiple gated acquisition (MUGA) scan (see 
Section 9.6.3.6).
Within 21 days before the start of study treatment:
A separate subsection was created for the following bullet point by amendment 4.

A detailed ophthalmologic examination (visual acuity, IOP, Schirmer test and slit 
lamp) (see Section 9.6.3.7).
Within 7 days before the start of study treatment:

PROs (LCSS-Meso and MDASI-MPM) (see Section 9.4.3) before the patient meets 
with a clinician and before any examination or test is performed (clarified by 
amendment 2, see section 15.1.1.20).

Toxicity/AE assessment (see Section 9.6.1).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  75 of 269

Vital signs (see Section 9.6.3.4).

Laboratory (see Section 9.6.3.1).

Complete blood count.

Electrolyte and chemistry panel. 

Measurement of estimated GFR (eGFR) (see Appendix 16.7). 

Coagulation panel. 

Urine dipstick. During the study, complete urinalysis should be done when 
dipstick results are indicative or clinically indicated. 

Serum pregnancy test. Test should be repeated at least every 4 weeks until 
safety follow-up visit; only for WOCBP.
9.2.3
Treatment period
After all screening assessments have been completed and the patient’s eligibility has been 
confirmed and documented (confirmation of mesothelin overexpression moderate and 
stronger membrane staining in at least 30% of viable tumor cells will be obtained from central 
lab and confirmation of radiological eligibility will be obtained from central radiological 
review), the patient may begin treatment (paragraph modified by amendments 2 and 5, see 
section 15.1.1.6, 15.1.1.15 and 15.3.1.2).
9.2.3.1
Treatment – Cycle 1
Cycle 1 Day 1
The following procedures should be performed on C1D1 before receiving study treatment 
unless otherwise specified in the protocol. Eligibility criteria check, IxRS transaction to 
randomize the patient, toxicity / AE assessment, concomitant medication review, brief 
physical examination, vital signs and weight measurement, and ECOG PS assessment can be 
done within 24 hours before administration of the first dose of study drug. Eligibility must be 
confirmed prior to randomizing the patient in IxRS (modified by amendment 2, see section 
15.1.1.19).

Check eligibility criteria for full study, and exclusion criteria (see Section 6.1.2 and 
6.2, respectively).

IxRS transaction to randomize the patient (see Section 6.4) and for medication 
dispensing in both treatment arms (see Section 7.3) (modified by amendment 2, see 
section 15.1.1.19).

Toxicity/AE assessment (see Section 9.6.1).

Concomitant medication review (see Section 8.1).

Brief physical examination (see Section 9.6.3.2.2).

Vital signs (see Section 9.6.3.4).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  76 of 269

Weight.

ECOG PS assessment (see Section 9.6.3.3).
Laboratory test: urine dipstick was removed by amendment 2

PK sampling (see Section 9.5):

In the anetumab ravtansine arm: Pre-infusion (within 1 h before the start of 
infusion), end of infusion (within 5 min after the end of infusion) and 
approximately 3 h (range: 2 to 4 h) after the start of infusion. 

In the comparator arm: Pre-infusion (within 1 h before the start of infusion), 
end of infusion (within 5 min after the end of infusion), approximately 3 h 
(range: 2 to 4 h) after the start of infusion. 

A pharmacogenetic sample (pre-dose) for determination of patient’s CYP2D6 status 
(see Section 9.5) in the anetumab ravtansine arm.

Serum collection for immunogenicity assessment (see Section 9.7.2) in the anetumab 
ravtansine arm.

Biomarker plasma collection for soluble mesothelin (see Section 9.7.1).

Biomarker plasma collection for exploratory analysis (see Section 9.7.1).

Study treatment administration (IV infusion in both anetumab ravtansine and 
comparator arms [see Section 7.4]).

12-lead ECG (see Section 9.6.3.5), 30 min (+/- 5 min) post-dose (modified by 
amendment 4, see section 15.2.1.19).
For patients who consent to provide optional additional archival tissue, this should be 
collected and sent to the central laboratory at any time post randomization (added by 
amendment 4, see section 15.2.1.11).
Cycle 1 Day 2

PK sampling (see Section 9.5) for patients in the comparator arm: Approximately 24 h 
after the start of C1D1 infusion.
Cycle 1 Day 8
For assessments of this visit, time windows of -1 day and +1 day are acceptable unless 
otherwise specified in the protocol.
The following procedures should be performed on C1D8 before receiving study treatment 
unless otherwise specified in the protocol: 

PRO (MDASI-MPM) (see Section 9.4.3) before the patient meets with a clinician and 
before any examination or test is performed (added by amendment 2, see section 
15.1.1.20).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  77 of 269

IxRS transaction for medication dispensing in the comparator arm (see Section 7.3).

Toxicity/AE assessment (see Section 9.6.1).

Concomitant medication review (see Section 8.1).

Brief physical examination (see Section 9.6.3.2.2).

Vital signs (see Section 9.6.3.4).

Weight.

Laboratory (see Section 9.6.3.1):

Complete blood count. 

Electrolyte and chemistry panel (only AST, ALT and bilirubin). 

PK sampling (see Section 9.5) for patients in the anetumab ravtansine arm: 
Approximately 168 (± 24) h after the start of C1D1 infusion.

Study treatment administration (IV infusion in the comparator arm [see Section 7.4]).
Cycle 1 Day 15
For assessments of this visit, time windows of -1 day and +1 day are acceptable unless 
otherwise specified in the protocol.
The following procedures should be performed on C1D15 before receiving study treatment 
unless otherwise specified in the protocol: 

PRO (MDASI-MPM) (see Section 9.4.3) before the patient meets with a clinician and 
before any examination or test is performed (added by amendment 2, see section 
15.1.1.20).

IxRS transaction for medication dispensing in the comparator arm (see Section 7.3).

Toxicity/AE assessment (see Section 9.6.1).

Concomitant medication review (see Section 8.1).

Brief physical examination (see Section 9.6.3.2.2).

Vital signs (see Section 9.6.3.4).

Weight.

Laboratory (see Section 9.6.3.1):

Complete blood count. 

Electrolyte and chemistry panel (only AST, ALT and bilirubin). 

Study treatment administration (IV infusion in the comparator arm [see Section 7.4]).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  78 of 269
9.2.3.2
Treatment – Cycle 2 and higher – prior to OS maturation
Section heading modified by amendment 6, see section 15.4.1.1.
Cycle 2 and higher Day 1
For assessments of this visit, time windows of -1 day and +1 day are acceptable unless 
otherwise specified in the protocol.
The following procedures should be performed on Cycle 2 and higher, Day 1 before 
receiving study treatment unless otherwise specified in the protocol.

PROs (LCSS-Meso and MDASI-MPM) (see Section 9.4.3) before the patient meets 
with a clinician and before any examination or test is performed (clarified by 
amendment 2, see section 15.1.1.20).

IxRS transaction for medication dispensing in both treatment arms (see Section 7.3).

Toxicity/AE assessment (see Section 9.6.1).

Concomitant medication review (see Section 8.1).

Brief physical examination (see Section 9.6.3.2.2).

Vital signs (see Section 9.6.3.4).

Weight.

12-lead ECG (see Section 9.6.3.5) on C2D1, C3D1, C4D1, C5D1 and C6D1.

ECOG PS assessment (see Section 9.6.3.3).

EchoCG or MUGA scan (see Section 9.6.3.6) on C2D1, C4D1, and afterwards at the 
investigator’s discretion based on clinical need. During treatment, cardiac function test 
can be done up to 7 days before study drug administration (bullet point modified by 
amendment 4, see section 15.2.1.19).

Ophthalmologic examinations (visual acuity and slit lamp mandatory; IOP and 
Schirmer test optional) (see Section 9.6.3.7) for patients treated in the anetumab 
ravtansine arm in every cycle from C2D1 onwards, or more frequently at 
investigator’s and ophthalmologist/optometrist’s discretion (important to refer to 
Table 7–5 and Table 7–6) (modified by amendment 2, see section 15.1.1.10). To be 
performed within 7 days before anetumab ravtansine infusion.

Laboratory (see Section 9.6.3.1).

Complete blood count. 

Electrolyte and chemistry panel (lipase testing can be performed within 8 days 
before administration of the study treatment) (modified by amendment 4, see 
section 15.2.1.19).

Measurement of eGFR (see Appendix 16.7). 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  79 of 269

Coagulation panel. 

Urine dipstick.

PK sampling (see Section 9.5) for patients in the anetumab ravtansine arm will be 
done on C2D1, C3D1, C4D1, C6D1, C9D1 and on Day 1 of every 3 cycles thereafter:

C2D1: Pre-infusion (within 1 h before the start of infusion). 

C3D1: Pre-infusion (within 1 h before the start of infusion), end of infusion 
(within 5 min after the end of infusion) and approximately 3 h (range: 2 to 4 h) 
after the start of infusion. 

C4D1: Approximately 504 h after the start of C3D1 infusion (within 1 h before 
the start of infusion on C4D1). 

C6D1, C9D1 and on Day 1 of every 3 cycles thereafter: Pre-infusion (within 
1 h before the start of infusion) and end of infusion (within 5 min after the end 
of infusion). 
Unscheduled PK samples are requested at the next clinic visit after the initial onset of 
corneal epitheliopathy (modified by amendment 2, see section 15.1.1.5) and after the 
radiological assessment of the first PR (the first local observation of at least a 30% 
reduction in the total tumor measurement according to mRECIST).

Serum for immunogenicity assessment (see Section 9.7.2) in the anetumab ravtansine 
arm will be collected on C2D1, C3D1, C6D1, C9D1 and on Day 1 of every 3 cycles 
thereafter.

Biomarker plasma for exploratory analysis (see Section 9.7.1) will be collected on 
C6D1.

Study treatment administration (IV infusion in both anetumab ravtansine and 
comparator arms [see Section 7.4]).
Cycle 2 and higher Day 8
Patients in the anetumab ravtansine arm: Site visits and below-described procedures on D8 
will be performed on C1, C2 and C3 only. From Cycle 4 onwards, visits on D8 are no longer 
required. Patients in the comparator arm: Site visits and below-described procedures will be 
performed on D8 of each cycle.
For assessments of this visit, time windows of -1 day and +1 day are acceptable unless 
otherwise specified in the protocol.
The following procedures should be performed on Cycle 2 and higher, Day 8 before 
receiving study treatment unless otherwise specified in the protocol:

PRO (MDASI-MPM) (only C2D8 and C3D8, see Section 9.4.3) before the patient 
meets with a clinician and before any examination or test is performed (added by 
amendment 2, see section 15.1.1.20).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  80 of 269

IxRS transaction for medication dispensing in the comparator arm (see Section 7.3).

Toxicity/AE assessment (see Section 9.6.1).

Concomitant medication review (see Section 8.1).

Brief physical examination (optional as per local practice and/or at investigator’s 
discretion, see Section 9.6.3.2.2).

Vital signs (see Section 9.6.3.4).

Weight.

Laboratory (see Section 9.6.3.1):
o
Complete blood count. 
o
Electrolyte and chemistry panel (only AST, ALT and bilirubin).

PK sampling (see Section 9.5) for patients in the anetumab ravtansine arm will be 
done on C3D8 only: Approximately 168 (± 24) h after the start of C3D1 infusion.

Study treatment administration (IV infusion in the comparator arm [see Section 7.4]).
Cycle 2 and higher Day 15
Patients in the anetumab ravtansine arm: Site visits and below-described procedures on D15 
will be performed on C1, C2 and C3 only. From Cycle 4 onwards, visits on D15 are no longer 
required. Patients in the comparator arm: Site visits and below-described procedures will be 
performed on D15 of each cycle.
For assessments of this visit, time windows of -1 day and +1 day are acceptable unless 
otherwise specified in the protocol.
The following procedures should be performed on Cycle 2 and higher, Day 15 before 
receiving study treatment unless otherwise specified in the protocol:

PRO (MDASI-MPM) (only C2D15 and C3D15, see Section 9.4.3) before the patient 
meets with a clinician and before any examination or test is performed (added by 
amendment 2, see section 15.1.1.20).

IxRS transaction for medication dispensing in the comparator arm (see Section 7.3).

Toxicity/AE assessment (see Section 9.6.1).

Concomitant medication review (see Section 8.1).

Brief physical examination (optional as per local practice and/or at investigator’s 
discretion, see Section 9.6.3.2.2).

Vital signs (see Section 9.6.3.4).

Weight.

Laboratory (see Section 9.6.3.1):


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  81 of 269
o Complete blood count.
o Electrolyte and chemistry panel (only AST, ALT and bilirubin).

PK sampling (see Section 9.5) for patients in the anetumab ravtansine arm will be 
done on C3D15 only: Approximately 336 (± 24) h after the start of C3D1 infusion.

Study treatment administration (IV infusion in the comparator arm [see Section 7.4]).
9.2.3.3
Treatment post OS maturation – anetumab ravtansine arm - Day 1
Section added by amendment 6, see section 15.4.1.1.
For assessments of this visit, time windows of -1 day and +7 days are acceptable unless 
otherwise specified in the protocol.
The following procedures should be performed at Day 1 of each cycle before receiving study 
treatment unless otherwise specified in the protocol.

IxRS transaction for medication dispensing (see Section 7.3).

Toxicity/AE assessment (see Section 9.6.1).

Concomitant medication review (see Section 8.1) – only medications related to SAEs 
are required to be reported.

Brief physical examination (see Section 9.6.3.2.2).

Weight.

Ophthalmologic examinations (visual acuity and slit lamp mandatory; IOP and 
Schirmer test optional) (see Section 9.6.3.7) at every other cycle or more frequently at 
investigator’s and ophthalmologist/optometrist’s discretion (e.g. for patients with 
corneal epitheliopathy ≥ Grade 2, ophthalmologic examination will occur at least at 
every cycle until resolution of corneal epitheliopathy to Grades 0 or 1; important to 
refer to Table 7–5 and Table 7–6). To be performed within 7 days before anetumab 
ravtansine infusion.

Laboratory (see Section 9.6.3.1).

Complete blood count. 

AST/ALT/total bilirubin/creatinine – other chemistry laboratory parameters 
can be performed at the investigator’s discretion but do not need to be reported 
unless related to an SAE or a drug-related AE of Grade ≥ 3.

Urine dipstick.

PK sampling (see Section 9.5) at Day 1 of every 3 cycles.

Serum for immunogenicity assessment (see Section 9.7.2) at Day 1 of every 3 cycles

Study treatment administration (IV infusion, see Section 7.4).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  82 of 269
Serum pregnancy test should be repeated at least every 4 weeks until the safety follow-up visit 
for WOCBP.
9.2.3.4
Treatment post OS maturation – vinorelbine arm – Days 1, 8 and 15
Section added by amendment 6, see section 15.4.1.1.
For assessments of this visit, time windows of -1 day and +1 day are acceptable unless 
otherwise specified in the protocol.
The following procedures should be performed at Day 1, Day 8 and Day 15 of each cycle 
before receiving study treatment unless otherwise specified in the protocol.

IxRS transaction for medication dispensing (see Section 7.3).

Toxicity/AE assessment (see Section 9.6.1).

Concomitant medication review (see Section 8.1) – only medications related to SAEs 
are required to be reported.

Brief physical examination (see Section 9.6.3.2.2).

Weight.

Laboratory (see Section 9.6.3.1).

Complete blood count. 

AST/ALT/total bilirubin/creatinine – other chemistry laboratory parameters 
can be performed at the investigator’s discretion but do not need to be reported 
unless related to an SAE or a drug-related AE of Grade ≥ 3.

Urine dipstick (only at Day 1 of each cycle).

Study treatment administration (IV infusion, see Section 7.4).
Serum pregnancy test should be repeated at least every 4 weeks until the safety follow-up visit 
for WOCBP.
9.2.4
Efficacy assessments
Radiological tumor evaluations (modified by amendment 2)
Post OS maturation, tumor assessments should be performed as per local standard of 
care and will no longer be required to be performed per protocol scheduling or 
assessment requirements, or sent for central review (sentence added by amendment 6, see 
section 15.4.1.1).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  83 of 269
Prior to OS maturation, radiological tumor evaluation with contrast-enhanced CT/MRI of 
chest/abdomen/pelvis will be performed at the following intervals (for further details, see 
Section 9.4.1) (modified by amendments 2 and 6, see section 15.1.1.3 and 15.4.1.1).
Full screening (baseline):

Within 28 days before the start of study treatment (modified by amendment 2, see 
section 15.1.1.19).
Treatment and active follow-up:

Every 6 weeks during the first 6 months after the start of study treatment.

Every 9 weeks until the end of year 2.

Every 12 weeks thereafter, until the earlier of centrally confirmed radiological disease 
progression, OS analysis data maturation, or end of study (modified by amendment 6, 
see Section 15.4.1.1).
Visit window of +/- 7 days is allowed.
9.2.5
Follow-up periods
9.2.5.1
Safety follow-up prior to OS maturation 
Section heading modified by amendment 6, see section 15.4.1.1.
When a patient discontinues the study treatment for any reason (except death, consent 
withdrawal or lost to follow-up) a safety follow-up visit will be performed 30 (+7) days after 
the last administration of study treatment. Scheduling should ensure that a minimum of 
30 days have elapsed prior to the evaluation visit to ensure adequacy of safety follow-up 
period.
Prior to OS maturation, the following assessments should be performed at the safety follow-
up visit (modified by amendment 6, see section 15.4.1.1):

PROs (LCSS-Meso and MDASI-MPM) (see Section 9.4.3) before the patient meets 
with a clinician and before any examination or test is performed (clarified by 
amendment 2, see section 15.1.1.20).

IxRS transaction to register the end of treatment.

Toxicity/AE assessment (see Section 9.6.1).

Concomitant medication review (see Section 8.1).

Brief physical examination (see Section 9.6.3.2.2).

Vital signs (see Section 9.6.3.4).

Weight.

12-lead ECG (see Section 9.6.3.5).

ECOG PS assessment (see Section 9.6.3.3).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  84 of 269

Ophthalmologic examinations (visual acuity and slit lamp mandatory; IOP and 
Schirmer test optional) (see Section 9.6.3.7) for patients treated in the anetumab 
ravtansine arm.

Laboratory (see Section 9.6.3.1).

Complete blood count.

Electrolyte and chemistry panel.

Measurement of eGFR (see Appendix 16.7).

Coagulation panel.

Serum pregnancy test; only for WOCBP.

Biomarker plasma collection for exploratory analysis (see Section 9.7.1).
9.2.5.2
Safety follow-up post OS maturation
Section added by amendment 6, see section 15.4.1.1.
When a patient discontinues the study treatment for any reason (except death, consent 
withdrawal or lost to follow-up) a safety follow-up visit will be performed 30 (+7) days after 
the last administration of study treatment. Scheduling should ensure that a minimum of 
30 days have elapsed prior to the evaluation visit to ensure adequacy of safety follow-up 
period.
The following assessments should be performed at the safety follow-up visit:

IxRS transaction to register the end of treatment.

Toxicity/AE assessment (see Section 9.6.1).

Concomitant medication review (see Section 8.1) – only medications related to SAEs 
are required to be reported.

Brief physical examination (see Section 9.6.3.2.2).

Weight.

Ophthalmologic examinations (visual acuity and slit lamp mandatory; IOP and 
Schirmer test optional) (see Section 9.6.3.7) for patients treated in the anetumab 
ravtansine arm.

Laboratory (see Section 9.6.3.1).

Complete blood count.

AST/ALT/total bilirubin/creatinine.

Serum pregnancy test; only for WOCBP.

Biomarker plasma for exploratory analysis (see Section 9.7.1) for patients treated in 
the anetumab ravtansine arm.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  85 of 269
9.2.5.3
Active follow-up
Following OS maturation, active follow-up is no longer required (sentence added by 
amendment 6, see section 15.4.1.1).
Prior to OS maturation, patients who discontinue study treatment due to any other reason than 
centrally confirmed radiological PD, will continue clinic visits during active follow-up for 
efficacy assessments including tumor response, disease-related-symptoms, and QoL (modified 
by amendments 2, 4, and 6 see section 15.1.1.3, 15.2.1.17, and 15.4.1.1). These assessments 
will continue until disease progression, consent withdrawal, lost to follow-up or end of study.

PROs (LCSS-Meso and MDASI-MPM) (see Section 9.4.3) before the patient meets 
with a clinician and before any examination or test is performed (clarified by 
amendment 2, see section 15.1.1.20). During active follow-up period MDASI-MPM 
and LCSS-Meso are to be taken in parallel with CT/MRI.

Radiological tumor evaluation with contrast-enhanced CT/MRI of 
chest/abdomen/pelvis. During active follow-up, tumor scans will be performed with 
the same modality every 6 weeks during the first 6 months after the start of study 
treatment, every 9 weeks until the end of year 2, and every 12 weeks thereafter, until 
the earlier of centrally confirmed radiological disease progression, OS analysis data 
maturation, or end of study (see Section 9.4.1) (modified by amendment 6, see 
section 15.4.1.1). Visit window of +/- 7 days is allowed.
Forced vital capacity measurement removed by amendment 2

Toxicity/AE assessment (see Section 9.6.1), in parallel with CT/MRI. During active 
follow-up period, only AEs and SAEs that are related to study-specific procedures are 
mandatory to be reported. However, at the investigator’s discretion, SAEs may be 
reported if considered potentially relevant. In such cases, the SAEs will be processed 
by the sponsor according to all applicable regulations.

Concomitant medication review (see Section 8.1), in parallel with CT/MRI. During 
active follow-up period, only concomitant medications that are administered to treat 
AEs related to study-specific procedures are mandatory to be reported.

New anti-cancer treatment, in parallel with CT/MRI.
9.2.5.4
Long-term follow-up
Patients enter the long-term follow-up period following centrally confirmed radiological 
progression, or withdrawal of consent to active follow-up. Patients with centrally confirmed 
PD during the treatment period enter long-term follow-up immediately after the safety follow-
up visit. 
Following OS maturation, all patients who discontinue treatment will enter the long-term 
follow-up period following the safety follow-up visit (sentence added by amendment 6, see 
section 15.4.1.1 and 15.4.1.2).
All patients in the long-term follow-up period will be contacted every 3 months (±14 days) 
until death, withdrawal of consent, lost to follow-up, or 24 months after the last patient’s last 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  86 of 269
treatment or end of study, whichever occurs first (modified by amendment 6, see section 
15.4.1.2). Patients or their health care providers will be contacted either in person or by 
telephone. In addition, extra survival sweep contacts will be conducted at the time of PFS 
final analysis and prior to OS final analysis to ensure that long-term follow-up data is current.
The information to be recorded at these contacts:

Survival status.

Date of death.

New anti-cancer treatment.
Date of locally confirmed progression removed by amendment 6, see section 15.4.1.2.
9.3
Population characteristics
Population characteristics including patient demographics, medical history, and other baseline 
characteristics listed in this section must be documented on the CRF by the investigator 
before the start of study treatment.
9.3.1
Demographic
Baseline patient data pertaining to demographic information will be collected at prescreening, 
including:

Year of birth and age

Sex

Race (where legally allowed)

Ethnicity (where legally allowed)

Region.
9.3.2
Medical history
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected after consent for full study is signed as available to the 
investigator:

Start before signing of the informed consent for full study

Considered relevant for the patient’s study eligibility.
Detailed instructions on the differentiation between (i) medical history and (ii) AEs can be 
found in Section 9.6.1.1.
9.3.3
Other baseline characteristics
The following study disease characteristics will be collected as of prescreening and will be 
updated if applicable during screening for full study:

Date of MPM diagnosis


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  87 of 269

Stage of MPM at diagnosis

Treatment of MPM before enrollment (e.g. surgery, radiation and systemic therapy)
All prior medications and significant non-drug therapies for the study indication will be 
collected as of prescreening and will be updated if applicable during screening for full study, 
including:

Trade name of medication

Reason for medication (indication)

Dose of medication

Start date and end date or if continuing at patient's last visit
All non-study-indication-related medications and significant non-drug therapies taken 
within 30 days before ICF signature for full study will be documented, including:

Trade name of medication

Reason for medication (indication)

Dose of medication

Start date and end date or if continuing at patient's last visit.
9.4
Efficacy
The primary efficacy variable is progression-free survival (PFS) based on assessment of 
blinded independent central review. For definition and analysis of the primary variable and 
for description of secondary and other variables, please refer to Section 10.3.
9.4.1
Radiological tumor assessments
Post OS maturation, tumor assessments should be performed as per local standard of 
care and will no longer be required to be performed per protocol scheduling or 
assessment requirements, or sent for central review (sentence added by amendment 6, see 
section 15.4.1.1).
The first radiological (contrast-enhanced CT/MRI of chest/abdomen/pelvis) tumor evaluation 
will be conducted during full screening within 28 days before the start of study treatment (see 
flow chart in Section 9.1). Pre-study CT/MRI may be acceptable as a baseline scan if done 
within 28 days before start of study drug (modified by amendment 2, see section 15.1.1.19), if 
centrally evaluable for mRECIST and if performed according to the Imaging Acquisition 
Guidance provided in the Imaging Manual. Baseline CT/MRI should be obtained prior to 
randomization. A sole positron emission tomography (PET) scan without a diagnostic 
CT/MRI is not acceptable for radiological evaluation of target lesions; findings must be 
confirmed by CT or MRI. Although PET scan findings may be used as supportive evidence of 
tumor assessment, the CT or MRI results will be the definitive and documented data for the 
study. All subsequent scans should be done with the identical method and technique (e.g. slice 
thickness, field of view) to those obtained at baseline. These screening images will be 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  88 of 269
provided to blinded central review to assess radiological eligibility (central confirmation of 
radiological eligibility required before randomization) (modified by amendment 2, see section 
15.1.1.15). If focal neurological symptoms are present at screening, a CT scan or MRI of the 
brain and/or other areas of the CNS as applicable is required to rule out metastastic disease in 
the CNS within 28 days before the start of study treatment by the investigator. All additional 
suspected sites of disease should be imaged (e.g. cervical lymph nodes, bone etc.) (paragraph 
modified by amendment 4, see section 15.2.1.5).
During treatment as well as active follow-up, tumor imaging and local assessments will be 
performed for the following time points: every 6 weeks for the first 6 months after the start of 
study treatment, every 9 weeks until the end of year 2, and every 12 weeks thereafter, until the 
earlier of centrally confirmed radiological disease progression, OS analysis data maturation, 
or end of study (modified by amendment 6, see section 15.4.1.1). Visit window of +/- 7 days is 
allowed. MRI shall be performed instead of CT when local regulations do not permit the use 
of CT as requested per protocol schedule.
All images need to be sent to the central review service immediately after they are obtained.
Investigators will determine treatment response locally at each investigational site according 
to mRECIST criteria for MPM. Preferably all scans should be interpreted by the same 
radiologist/investigator during the study.
In the event of locally suspected progression, the site will inform the central review service 
and central review will start. Radiological real-time confirmation by central independent 
blinded evaluation is required before a final decision to stop the treatment is made. The site 
should also wait for the central review results before administering the next dose of treatment. 
In case of uncertain radiological disease progression, the patient may stay on treatment at the 
investigator’s discretion until progression is definitely confirmed by central review on the 
subsequent tumor assessment.
When the central review assessment confirms progression, treatment may be continued if the 
patient derives clinical benefit as determined by the treating physician per the withdrawal 
criteria (see Section 6.3.1.2). Otherwise, study treatment should be stopped permanently and 
patient will enter safety follow-up (safety follow-up visit to be scheduled 30+7 days after the 
last administration of study treatment) and long-term follow-up period (paragraph modified 
by amendment 5, see section 15.3.1.3).
Once centrally confirmed radiological progression is reported, protocol tumor assessment 
requirements end. Subsequent tumor imaging may be performed according to treating 
physician’s discretion if study treatment is continued. The investigator is not required to send 
imaging taken following centrally confirmed PD to central review, and the central reviewer is 
not required to review any such imaging sent (paragraph added by amendment 5, see 
section 15.3.1.3).
In the event the central review assessment does not find progression, the severity and clinical 
significance of local PD finding should be assessed. If patient has not significantly clinically 
deteriorated and has no toxicity requiring withdrawal, the patient should continue on 
treatment and further imaging should be conducted as per protocol required timelines. If 
patient has clinically deteriorated or has toxicity such that keeping patient on treatment would 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  89 of 269
be against patient’s interest, the study treatment should be stopped permanently. The patient 
will enter the safety follow-up (safety follow-up visit to be scheduled 30+7 days after the last 
administration of study treatment) and active follow-up period.
The PD events for the primary endpoint of this study, and the time point and best response 
values for the secondary response endpoints, will be determined by independent blinded 
central reviewers according to mRECIST criteria (see Appendix 16.3) at the central image 
review. The blinded central reviewers including the adjudicator will be radiology board 
certified, experienced and independent radiologists with broad expertise in oncology, 
radiology and MPM as well as good knowledge of mRECIST criteria for MPM (21). The 
central reviewers must not be otherwise involved in this study, i.e. listed or identified 
investigator or subinvestigator who is directly involved in the treatment or evaluation of 
research patients is not accepted. The central reviewers will be blinded to patient identity and 
study treatment. Central reviewers will be isolated from knowledge of investigator PD 
assessments through read lock procedures and communication controls. All image sets, i.e. 
CT and MRI, must be anonymized by the study sites and provided digitally as Digital 
Imaging and Communications in Medicine (DICOM) format. The investigator must assure 
that the images are of acceptable diagnostic quality and fulfill the requirements outlined in the 
Imaging Manual. Additional specific information on the handling (i.e. collection, shipment, 
tracking) of the images for the central image review will be provided separately.
The final evaluation of treatment response for those patients not undergoing central review for 
PD confirmation will be done by central blinded review retrospectively. The central reviewer 
will determine the response per mRECIST criteria of each patient as of each time point. 
Responses of CR and PR will be confirmed by repeated observation per mRECIST criteria. 
Confirmed responses of CR and PR will be dated per mRECIST criteria (paragraph modified 
by amendment 4, see section 15.2.1.12).
In case a patient discontinues study for reasons other than centrally confirmed disease 
progression and doesn’t want to enter or stay in the active-follow-up, information on locally 
confirmed date of progression should be collected during long-term follow-up. Progression 
results not documented by centrally collected imaging will be classified as clinical 
progression and used in sensitivity analysis.
Section Pulmonary function assessment removed by amendment 2; numbering of the 
following sections changed accordingly.
9.4.2
Survival
Patients will be contacted for survival every 3 months (±14 days) during long-term follow-up 
until death, withdrawal of consent, lost to follow-up, or 24 months after the last patient’s last 
treatment or the end of study, whichever occurs first (see flow chart in Section 9.1) (modified 
by amendment 6, see section 15.4.1.2). In addition, extra survival sweep contacts will be 
conducted prior to PFS final analysis and prior to OS final analysis to ensure that long-term 
follow-up data is current (clarified by amendment 2, see section 15.1.1.26).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  90 of 269
9.4.3
Patient-reported outcomes
PRO will no longer be collected after OS maturation (sentence added by amendment 6, see 
section 15.4.1.1).
The effect of treatment on disease-related symptoms and disease-specific health-related 
quality of life (QoL) will be assessed using the MD Anderson Symptom Inventory-Malignant 
Pleural Mesothelioma (MDASI-MPM) and the Lung Cancer Symptom Scale-Mesothelioma 
(LCSS-Meso), respectively (clarified by amendment 4, see section 15.2.1.17).
The LCSS-Meso will be used to assess change in thoracic cancer symptoms and health-related 
Quality of Life (HRQoL). In addition to the LCSS-Meso, the MDASI-MPM will be used to 
assess change in thoracic cancer symptoms and interference of these symptoms with daily 
activities (paragraph clarified by amendment 4, see section 15.2.1.17).
The MDASI-MPM questionnaires will be completed at full screening (within 7 days before 
the start of study treatment), on C1D8, C1D15, C2D1, C2D8, C2D15, C3D1, C3D8, C3D15 
and on Day 1 of every cycle thereafter (i.e. C4D1, C5D1 etc.), at safety follow-up visit and 
during active follow-up period. The LCSS-Meso questionnaires will be completed at full 
screening (within 7 days before the start of study treatment), C2D1 and on Day 1 of every 
cycle thereafter (i.e. C3D1, C4D1 etc.), at safety follow-up visit and during active follow-up 
period. During active follow-up period, MDASI-MPM and LCSS-Meso are to be taken in 
parallel with tumor scans i.e. with the same modality every 6 weeks during the first 6 months 
after the start of study treatment, every 9 weeks until the end of year 2, and every 12 weeks 
thereafter, until the earlier of centrally confirmed radiological disease progression, OS 
analysis data maturation, or end of study (modified by amendment 6, see section 15.4.1.1). 
MDASI-MPM and LCSS-Meso are to be completed before the patient meets with a clinician 
and before any examination or test is performed on that day. A PRO information sheet will be 
provided and completed by the study personnel for each questionnaire at each visit at which 
the LCSS-Meso and the MDASI-MPM are to be administered, regardless of whether or not 
the LCSS-Meso or the MDASI-MPM are completed by the patient (paragraph modified by 
amendment 2, see section 15.1.1.20).
Questionnaires should be completed by all patients at the time points described in the flow 
chart of Section 9.1, except when not logistically possible.
9.4.3.1
MDASI-MPM
The MDASI-MPM has been derived from the MD Anderson Symptom Inventory-Lung 
Cancer (MDASI-LC). The MDASI-MPM was developed for use in mesothelioma through 
qualitative interviews with 20 patients with MPM. This questionnaire, the MDASI-MPM, 
asks patients to rate a list of symptoms (at the worst) and activities (amount of interference 
from symptoms) on a 0 (symptom not present or no interference) to 10 (symptom as bad as 
can be imagined or complete interference) numeric scale in the last 24 hours. The MDASI-
MPM contains the 13 symptom items (those found to have the highest frequency and/or 
severity in patients with various cancers and treatment types) and 6 interference items of the 
validated MDASI-Core and an additional 6 symptom items developed by qualitative 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  91 of 269
interviews of 20 patients with pleural mesothelioma and 6 patients with different types of 
cancer receiving anetumab ravtansine (see Appendix 16.5.1).
Patient interviews containing open-ended questions were conducted by trained MD 
Anderson Cancer Center (MDACC) research staff. Analysis of the qualitative interviews 
produced a list of symptom and interference items for the content domain of the MDASI-
MPM. An expert panel composed of physicians, nurses, patients, and family caregivers 
familiar with pleural mesothelioma rated the symptom list for relevance to reduce the number 
of items to the provisional list.
Psychometric characteristics will be obtained from patients in the Thoracic Medical Oncology 
Clinic at MD Anderson, and qualitative and psychometric results will be presented to 
FDA/COA reviewers for consultation. Input is being sought concerning the conceptual 
framework of the measure, recall period, and a sub-set of disease-related symptoms that might 
be included in a composite score for a responder analysis.
The MDASI-MPM will be used to assess the severity of multiple symptoms and the impact of 
symptoms on daily functioning.
9.4.3.2
LCSS-Meso
The LCSS-Meso (28) is designed as a site-specific measure of QoL, particularly for use in 
clinical trials (see Appendix 16.5.2). It evaluates 5 major symptoms associated with 
mesothelioma and their effect on overall symptomatic distress, functional activities, and 
global QoL. It captures in detail those dimensions most likely to be influenced by therapeutic 
interventions and evaluates other dimensions globally.
The patient questionnaire consists of visual analogue scales (VAS) (100 mm horizontal line). 
The patient is instructed to put a mark on the line to indicate intensity of response to the items 
in question (0 = lowest rating; 100 = highest rating). Completion of the patient scale takes 
approximately 8 min initially, including demonstration of the VAS and 3-5 min for 
subsequent administrations.
9.5
Pharmacokinetics / pharmacodynamics
Anetumab ravtansine arm
PK samples will be collected for the analysis of the ADC and total antibody, DM4 and DM4-
Me. Sparse PK samples will be collected as follows (see Sections 9.1 and 9.2): 

C1D1: Pre-infusion (within 1 h before the start of infusion), end of infusion (within 
5 min after the end of infusion) and approximately 3 h (range: 2 to 4 h) after the start 
of infusion. A pharmacogenetic sample should be collected on C1D1 (pre-dose) for 
determination of patient’s CYP2D6 status. Results will be used to correlate to DM4 
exposure.

C1D8: Approximately 168 (± 24) h after the start of C1D1 infusion (sample collection 
to coincide with the clinic safety visit).

C2D1: Pre-infusion (within 1 h before the start of infusion).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  92 of 269

C3D1: Pre-infusion (within 1 h before the start of infusion), end of infusion (within 
5 min after the end of infusion) and approximately 3 h (range: 2 to 4 h) after the start 
of infusion.

C3D8 and C3D15: Approximately 168 (± 24) h and 336 (± 24) h after the start of 
C3D1 infusion (sample collection to coincide with the clinic safety visit).

C4D1: Approximately 504 h after the start of C3D1 infusion (within 1 h before the 
start of infusion on C4D1).

C6D1, C9D1 and on Day 1 of every 3 cycles thereafter: Pre-infusion (within 1 h 
before the start of infusion) and end of infusion (within 5 min after the end of 
infusion).
Unscheduled PK samples are requested at the next clinic visit after the initial onset of corneal 
epitheliopathy (modified by amendment 2, see section 15.1.1.5) and after the radiological 
assessment of the first PR (the first local observation of at least a 30% reduction in the total 
tumor measurement according to mRECIST). The date and actual clock time of this 
unscheduled PK sample and of the last dose of anetumab ravtansine has to be recorded on the 
CRF as an Unscheduled Procedure.
Unscheduled PK will no longer be performed after OS maturation (sentence added by 
amendment 6, see section 15.4.1.1).
Measurement of alpha-1 acid glycoprotein (AAG) may be performed in select 
pharmacokinetic samples to estimate unbound DM4 and DM4-Me exposure (sentence added 
by amendment 5, see section 15.3.1.4).
Comparator (vinorelbine) arm
Sparse PK samples will be collected for vinorelbine as follows (see Sections 9.1 and 9.2):

C1D1: Pre-infusion (within 1 h before the start of infusion), end of infusion (within 
5 min after the end of infusion), approximately 3 h (range: 2 to 4 h) after the start of 
infusion.

C1D2: Approximately 24 h after the start of C1D1 infusion.
For all PK samples collected in this study, sampling times outside the suggested intervals will 
not be considered as protocol deviations. It is important that the actual date and time of blood 
sampling and start and stop times of study drug administration are documented on the CRF 
and patient’s source document because PK calculations will be based on the actual sampling 
times relative to dosing times. Details about the collection, processing, storage and shipment 
of samples will be provided in a separate document (e.g. laboratory manual).
Plasma concentrations of all analytes will be measured using a validated method. If required, 
other metabolites may be measured. Exploratory measurements of other moieties may be 
performed, if needed.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  93 of 269
9.6
Safety
9.6.1
Adverse events
9.6.1.1
Definitions
Definition of adverse event (AE)
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
A surgical procedure that was planned prior to the start of the study by any physician treating 
the patient should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).
New lesions or disease progression per se should not be regarded as AEs. Instead, the 
associated signs and symptoms should be recorded as AEs.
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g. physical examination findings, symptoms, diseases, laboratory, ECG.
Conditions that started before signing of informed consent for full study and for 
which no symptoms or treatment are present until signing of informed consent for 
full study are recorded as medical history (e.g. seasonal allergy without acute 
complaints).
Conditions that started before signing of informed consent for full study and for 
which symptoms or treatment are present after signing of informed consent for full 
study, at unchanged intensity, are recorded as medical history (e.g. allergic 
pollinosis).
Conditions that started or deteriorated after signing of informed consent for full 
study will be documented as AEs. This includes intercurrent illnesses.
Definition of serious adverse event (SAE)
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a.
Results in death.
b. Is life-threatening.
The term ‘life-threatening’ in the definition refers to an event in which the patient was 
at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  94 of 269
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:
The admission results in a hospital stay of less than 12 hours.
The admission is pre-planned. 
(e.g. elective or scheduled surgery arranged prior to the start of the study; 
admission is part of the study procedures as described in Section 9.2).
The admission is not associated with an AE 
(e.g. social hospitalization for purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment. In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability / incapacity.
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e.
Is a congenital anomaly / birth defect.
f.
Is another serious or important medical event as judged by the investigator.
9.6.1.2
Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.
9.6.1.2.2
Intensity
The intensity of an AE should be documented using the NCI-CTCAE v4.03 or by the Bayer 
grading system (see Table 7–5 and Table 7–6) for corneal epitheliopathy (sentence added by 
amendment 2, see section 15.1.1.26). For events not listed in the NCI-CTCAE, the following 
scale will be used:

Grade 1: Mild

Grade 2: Moderate

Grade 3: Severe

Grade 4: Life-threatening

Grade 5: Fatal


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  95 of 269
9.6.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the CRF.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”
An assessment of “no” would include:
1.
The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site.
or
2.
Non-plausibility, e.g. the patient is struck by an automobile when there is no indication 
that the drug caused disorientation that may have caused the event; cancer developing a 
few days after the first drug administration.
An assessment of “yes” indicates that that the AE is reasonably associated with the use of the 
study treatment.
Important factors to be considered in assessing the relationship of the AE to study treatment 
include:

The temporal sequence from drug administration: The event should occur after the 
drug is given. The length of time from drug exposure to event should be evaluated in 
the clinical context of the event. 

Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge): Patient’s response after de-challenge or re-challenge should be 
considered in view of the usual clinical course of the event in question. 

Underlying, concomitant, intercurrent diseases: 
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have. 

Concomitant medication or treatment: 
The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might have caused the event in question. 

Known response pattern for this class of drug: Clinical/preclinical. 

Exposure to physical and/or mental stresses: The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event. 

The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  96 of 269
of the study treatment, coupled with the individual patient’s pharmacodynamics 
should be considered. 

The assessment is not possible. 
Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).
Possible answers are “yes” or “no”.
9.6.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.

Drug withdrawn

Drug interrupted

Dose reduced

Dose not changed

Dose increased (added by amendment 2, see section 15.1.1.21)

Not applicable

Unknown
9.6.1.2.5
Other specific treatment(s) of adverse events

None

Remedial drug therapy

Other
9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 

Recovered/resolved

Recovering/resolving

Recovered/resolved with sequelae

Not recovered/not resolved

Fatal

Unknown


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  97 of 269
9.6.1.3
Assessments and documentation of adverse events
AEs observed, mentioned upon open questioning by a member of the investigator team or 
spontaneously reported by the patient will be documented in the patient’s records and on the 
appropriate CRF. AEs will be documented in an event-based manner, using NCI-CTCAE 
version 4.03 guidelines. In addition, since the NCI-CTCAE may not adequately capture the 
severity of new corneal epitheliopathy, an alternative severity grading system for corneal 
epitheliopathy will be used (see Table 7–5 and Table 7–6) (modified by amendment 2, see 
section 15.1.1.5).
All AE’s occurring in the period between the signing of the informed consent for the full 
study and the end of the safety follow-up phase (safety follow-up visit) have to be recorded on 
the respective CRF pages by the investigator. After the end of the safety follow-up phase 
there is no requirement to actively collect AEs including deaths. An AE (irrespective of causal 
relationship) not completely resolved at the end of the pre-defined collection period must be 
followed up until resolution (chronicity, baseline grade or complete resolution) or until the 
investigator considers the event will not improve further. At prescreening and during active 
follow-up period, only AEs and SAEs that are related to study-specific procedures have to 
be reported. The type of information that should be assessed and recorded by the investigator 
for each AE is listed in Section 9.6.1.2.
“Death” should not be recorded as an AE on the AE page. Instead, “death” is the outcome of 
underlying AE(s).
For all SAEs the sponsor has to carry out a separate assessment for expectedness, seriousness 
and causal relationship to study drug.
9.6.1.4
Reporting of serious adverse events
The definition of SAEs is given in Section 9.6.1.1. Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated recipient.
It is not mandatory to report new SAEs occurring after the protocol-defined observation 
period, however, at the investigator’s discretion these may be reported if considered 
potentially relevant. In such cases, the SAEs will be processed by the sponsor according to all 
applicable regulations.
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs. This information, including all relevant contact 
details, is summarized in the investigator site file. This information will be updated as needed.
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs occurring during the observation period defined in Section 9.6.1.3 to the recipient 
detailed in the instructions for SAE reporting included in the Investigator File. For this, an AE 
page in the CRF as well as the complementary pages provided in the Investigator File must be 
completed for each SAE. 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  98 of 269
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
If disease progression leads to signs and symptoms that meet the criteria for seriousness (see 
Section 9.6.1.1), the associated signs and symptoms should be reported as SAE, not the 
underlying cause (i.e. “progressive disease” should not be recorded as SAE). In this case, 
disease progression should be mentioned on the SAE form as “alternative explanation”.
If a new primary malignancy is noted at any time before end of active follow-up, it must be 
reported as an SAE, whether or not it is assessed as related to study treatment.
For documentation of laboratory findings as SAE, please refer to Section 9.6.3.1.
Notification of the IECs / IRBs
Notification of the IECs / IRBs about all relevant events (e.g. SAEs, suspected, unexpected, 
serious adverse reactions [SUSARs]) will be performed by the sponsor and/or by the 
investigator according to all applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations.
9.6.1.5
Expected adverse events
For this study, the applicable reference document for anetumab ravtansine is the most current 
version of the IB. For vinorelbine, applicable product information leaflets will be used.
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB. If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
9.6.1.6
Adverse events of special safety interest
Anetumab ravtansine is an investigational drug and current knowledge of the AEs associated 
with this compound is limited.
As with any new chemical entity, there is always potential for unexpected AEs, including 
hypersensitivity reactions.
Corneal epitheliopathy is considered as AE of special interest. Specific dose modification 
schemes are defined in Section 7.4.2.1. An alternative severity grading system for corneal 
epitheliopathy will be used in addition to NCI-CTCAE version 4.03 criteria, since the NCI-


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  99 of 269
CTCAE may not adequately capture the severity of these novel adverse reactions (see Table 
7–5 and Table 7–6) (paragraph modified by amendment 2, see section 15.1.1.5).
There is no need for expedited reporting or use of complementary pages to report corneal 
epitheliopathy, unless it meets the criteria for an SAE as defined in Section 9.6.1.1 (modified 
by amendment 2, see section 15.1.1.14); however these events will need to be closely 
monitored and reviewed, and documented timely and accurately both in source data and on 
the CRF. Details of ophthalmologic examination will be documented on the “ophthalmologic 
examination” and “slit lamp” CRF pages and in case AEs occur, also on “AE” CRF page, 
ensuring the reporting terminology used on those pages matches and reflects the source.
9.6.2
Pregnancies
The investigator must report to the sponsor any pregnancy occurring in a female study patient 
during her participation in this study. The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported.
The child’s health should be followed up until 4 weeks after birth.
For a pregnancy in the partner of a male study patient, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE.
Only those pregnancies with abnormal outcome need to be reported as SAEs. All pregnancies 
must be reported on additional pregnancy report forms provided to the site (paragraph added 
by amendment 4, see section 15.2.1.19).
9.6.3
Further safety
9.6.3.1
Laboratory evaluations
Safety laboratory analyses will be performed locally according to the schedule summarized in 
the flow charts of Section 9.1.

Complete blood count: Hemoglobin, hematocrit, platelet count, red blood cell count 
(RBC), white blood cell count (WBC). WBC must include differential including 
neutrophil, lymphocyte, monocyte, basophil, and eosinophil counts (bullet point 
modified by amendment 4, see section 15.2.1.19).

Electrolyte and chemistry panel: sodium, potassium, chloride, calcium (total, 
corrected, or ionized), phosphorus, glucose (fasting or random/unspecified), AST, 
ALT, gamma-glutamyl transferase (GGT), bilirubin (total and direct), ALP, uric acid, 
total protein, albumin, lipase, amylase, lactic dehydrogenase (LDH), blood urea 
nitrogen (BUN) or urea, and creatinine (bullet point modified by amendment 4, see 
section 15.2.1.19).

Post OS maturation, only AST, ALT, total bilirubin and creatinine are required; 
other chemistry laboratory parameters can be performed at the investigator’s discretion 
but do not need to be reported unless related to an SAE or a drug-related AE of 
Grade ≥ 3 (bullet point added by amendment 6, see section 15.4.1.1).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  100 of 269

Coagulation panel: PTT or aPTT or PTT ratio, and PT or PT-INR or PT ratio.

Urinalysis: Only dipstick test will be done, and complete urinalysis (e.g. microscopic 
analysis of the urine sediment) will only be done if the dipstick results are indicative 
or clinically indicated.

Serum pregnancy test in WOCBP. Test should be repeated at least every 4 weeks until 
safety follow-up visit. Postmenopausal women who have not had periods for more 
than 1 year without an alternative medical cause or surgically sterilized women will 
not be required to undergo a serum pregnancy test (this information should be 
recorded under medical history on the CRF).

eGFR according to the MDRD abbreviated formula (see Appendix 16.7).
An isolated laboratory abnormality that meets the criteria for a CTCAE Grade 4 classification 
is not reportable as an SAE, unless the investigator assesses that the event meets standard 
International Council for Harmonization (ICH) criteria for an SAE (see SAE definition in 
Section 9.6.1.1) (updated by amendment 2, see section 15.1.1.26). All laboratory 
abnormalities, including CTCAE Grade 4 abnormalities, will be documented on the 
laboratory CRF.
9.6.3.2
Physical examination 
Physical examinations will be performed according to the schedule summarized in the flow 
charts of Section 9.1. Clinically significant abnormal physical examination findings are 
recorded either as medical history or as AEs (see Section 9.6.1.1).
9.6.3.2.1
Complete physical examination
Complete physical examination of all organ systems includes:

General appearances

Skin

Eyes

Ears, nose and throat

Head and neck

Pulmonary/thoracic

Cardiovascular

Abdomen

Lymph nodes

Musculoskeletal system (including extremities and spine)

Genito-urinary system
If indicated by the patient’s history, the following will be examined by specialists, if 
applicable:


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  101 of 269

Gynecological organs 

Rectum
9.6.3.2.2
Brief physical examination
Brief physical examination includes, but is not limited to, review of organ systems and 
physical areas of symptomatic concern or investigator’s degree of suspicion for any 
abnormality. After Cycle 1, brief physical examinations are only mandatory on Day 1 of each 
cycle and are optional as per local practice at Day 8 and Day 15 visits.
9.6.3.3
ECOG Performance Status
ECOG PS will no longer be collected after OS maturation (sentence added by 
amendment 6, see section 15.4.1.1).
Change of ECOG PS will be measured for safety reason; grading definitions are given in 
Appendix 16.1. ECOG PS will be assessed at prescreening, full screening, on Day 1 of each 
cycle and at safety follow-up visit (see flow chart in Section 9.1).
9.6.3.4
Vital signs
Vital signs will no longer be collected after OS maturation apart from body weight for 
dose calculation (sentence added by amendment 6, see section 15.4.1.1). 
Body weight/height, heart rate, blood pressure, body temperature, and respiratory rate will be 
assessed according to the schedule summarized in the flow chart of Section 9.1. Height is 
measured in centimeters (cm) and obtained only at full screening. Body weight will be 
measured in kilograms (kg), measurement units 0.1 kg, and should be obtained without shoes. 
If clinically indicated (e.g. excessive weight loss), it is at the investigator’s discretion to 
perform these measurements more frequently. Blood pressure has to be measured in a 
consistent manner throughout the study (preferably using a manual cuff at the same arm with 
the patient sitting for 5 min before the measurement). Any clinically relevant measurements 
or changes are to be reported as AEs (e.g. weight gain or loss, hypertension, tachycardia, 
bradycardia, etc.).
9.6.3.5
12-lead ECG
ECGs will no longer be performed after OS maturation (sentence added by amendment 6, 
see section 15.4.1.1). 
12-lead ECGs will be performed according to the schedule summarized in the flow chart of 
Section 9.1. The overall interpretation of the ECG (normal/abnormal, clinical relevance) and 
the ECG diagnosis will be documented in the source documents and on the CRF. This review 
should be completed by a qualified physician and signed and dated at the time of review.
9.6.3.6
Cardiac function
Cardiac function test is mandatory. It will be measured by EchoCG or MUGA scan at full 
screening and on C2D1, C4D1, and afterwards at the investigator’s discretion based on 
clinical need (see flow chart in Section 9.1). During treatment, cardiac function test can be 
done up to 7 days before study drug administration. EchoCG shall be performed instead of 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  102 of 269
MUGA when local regulations do not permit the use of MUGA as requested per protocol 
schedule (paragraph modified by amendment 4, see section 15.2.1.19).
9.6.3.7
Ophthalmologic examinations
Corneal epitheliopathy has been identified as a TEAE of special interest for which a causal 
relationship with anetumab ravtansine has been deemed probable by the investigators in Phase 
I trial. A detailed ophthalmologic examination (visual acuity [BCVA according to ETDRS, or 
Snellen, or Landolt C or other charts], IOP, dry eye test [Schirmer test] and slit lamp) will be 
done for all patients during full screening within 3 weeks before the start of study treatment 
(see flow chart in Section 9.1). For patients treated in the anetumab ravtansine arm, visual 
acuity test and slit lamp examination will be repeated before infusion in every cycle except 
C1D1 (and every other cycle after OS maturation), and at safety follow-up visit, or more 
frequently at investigator’s and ophthalmologist/optometrist’s discretion (e.g. for patients 
with corneal epitheliopathy ≥ Grade 2, ophthalmologic examination will occur at least at 
every cycle until resolution of corneal epitheliopathy to Grades 0 or 1) (important to refer to 
Table 7–5 and Table 7–6). IOP measurement is to be repeated during anetumab ravtansine 
therapy if the patient receives steroid eye drops as treatment for corneal epitheliopathy; dry 
eye (Schirmer) test may be repeated during treatment at investigator’s discretion (e.g. in case 
of eye dryness during anetumab ravtansine therapy). During treatment, ophthalmologic 
examination can be done up to 7 days before anetumab ravtansine infusion (paragraph 
modified by amendments 2 and 6, see section 15.1.1.5, 15.1.1.10 and 15.4.1.1).
In certain countries, an optometrist or equivalent specialist may be licensed to perform the eye 
examinations as detailed above; as per ICH-GCP, at the Principal Investigator’s discretion, a 
chosen specialist can perform required eye exams (added by amendment 2, see 
section 15.1.1.10).
9.7
Other procedures and variables
9.7.1
Biomarkers
Preclinical and Phase I evidence suggests that mesothelin expression (or expression level 
above a certain threshold) in human tumors may be required for binding, internalization, and 
anti-tumor activity of anetumab ravtansine. All patients will have formalin-fixed, paraffin-
embedded (FFPE) tumor samples available for IHC determination of mesothelin expression at 
prescreening as a potential predictive biomarker (see also flow chart in Section 9.1). In the 
absence of archival tissue, fresh biopsies may be used if deemed safe by the investigator and 
there is no additional risk for the patient in the investigator’s judgement. Only patients whose 
tumors express mesothelin at membrane staining intensity of moderate and stronger in at least 
30% of viable tumor cells will participate further in this study (modified by amendments 2 and 
5, see section 15.1.1.6 and 15.3.1.2). Mesothelin levels will be determined using a validated 
IHC assay (clone SP74).
In addition to obligatory measurement of mesothelin expression levels, plasma levels of 
soluble mesothelin at baseline (whole blood on C1D1 pre-dose) will be studied to evaluate 
whether plasma mesothelin levels may correlate with response rate and be of predictive value. 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  103 of 269
Biomarker plasma (from whole blood) will be collected on C1D1 pre-dose, on C6D1, and at 
safety follow-up visit to analyze circulating tumor DNA, too.
For patients who provide optional consent, exploratory biomarker analysis may also be 
performed using additional fresh or archival tumor tissue to determine alterations in tumor-
associated genes and to perform gene expression analysis. If additional archival tissue is 
available after randomization, tissue should be sent for analysis to the central laboratory. 
Fresh tumor tissue should be collected after a local assessment of response (complete 
response [CR] or partial response [PR]) for patients who consent to this procedure. The 
exploratory biomarkers may include, but are not limited to, DNA sequencing of tumor-
associated genes and gene expression profiling. Next generation sequencing (NGS), and 
RNA, protein or miRNA expression analysis may be performed. The analysis of changes in 
the genomic and expression profile (e.g. mesothelin expression) in tumor tissue over time on 
drug treatment may elucidate the underlying molecular mechanism of drug response and 
intrinsic and acquired resistance to anetumab ravtansine (paragraph modified by 
amendment 4, see section 15.2.1.11).
In addition to the biomarkers listed above, other biomarkers deemed relevant to gain further 
knowledge about the pathomechanism of the disease or about the drug (i.e. mode of action-
related effect or safety of the drug) may be measured, based on newly emerging data from 
other ongoing studies and/or literature data (clarified by amendment 5, see section 15.3.1.7).
Details on the collection, processing, storage and shipment of biomarker samples will be 
provided in separate documents (e.g. sample handling sheets or lab manual).
9.7.2
Immunogenicity
Serum samples for immunogenicity assessment should be collected for patients in the 
anetumab ravtansine arm on C1D1, C2D1, C3D1, C6D1, C9D1 and on Day 1 of every 
3 cycles thereafter (see flow charts in Section 9.1). On all days, serum sample for 
immunogenicity assessment should be collected before infusion. Immunogenicity assessment 
will include a determination of binding and neutralizing anti-drug antibodies (ADAs and 
NABs, respectively) and a titer determination.
9.8
Appropriateness of procedures / measurements
The efficacy assessments used in the study include those considered SoC to evaluate anti-
tumor activity in patients with advanced or metastatic MPM. 
The safety assessments are appropriate and standard to monitor safety and assess toxicity.
Appropriateness of PFS as primary endpoint. OS is generally recognized as the gold 
standard for establishing treatment efficacy in late-stage cancer. However, MPM is a rare 
disease. The 10.5 patients/month accrual rate with 8-months ramp-up estimated as feasible in 
this study would be insufficient to support the sample sizes needed to reliably power an OS 
study in a time period reasonable for a Phase II study in the context of an unmet medical need. 
PFS represents a widely-used and accepted clinical endpoint achievable in the present context. 
Accordingly, PFS represents an appropriate primary endpoint in this study.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  104 of 269
Appropriateness of mRECIST criteria. RECIST 1.1 criteria, designed to assess spherically 
shaped solid tumors, may be an unreliable method in the context of the lens/crescent-shaped 
pleural lesions found in MPM (29). mRECIST criteria were designed and validated to 
measure the specific context of MPM (21, 30). Accordingly, mRECIST criteria are 
appropriate for the study context.
Appropriateness of forced vital capacity measurement removed by amendment 2
Appropriateness of PROs. The Lung Cancer Symptom Scale (LCSS) modified for patients 
with mesothelioma (LCSS-Meso) is a potentially appropriate instrument for clinical trials of 
mesothelioma therapies. The original model underpinning the psychometric testing of the 
LCSS was modified slightly and tested in 495 patients who had MPM. The LCSS-Meso is an 
8-item patient scale (the item evaluating hemoptysis was dropped from the original LCSS; the 
rest of the items remain the same). The findings of the validation study support the use of the 
LCSS-Meso as a sensitive instrument for serial measurement during clinical trials and yields 
reproducible results for patients with mesothelioma (31, 32).
In addition to the LCSS-Meso, the MDASI-MPM will be completed by patients (according to 
Table 9–1). The MDASI contains 13 “core” symptoms that are reported with high frequency 
or unusual severity in an outpatient cancer patient population. The measure also has 6 items 
that describe how much the symptoms have interfered with different aspects of the patient’s 
life during the past 24 h. These include: general activity, mood, walking ability, normal work 
(including both work outside the home and housework), relations with other people, and 
enjoyment of life, with 0 being “did not interfere,” and 10 being “interfered completely”. This 
questionnaire has been used extensively to measure symptoms and symptom interference in 
patients with different types of cancer. In addition to the 13 core symptom items, and the 
6 interference items, the MDASI-MPM includes 6 mesothelioma-specific and treatment-
specific items: Mesothelioma-specific symptom items are being identified through qualitative 
interviews with patients with MPM and will be used in this study. This questionnaire is 
intended to be a “fit for purpose” questionnaire to assess the symptoms most common to 
patients with locally advanced or metastatic MPM.
10.
Statistical methods and determination of sample size
10.1
General considerations
Statistical analysis will be performed using SAS version 9.2 or later; the version used will be 
specified in the SAP.
In general, continuous variables will be summarized using number of non-missing values (n), 
number of missing values, means, standard deviations, medians, maximum, minimum, and 
interquartile range.
Ordinal variables will be summarized using n, number of missing values, medians, maximum, 
minimum, and interquartile range.
Categorical variables will be summarized using n, number of missing values, and percentages.
Time-to-event variables will be summarized using Kaplan-Meier estimates.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  105 of 269
Further details on the statistical analyses will be provided in the SAP.
Reports of data updated following the cut-off for the final OS analysis will be descriptive in 
character, and may consist of listings (sentence added by amendment 6, see section 15.4.1.1).
10.2
Analysis sets
The statistical analysis sets are defined as follows:
Intent-to-treat set (ITT). All randomized patients will be included in the ITT. Patients in this 
set will be reported by treatment arm as randomized. This set will be used for patient 
characteristics, demographic, and efficacy evaluations.
PK set. All patients with at least one valid PK sample for anetumab ravtansine will be 
included in the analysis set for the anetumab ravtansine PK analysis. All patients with at least 
one valid PK sample for vinorelbine will be included in the analysis set for the PK analysis of 
vinorelbine. PK samples will be considered valid under the following conditions: known dose, 
known duration of treatment, known time of sample collection (paragraph modified by 
amendment 4, see section 15.2.1.13).
Immunogenicity set. All patients who have received at least one dose of anetumab ravtansine 
and have valid post-baseline measurement of ADAs or NABs will be included in the analysis 
set for the immunogenicity analysis of anetumab ravtansine which is defined as the 
immunogenicity set.
Safety set (SAF). All treated patients, that is, all randomized patients receiving any amount of 
any study treatment, will be included in the SAF. Patients in this set will be reported by 
treatment arm as treated. The SAF will be used for safety evaluations.
Quality of life set (QOL). All randomized patients with a non-missing LCSS-Meso 
evaluation at baseline will be included in the QOL dataset. Patients in this set will be reported 
by treatment arm as randomized. The QOL set will be used for QoL evaluations (paragraph 
clarified by amendment 4, see section 15.2.1.17).
Biomarker set (BIO). All patients evaluated for mesothelin expression at prescreening will 
be included in the biomarker set. The biomarker set will be used for biomarker analyses. 
Evaluability for analyses of efficacy and safety by biomarker status will be described in the 
SAP.
Enrolled set (ENR). All patients who signed the informed consent for any portion of the 
study including prescreening (clarified by amendment 2, see section 15.1.1.26). Enrolled 
patients will be used for patient disposition.
Further details on analysis sets will be described in the SAP.
10.3
Variables and planned statistical analyses
For missing data, please refer to Section 11.4.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  106 of 269
10.3.1
Population characteristics
Population characteristics (see Section 9.3) will be reported by summary statistics and 
listings. Further details will be described in the SAP.
10.3.2
Primary efficacy variable
Progression-free survival (PFS) is defined as time from randomization until disease 
progression (according to mRECIST for MPM, per blinded central radiology review) or 
death. Patients not experiencing death or progression will be censored at the last tumor 
assessment.
Additional details, including additional censoring rules, will be described in the SAP.
Primary efficacy analysis
The primary efficacy analysis tests the following hypotheses:
H0: In patients with advanced or metastatic MPM overexpressing mesothelin and progressed 
on 1st line platinum/pemetrexed-based chemotherapy, PFS under treatment with anetumab 
ravtansine at 6.5 mg/kg Q3W is not superior to PFS under treatment with 30 mg/m2 QW 
vinorelbine.
versus 
HA: In patients with advanced or metastatic MPM overexpressing mesothelin and progressed 
on 1st line platinum/pemetrexed-based chemotherapy, PFS under treatment with anetumab 
ravtansine at 6.5 mg/kg Q3W is superior to PFS under treatment with 30 mg/m2 QW 
vinorelbine.
These hypotheses will be tested at the primary efficacy final analysis using a 1-sided log-rank 
test at significance level of 0.0125, stratified by geographic region (RoW versus Asia) and per 
TTP on 1st line treatment (≥ 6 months versus < 6 months).
Assuming true median PFS of 3.6 months under vinorelbine treatment and constant hazards, 
the study primary hypothesis test is designed to detect a 100% prolongation of true PFS 
(median 7.2 months) in the anetumab ravtansine arm in comparison to the comparator arm 
(hazard ratio 0.5) with 90% power with a 1-sided significance level of 0.0125 (sentence 
clarified by amendment 2, see section 15.1.1.26).
The final primary endpoint analysis will be performed after approximately 117 PFS events 
have been observed. In addition to the stratified log-rank test described above, PFS will be 
summarized using Kaplan-Meier (33) estimates. Plots will be produced by treatment arm. 
Medians and Brookmeyer-Crowley (34) confidence intervals will be reported. Hazard ratios 
(anetumab ravtansine regimen/vinorelbine) will be estimated using Cox proportional hazards 
models (35) stratified by the same factors. Subgroup analyses will be performed as described 
in the SAP. Additional details will be described in the SAP.
Assumption-checking and sensitivity analyses will be performed, consistent with regulatory 
guidance on progression-free survival endpoints including Appendix 1 to the EMA guideline 
on the evaluation of anti-cancer medicinal products in man (36) and the FDA guidance on 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  107 of 269
clinical trial endpoints for the approval of non-small cell lung cancer drugs and biologics (37), 
including analyses to assess the impact of missing data; the possibility of informative 
censoring, survivorship, and selection biases; the proportional hazards assumption; and the 
impact of clinical progression and subsequent therapy. Investigator progression will be 
evaluated as a sensitivity analysis, and concordance between investigator and independent 
central review determinations will be evaluated. Details will be described in the SAP 
(paragraph modified by amendment 4, see section 15.2.1.15).
An updated analysis of PFS will be performed at the time of the final Overall Survival 
analysis (See Section 10.3.3.1). Details will be described in the SAP (paragraph added by 
amendment 4, see section 15.2.1.14).
10.3.3
Secondary variables
10.3.3.1
Secondary efficacy variables
Additional details, including additional censoring rules for time-to-event variables, will be 
described in the SAP (sentence added by amendment 2, see section 15.1.1.26).
Overall survival (OS), defined as time from randomization until death from any cause. 
Patients lost to follow-up or alive at the time of analysis will be censored at the last known 
alive date.
Forced vital capacity response rate was removed by amendment 2
Objective response rate (ORR): A patient is a responder if the patient has a confirmed tumor 
response on-study of CR or PR, as determined by the central radiological reviewer per 
mRECIST criteria. The ORR in each arm is the number of responders divided by the number 
of randomized patients.
Disease control rate (DCR): A patient has disease control if the patient has a confirmed 
tumor response of CR or PR or a tumor response of SD as determined by the central 
radiological reviewer per mRECIST criteria. The DCR in each arm is defined as the number 
of patients with disease control divided by the number of randomized patients (definition 
modified by amendment 4, see section 15.2.1.19).
Duration of response (DOR) is defined in responders as the time from documentation of 
tumor response to disease progression or death without documented progression, as 
determined by the central radiological reviewer.
Durable response rate (DRR): A durable responder is defined as a responder with a duration 
of response (CR or PR per mRECIST criteria, as determined by the central radiological 
reviewer) of 180 days or more. The DRR in each arm is the number of durable responders 
divided by the number of randomized patients (variable added by amendment 4).
Patient-reported outcomes
Subsection modified by amendment 4, see section 15.2.1.16.
Patient-reported outcomes (PROs) will be evaluated based on the MD Anderson Symptom 
Inventory-Malignant Pleural Mesothelioma (MDASI-MPM).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  108 of 269
An independent PRO review committee of PRO, statistical, and psychometric experts, blinded 
to study treatment, will conduct analyses based on regulatory feedback, data from 
independent studies, and pooled study data from this study following database lock at primary 
analysis, to support validation of the MDASI-MPM instrument and determine key definitions 
and details as described below.
Time to worsening of symptoms characteristic of mesothelioma is defined in patients 
evaluable for assessing worsening of symptoms, as the time from randomization until the 
first worsening of symptoms characteristic of mesothelioma. Worsening must be confirmed 
by a second MDASI-MPM assessment. Patients who died, were lost to follow-up, or ended 
MDASI-MPM assessments without confirmed worsening of symptoms will be censored at the 
date of their last MDASI-MPM assessment with a non-missing total subset score.
Time to worsening of pain is defined in patients evaluable for assessing worsening of pain, 
as time from randomization until the first worsening of pain. Worsening must be confirmed 
by a second MDASI-MPM assessment. Patients who died, were lost to follow-up, or ended 
MDASI-MPM assessments without confirmed worsening of pain will be censored at the date 
of their last MDASI-MPM assessment with a non-missing pain score.
Improvement rate of symptoms characteristic of mesothelioma is defined in each 
randomized study arm as the number of patients with confirmed improvement of symptoms 
characteristic of mesothelioma, divided by the number of patients evaluable for 
improvement of symptoms characteristic of mesothelioma. Improvement in each patient 
must be confirmed by a second MDASI-MPM assessment.
Improvement rate of pain is defined in each randomized study arm as the number of patients 
with confirmed improvement of pain, divided by the number of patients evaluable for 
improvement of pain. Improvement in each patient must be confirmed by a second MDASI-
MPM assessment.
For analyses of the above PRO endpoints, the following terms will be defined by the 
independent blinded PRO review committee:

Worsening of symptoms characteristic of mesothelioma as measured by the 
MDASI-MPM questionnaire total score of the subset of symptoms. 

Improvement of symptoms characteristic of mesothelioma as measured by the 
MDASI-MPM questionnaire total score of the subset of symptoms.

Worsening of pain as measured by the “pain at its worst” item of the MDASI-MPM.

Improvement of pain as measured by the “pain at its worst” item of the MDASI-
MPM.
For each term, the independent blinded PRO review committee will determine the specific 
change from baseline constituting improvement or worsening, and will define the minimum 
and/or maximum baseline score and other criteria constituting evaluability to determine 
improvement or worsening for the respective term.
For symptoms characteristic of mesothelioma, the independent blinded PRO review 
committee will also define the applicable subset of MDASI-MPM items, and the calculation 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  109 of 269
algorithm to calculate the total subset score on that subset at each assessment, including 
handling of missing or partially missing data.
The independent blinded PRO review committee and its analyses will be further described in 
the Independent Blinded PRO Review Committee Charter and/or the Independent Blinded 
PRO Review Analysis Plan.
Secondary efficacy analysis
Subsection modified by amendment 4, see section 15.2.1.18 and 15.2.1.14.
For regulatory label claim purposes, to preserve the overall Type I error rate, secondary 
endpoint hypothesis testing will be performed for the following key secondary efficacy 
variables in the event of primary endpoint superiority, according to the following hierarchy:

Overall survival

Time to worsening of symptoms characteristic of mesothelioma

Time to worsening of pain

Improvement rate of symptoms characteristic of mesothelioma

Improvement rate of pain
Secondary OS will be evaluated separately in a 2-stage group sequential procedure as further 
described below, with final analysis expected to occur after the primary endpoint analysis. 
Final analysis for duration of response and durable response rate will be performed at the time 
of the final OS analysis. An interim analysis of these variables will be performed at time of 
the final PFS analysis. Details will be described in the SAP. 
Final analysis for other secondary variables will occur at the same time as the primary 
endpoint analysis. To preserve the validity of the secondary endpoint hierarchy and control of 
overall study-wide secondary Type I error, superiority for secondary endpoint hypothesis tests 
ranking below OS in the hierarchy cannot be declared for regulatory label claim purposes 
until OS hypothesis testing succeeds. Accordingly, unless OS superiority is found at the 
interim OS analysis, the hypothesis testing outcome of endpoints ranking below it will not be 
fully effective, and any superiority for these endpoints cannot be declared for regulatory label 
claim purposes, until the outcome of the OS hypothesis test is determined and OS superiority 
found at the final OS analysis. An updated analysis of these secondary variables will occur at 
time of the final OS analysis. 
The secondary efficacy OS analysis tests the following hypotheses:
H0: In patients with advanced or metastatic MPM overexpressing mesothelin and progressed 
on 1st line platinum/pemetrexed-based chemotherapy, OS under treatment with anetumab 
ravtansine at 6.5 mg/kg Q3W is not superior to OS under treatment with 30 mg/m2 QW 
vinorelbine.
versus 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  110 of 269
HA: In patients with advanced or metastatic MPM overexpressing mesothelin and progressed 
on 1st line platinum/pemetrexed-based chemotherapy, OS under treatment with anetumab 
ravtansine at 6.5 mg/kg Q3W is superior to OS under treatment with 30 mg/m2 QW 
vinorelbine.
These hypotheses will be tested using a 2-stage group sequential hypothesis test procedure. 
Each stage will utilize a 1-sided log-rank test, stratified by geographic region (RoW versus 
Asia) and per TTP on 1st line treatment (≥ 6 months versus < 6 months).
Assuming true median OS of 9.6 months under vinorelbine treatment and constant hazards, 
the 2-stage group sequential hypothesis test is designed to detect a 60% prolongation of true 
OS (median 15.4 months) in the anetumab ravtansine arm in comparison to the comparator 
arm with an overall 80% power and an overall 1-sided significance level of 0.025 (hazard 
ratio 0.625) (modified by amendment 2, see section 15.1.1.1).
The interim OS analysis will be performed at the time of the final primary endpoint (PFS) 
analysis, when an estimated 80 OS events will be observed. If the study is not stopped for 
superiority at the interim analysis, the final OS analysis will occur when approximately 
159 OS events have been observed. A Lan-Demets alpha spending function (38) with 
O’Brien-Fleming boundaries (39) will be used, based on actual events at the time of the 
interim analysis. Approximately 0.00158 alpha is estimated to be spent at the interim analysis 
and 0.02342 at the final if 80 OS events are observed at the interim analysis. The actual alpha 
levels will be based on the actual number of events included in the interim analysis. The 
group sequential testing procedure is further described in Section 10.4, and additional details 
will be described in the SAP (paragraph modified by amendment 2, see section 15.1.1.1).
At each analysis, OS will also be evaluated be summarized using Kaplan-Meier (33) 
estimates. Plots will be produced by treatment arm. Medians and Brookmeyer-Crowley (34) 
confidence intervals will be reported.
Other key secondary time-to-event variables (time to worsening of symptoms characteristic of 
mesothelioma, time to worsening of pain) will be tested using a 1-sided log-rank test stratified 
by geographic region (RoW versus Asia) and per TTP on 1st line treatment (≥ 6 months versus 
< 6 months), with a 1-sided significance level of 0.025. In addition, all other secondary time-
to-event variables (time to worsening of symptoms characteristic of mesothelioma, time to 
worsening of pain, DOR) will be summarized using Kaplan-Meier (33) estimates. Plots will 
be produced by treatment arm. Medians and Brookmeyer-Crowley (34) confidence intervals 
will be reported. Further details will be described in the SAP.
Select secondary response rate variables (improvement rate of symptoms characteristic of 
mesothelioma, improvement rate of pain) will be tested using a Cochran-Mantel-Haenszel test 
(40) stratified by geographic region (RoW versus Asia) and per TTP on 1st line treatment 
(≥ 6 months versus < 6 months), with a 1-sided significance level of 0.025. In addition, all 
secondary response rate variables (ORR, DCR, DRR, improvement rate of symptoms 
characteristic of mesothelioma, improvement rate of pain) will be summarized by treatment 
arm including number of patients (N), response rates, and Clopper-Pearson (41) exact 
binomial confidence intervals. In addition, each response category will be summarized. 
Further details will be described in the SAP.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  111 of 269
Sensitivity analyses will be performed, including analyses to assess the impact of missing data 
and the possibility of survivorship and selection biases. Further details will be described in the 
SAP.
Further details on secondary efficacy analyses will be described in the SAP.
10.3.3.2
Other efficacy variables

MDASI-MPM symptom interference score

LCSS-Meso total score

LCSS-Meso 3 summary item score
Other efficacy variables will be summarized descriptively. Plots of mean MDASI-MPM 
symptom interference score, LCSS-Meso total score, and LCSS-Meso 3 summary item score 
will be produced over time.
The complete list of variables to be analyzed for this study will be provided in the SAP.
10.3.3.3
Safety variables
Safety variables will include AEs, infusion-related reactions (IRRs), laboratory changes 
(hematology, clinical chemistry and clinical urinalysis), abnormal findings in physical 
examination, changes in ECOG PS, changes in vital signs (weight, blood pressure, heart rate, 
respiratory rate, and body temperature), changes in ECG, changes in cardiac function test 
(EchoCG or MUGA scan) and changes in ophthalmologic examinations (visual acuity and slit 
lamp examination, IOP and Schirmer test if repeated). All AEs whether considered drug-
related or not, will be reported on the CRF with a diagnosis, start/stop dates, action taken, 
whether treatment was discontinued, any corrective measures taken, outcome and other 
possible causes. For all events, the relationship to treatment and the intensity of the event 
according to CTCAE v4.03 will be determined by the investigator, using the terms and 
definitions given in Section 9.6.1.2 (paragraph modified by amendments 2 and 4, see section 
15.1.1.3 and 15.2.1.19).
Definition of treatment-emergent safety events
The treatment period for safety purposes is defined as the start of study treatment until 
30 days after the last day of study treatment.
Treatment-emergent safety events (e.g. TEAEs) are safety events which arise or worsen 
during the treatment period.
Additional details will be described in the SAP.
Safety analysis
The final safety analysis will be performed at the time of the final primary endpoint analysis.
An updated safety analysis will be performed at the time of the final analysis of the secondary 
endpoint OS.
All randomized patients who receive at least 1 dose of treatment will be valid for safety 
analysis.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  112 of 269
All observations pertinent to the safety of treatment will be recorded on the CRF and included 
in the Clinical Study Report (CSR).
Descriptive summary tables will be presented for all safety parameters. All TEAEs, treatment-
emergent and hematological/biochemical toxicities based on laboratory measurements, as 
well as drug-related AEs and SAEs, will be graded by CTCAE v4.03 and categorized by 
MedDRA.
Results of physical examination, vital signs, ECG, and other safety variables as described in 
the SAP will be summarized. The number (%) of patients who discontinue study drug due to 
AE or for whom a dose reduction or interruption is needed due to AE will also be 
summarized.
10.3.4
Other variables
10.3.4.1
Pharmacokinetic variables
PK data for all or selected analytes collected during the study will be analyzed at the end of 
study using nonlinear mixed effects models. Mixed effects models, or population type 
models, describe the relationship between e.g. dose, time and pharmacological observations 
such as plasma drug concentrations. Both structural and random effects are involved in this 
relationship. A population PK model will be developed to characterize the PK of all or 
selected analytes over the entire treatment period using individual drug concentration data. 
Individual PK parameters of all or selected analytes will be calculated. Furthermore, 
pharmacokinetic / pharmacodynamic modeling using population approaches to relate 
parameters of clinical safety and efficacy response with plasma concentrations of all or 
selected analytes will be investigated.
The details of the modeling analysis will be described in a separate Modelling and Simulation 
(M&S) Analysis Plan and the results will be reported in a separate M&S Report.
Plasma concentration data for all analytes will be listed in the CSR.
10.3.4.2
Biomarker variables
An analysis of mesothelin expression levels in all patients evaluated for mesothelin 
expression will be performed. For randomized patients, biomarker parameters that may 
predict response, e.g. mesothelin expression levels in tumors and in plasma, may be analyzed 
by patient, summarized by mesothelioma subtype, and associated with tumor response using 
descriptive statistics, if appropriate. The association between biomarker and selected safety, 
efficacy, or PK parameters may be graphically displayed. Further exploratory statistical 
analyses may be performed. Biomarker variables and analyses will be further described in the 
SAP and/or in a separate document (clarified by amendment 4, see section 15.2.1.19).
10.3.4.3
Immunogenicity variables
For both ADAs and NABs, the number and percent of patients with the positive 
immunogenicity result will be summarized by time point. The individual patient’s 
immunogenicity results for ADAs and NABs (positive or not applicable) will be listed by 
time point for each patient. Further details may be described in the SAP.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  113 of 269
10.4
Determination of sample size
The sample size is primarily designed to support hypothesis test of the primary endpoint PFS, 
and to provide a limited formal evaluation of secondary endpoint OS (paragraph modified by 
amendment 2, see section 15.1.1.1).
Power calculations were performed using East 6.3 software.
10.4.1
Primary endpoint progression-free survival
The sample size is designed to test the following hypotheses for primary endpoint PFS:
H0: In patients with advanced or metastatic MPM overexpressing mesothelin and progressed 
on 1st line platinum/pemetrexed-based chemotherapy, PFS under treatment with anetumab 
ravtansine at 6.5 mg/kg Q3W is not superior to PFS under treatment with 30 mg/m2 QW 
vinorelbine.
versus
HA: In patients with advanced or metastatic MPM overexpressing mesothelin and progressed 
on 1st line platinum/pemetrexed-based chemotherapy, PFS under treatment with anetumab 
ravtansine at 6.5 mg/kg Q3W is superior to PFS under treatment with 30 mg/m2 QW 
vinorelbine.
These hypotheses will be tested using a 1-sided log-rank test, stratified by geographic region 
(RoW versus Asia) and per TTP on 1st line treatment (≥ 6 months versus < 6 months).
Assuming median PFS of 3.6 months under vinorelbine treatment and constant hazards and a 
2:1 treatment:comparator randomization, a 100% prolongation of PFS in the anetumab 
ravtansine arm in comparison to the comparator arm can be detected at a 1-sided significance 
level of 0.0125 with 90% power, with a single-stage trial with approximately 117 PFS events 
(hazard ratio 0.5). Assuming a maximum accrual rate of 12.5 patients/month (25 patients/ 
month prescreened with 50% overall pre-screening and screening failure rate) with 6-month 
linear accrual ramp-up, and a 3.4%/month dropout (loss to follow-up and unevaluable for 
tumor assessment) rate, 210 patients be will accrued in approximately 19.8 months and reach 
endpoint maturation of 117 events in approximately 22.0 months. The total number of 
unevaluable/dropout patients over the duration of the study through final PFS analysis is 
estimated at 33 (15.7%) (paragraph modified by amendments 2 and 4, see section 15.1.1.2 
and 15.2.1.2).
10.4.2
Secondary endpoint overall survival
The sample size is also designed to test the following hypotheses in secondary endpoint OS 
(modified by amendment 2, see section 15.1.1.2):
H0: In patients with advanced or metastatic MPM overexpressing mesothelin and progressed 
on 1st line platinum/pemetrexed-based chemotherapy, OS under treatment with anetumab 
ravtansine at 6.5 mg/kg Q3W is not superior to OS under treatment with 30 mg/m2 QW 
vinorelbine.
versus


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  114 of 269
HA: In patients with advanced or metastatic MPM overexpressing mesothelin and progressed 
on 1st line platinum/pemetrexed-based chemotherapy, OS under treatment with anetumab 
ravtansine at 6.5 mg/kg Q3W is superior to OS under treatment with 30 mg/m2 QW 
vinorelbine.
Assuming true median OS of 9.6 months under vinorelbine treatment and constant hazards, a 
60% prolongation of true OS (median 15.4 months) in the anetumab ravtansine arm in 
comparison to the comparator arm (median 9.6 months) can be detected with an overall 80% 
power and an overall 1-sided significance level of 0.025 (hazard ratio 0.625), with a 2-stage 
group sequential test with a total of 159 events (modified by amendment 2, see 
section 15.1.1.1).
The OS analysis assumes the same accrual as for primary endpoint PFS, with 210 patients 
accrued in approximately 19.8 months. A 0.3% per month loss to OS follow-up rate is 
assumed. An interim OS analysis will be performed at the time of the final primary endpoint 
(PFS) analysis at an estimated 22 months from first patient randomized, when an estimated 80 
OS events will have been observed. If the study is not stopped for superiority at the OS 
interim analysis, the final OS analysis will occur after approximately159 OS events have been 
observed, at approximately 41.3 months from first patient randomized. A Lan-Demets alpha 
spending function (38) with O’Brien-Fleming boundaries (39) will be used, based on actual 
events at the time of the interim analysis. Under the null hypothesis of no anetumab 
ravtansine OS superiority, approximately 0.00158 alpha is estimated to be spent at the interim 
analysis and 0.02342 at the final (0.025 alpha overall). Under the alternative hypothesis of 
60% OS improvement under anetumab ravtansine treatment, the chance of finding superiority 
is estimated at 16.9% at the interim analysis and 63.2% at the final analysis (80% power 
overall). The total number of patients lost to OS follow-up over the duration of the study 
through final OS analysis is estimated at 10 (4.8%) (paragraph modified by amendment 2, see 
section 15.1.1.2).
10.5
Planned interim analyses
An interim analysis for OS will be performed, by the sponsor, at the same time as the final 
primary endpoint analysis, as described in Section 10.4 (clarified by amendment 2, see 
section 15.1.1.26).
In addition, the study will be monitored periodically for safety by a Data Monitoring 
Committee (DMC). Further details will be described in the DMC charter.
11.
Data handling and quality assurance
11.1
Data recording
The data collection tool for this study will be a validated electronic data capture (EDC) 
system called RAVE. Patient data necessary for analysis and reporting will be 
entered/transmitted into a validated database or data system (e.g. TOSCA; SAS).
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based EDC software system RAVE, which Bayer has licensed 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  115 of 269
from Medidata Solutions Worldwide. RAVE has been validated by Medidata Solutions 
Worldwide and Bayer for use in its clinical studies. RAVE allows for the application of 
software logic to set-up data entry screens and data checks to ensure the completeness and 
accuracy of the data entered by the site personnel. Bayer extensively applies the logic to 
ensure data are complete and reflect the clinical data requirements of the study. Data queries 
resulting from the application of the software logic are resolved by the site personnel. The 
data are stored at a secure host facility maintained by Medidata Solutions Worldwide and 
transferred on a periodic basis to Bayer's internal computer system via a secure Virtual Private 
Network.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software. All internal Bayer and external investigator site personnel seeking access 
must go through a thorough RAVE training process before they are granted access to RAVE 
for use in Bayer's clinical studies. Training records are maintained. Study-specific RAVE 
training will be provided at the investigator’s meetings, and a study-specific manual (CRF 
completion guidelines) will be provided to all sites.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made. This information is available both at the investigator’s site and at Bayer. Data 
entries made in the RAVE EDC screens are supported by source documents maintained for all 
patients enrolled in this study.
Source documentation
The site must implement processes to ensure availability of all required source 
documentation. A source document checklist (not part of this protocol) will be used at the site 
to identify the source data for key data points collected and the monitor will work with the site 
to complete this.
It is the expectation of the sponsor that all data entered into the CRF has source 
documentation available at the site.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  116 of 269
Data recorded from prescreening and full screening failures
At minimum, the following data should be recorded in the CRF:

Demographic information (patient number; year of birth / age; sex; if applicable race / 
ethnicity)

Disease characteristics (added by amendment 4, see section 15.2.1.19)

Date of all informed consent(s)that were signed

Relevant inclusion/exclusion criteria for prescreening and for full study (if available)

Reason for premature discontinuation

Result of mesothelin overexpression level testing (if available)

Date of last visit.
These data will be transferred to the respective database.
For prescreening failures who experienced an SAE related to prescreening procedures, and for 
full screening failures who had signed consent for full study and who experienced an SAE, 
the following data should be collected in the CRF in addition to the data specified above:

All information related to the SAE such as: 
o
The SAE itself
o
Concomitant medication
o
Medical history
o
Other information needed for SAE complementary page.
11.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements. When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete. 
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes). 

Safety and rights of patients are being protected.

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol).

Any other study agreements, GCP, and all applicable regulatory requirements are met.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  117 of 269
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
11.3
Data processing
Data will be collected as described in Section 11.1. Clinical data management will be 
performed in accordance with applicable sponsor’s/CRO’s standards and data cleaning 
procedures. This is applicable for data recorded on CRF as well as for data from other sources 
(e.g. IxRS, laboratory, ECG, adjudication committees).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
After its initial release for biometrical analysis, the clinical database is planned to be re-
opened for the inclusion of the following additional data: PK data, antibody data.
11.4
Missing data
For primary endpoint PFS, strategies to reduce the dropout rate (loss to follow-up and 
unevaluable for tumor assessment) include:

Seriousness of disease condition results in patients highly motivated to continue 
treatment and assessments.

Study regimen is continued indefinitely, during clinical benefit. Because the primary 
endpoint of progression is a well-accepted key indicator of presence of clinical benefit, 
use of progression or death as primary endpoint tends to encourage patients to 
continue coming to the clinic for continued treatment until the endpoint is met.

Patients who must withdraw from treatment early (e.g. due to toxicity) are required to 
continue to come to the clinic for tumor assessments until documented radiological 
progression per central review.

Use of real-time central review following investigator finding of progression provides 
consistent read quality, and reduces likelihood of censoring in the event investigator 
finds documented progression but central review does not, and increases likelihood 
patient will continue tumor assessments.

Requirement of real-time review of screening tumor assessments assures patients have 
measurable disease per central reviewer prior to randomization, reducing unevaluable 
rate.

Quality control and training program reduces likelihood of spoiled/unusable imaging.

Frequent imaging visit schedule (every 6 weeks during the first 6 months, every 
9 weeks until the end of year 2, and every 12 weeks thereafter) reduces likelihood of 
dropout prior to documented progression.
Strategies to reduce the dropout rate for secondary endpoints include:

For OS, every effort will be made to continue contacting study patients in long-term 
follow-up and to determine death status and dates. A survival sweep contact will be 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  118 of 269
conducted at the time of PFS final analysis and prior to OS final analysis to ensure that 
long-term follow-up data is current (paragraph modified by amendment2, see section 
15.1.1.26).

For other secondary efficacy endpoints, patients will continue to be assessed during 
active follow-up to mitigate bias due to differences in treatment withdrawal timing on 
results. Tumor response-related endpoints will be conducted by central review, and 
centrally determined measurable disease will be required prior to randomization to 
minimize inclusion of unevaluable patients.

For all endpoints and study data, clinical data will be closely monitored by strict 
clinical monitoring and data management. Missing data will trigger queries and 
follow-up. Active training of study personnel on study and data procedures will stress 
the importance of complete data.
Strategies to reduce impact of missing data when present include:

Time-to-event analysis approaches maximize available data and reduce impact of 
censoring, with unbiased results when censoring is uninformative.

Study is powered assuming a ~16% total dropout rate (3.4% per month) for PFS and a 
~5% total (0.3% per month) dropout rate for OS, ensuring a moderate dropout will not 
degrade reliability of study results (paragraph modified by amendment 2, see section 
15.1.1.2).

Analyses will ensure conservative treatment of missing values. For tumor response 
endpoints, missing assessments will count as non-responders (modified by 
amendment 2, see section 15.1.1.3). For non-time-to-event disease symptom and QoL 
endpoints, time point analysis will include patients present both at baseline and at the 
time point, mitigating survivorship bias (bullet point clarified by amendment 4, see 
section 15.2.1.17).
11.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or 
a designated CRO’s) QA unit may arrange to conduct an audit to assess the performance of 
the study at the study site and of the study documents originating there. The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  119 of 269
11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (hospital) files including tumor images will be archived according to local regulations 
and in accordance with the maximum period of time permitted by the hospital, institution or 
private practice. Where the archiving procedures do not meet the minimum timelines required 
by the sponsor, alternative arrangements must be made to ensure the availability of the source 
documents for the required period.
The central reading institution will archive the data for at least 15 years.
The investigator/institution notifies the sponsor if the archival arrangements change (e.g. 
relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due but not limited to the 
following reasons: 

If risk-benefit ratio becomes unacceptable owing to, for example,
o
Safety findings from this study (e.g. SAEs) 
o
Results of parallel clinical studies
o
Results of parallel animal studies 
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity). 

If the study conduct (e.g. recruitment rate; dropout rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.
The investigator has the right to close his/her center at any time.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  120 of 269
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties. Final decision 
on the closure must be in writing.

All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.

All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor. The investigator will retain all other documents until 
notification is given by the sponsor for destruction.

In the event of a partial study closure, ongoing patients, including those in post-study 
follow-up, must be taken care of in an ethical manner.
Details for individual patient's withdrawal can be found in Section 6.3.1.
13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
Sponsor’s medical expert 
Study medical expert was changed by amendment 4.
Name: 
Address: 
Telephone:
Mobile:
Co-ordinating investigators 
Name: 
Title: 
Address:
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  121 of 269
Name: 
Title: 
Address:
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate. This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g. health authority, ethics committee, sponsor) 
before patient recruitment may start at the respective center. Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.
The global sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
External data evaluation bodies
Data Monitoring Committee (DMC)
A DMC will be established which will closely interact with the sponsor’s Global 
Pharmacovigilance (GPV) department in order to assess all safety-relevant information. 
The DMC will include at least 3 members, including an independent Statistician and 
Oncologist. Safety review meetings will be held periodically as per separate DMC Charter. 
Enrollment to the study will continue throughout the scheduled meetings of the DMC. 
Decisions on trial termination, amendment, or cessation of patient recruitment based on 
risk/benefit assessment will be made after recommendations from the DMC have been 
assessed by the sponsor.
Steering Committee (SC)
An SC will support the sponsor during the conduct of the study in all aspects of safety and 
efficacy.
PPD
PPD
PPD
PPD
PPD
PPD


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  122 of 269
Decisions on continuation, trial termination, amendment, or cessation of patient recruitment 
based on risk/benefit assessment will be made after recommendations from the SC have been 
assessed by the sponsor.
Central radiological evaluation
Radiological evaluation of contrast-enhanced CT/MRI scans will be performed by an 
independent blinded central review. Further details will be provided in a separate Image 
Review Charter (IRC).
Central laboratory
Biomarker, PK, immunogenicity, mesothelin expression, and CYP2D6 pharmacogenetic tests 
will be performed centrally. Further details will be provided in the Laboratory Manual.
Independent blinded PRO review committee
An independent PRO review committee of PRO, statistical, and psychometric experts, blinded 
to study treatment, will conduct analyses based on regulatory feedback, data from 
independent studies, and pooled study data from this study following database lock at primary 
analysis, to support validation of the MDASI-MPM instrument and determine key definitions 
and details regarding secondary PRO endpoints (subsection added by amendment 5, see 
section 15.3.1.7).
13.2
Funding and financial disclosure
Funding
This study will be funded by its sponsor.
Financial disclosure 
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research patients has to provide a financial disclosure 
according to all applicable legal requirements. All relevant documentation will be filed in the 
TMF.
13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
GCP guidelines and the guiding principles detailed in the Declaration of Helsinki. The study 
will also be carried out in keeping with applicable local law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations. When necessary, an extension, amendment or renewal of the IEC/IRB approval 
must be obtained and also forwarded to the sponsor. The responsible unit (e.g. IEC/IRB, head 
of the study center/medical institution) must supply to the sponsor, upon request, a list of the 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  123 of 269
IEC/IRB members involved in the vote and a statement to confirm that the IEC/IRB is 
organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial patients without prior IEC/IRB/sponsor approval/favorable opinion. As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor. Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
13.4
Patient information and consent
Patient information and informed consent form for prescreening
A patient information (PI) and ICF with brief information on the study will be provided to 
patients with unresectable locally advanced or metastatic MPM who would like to participate 
in this study.
The PI/ICF for prescreening provided by the sponsor or the study center includes the general 
aspects of the study conduct, details on the tissue samples required to perform the mesothelin 
overexpression test, and information on risks in case a fresh biopsy is needed. A sample 
PI/ICF for prescreening is provided as a document separate to this protocol.
The patient has the right to ask the investigator to explain the study in detail and the right to 
withdraw from the study at any time without any disadvantage and without having to provide 
reasons for this decision.
Patient information and informed consent form for full study
A PI/ICF for screening of study treatment eligibility (ICF for full study) will be provided no 
longer than 28 days prior to start of study treatment to the patient who passes the 
prescreening, including mesothelin overexpression level test, and who still has interest to 
participate in this study. The PI/ICF for full study should be provided prior to activities 
related to the screening for full study.
All relevant information on the study will be summarized in the PI/ICF for full study provided 
by the sponsor or the study center. A sample PI/ICF for full study is provided as a document 
separate to this protocol.
Based on this PI sheet, the investigator or designee will explain all relevant aspects of the 
study to each patient / legal representative or proxy consenter (if the patient is under legal 
protection), prior to his/her entry into the full study (i.e. before any examinations and 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  124 of 269
procedures associated with the selection for the full study are performed excluding the 
prescreening procedures or further study-specific data is recorded on study-specific forms).
The following applies to PI/ICF for prescreening and for full study:
The investigator will also mention that written approval of the IRB/IEC has been obtained.
Each patient / legal representative or proxy consenter will be informed about the following 
aspects of premature withdrawal:

Each patient has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision.

The patient’s consent covers end-of-study examinations as specified in the visit 
description described in Section 9.2 to be conducted after withdrawal of consent. 

The patient’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the SAP. 

Patient-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such 
as blood, urine or tissues); these data would also be retained and statistically analyzed 
in accordance with the SAP. The patient has the right to object to the generation and 
processing of this post-withdrawal data. The patient’s oral objection must be 
documented in the patient’s source data.
Each patient / legal representative or proxy consenter will have ample time and opportunity to 
ask questions.
Only if the patient / legal representative or proxy consenter voluntarily agrees to sign the ICF 
and has done so, may he/she enter the study. Additionally, the investigator will personally 
sign and date the form. The patient / legal representative or proxy consenter will receive a 
copy of the signed and dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution.
In the event that informed consent is obtained on the date that screening study procedures are 
performed, the study record or patient´s clinical record must clearly show that informed 
consent was obtained prior to these procedures.

If the patient is not capable of providing a signature, a verbal statement of consent can 
also be given in the presence of an impartial witness (independent of the sponsor and 
the investigator). This is to be documented by a signature from the informing 
physician as well as by a signature from the witness.

For adults under legal protection, consent shall be given by the legal guardian(s). The 
consent of an adult under legal protection shall also be requested where such a person 
is able to express his/her own will. His/her refusal or the withdrawal of his/her consent 
may not be disregarded.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  125 of 269
The ICF and any other written information provided to patients / legal representatives or 
proxy consenters will be revised whenever important new information becomes available that 
may be relevant to the patient’s consent, or there is an amendment to the protocol that 
necessitates a change to the content of the PI and/or the written ICF. The investigator will 
inform the patient / legal representative or proxy consenter of changes in a timely manner and 
will ask the patient to confirm his/her participation in the study by signing the revised ICF. 
Any revised written ICF and written information must receive the IEC/IRB`s approval / 
favorable opinion in advance of use.
13.5
Publication policy and use of data
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations. The sponsor is interested in the publication of the 
results of every study it performs. 
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study. However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission. To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract. 
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.
13.6
Compensation for health damage of patients / insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  126 of 269
13.7
Confidentiality
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Patient names will not be supplied to the sponsor. Only the patient number will be recorded in 
the CRF, and if the patient name appears on any other document (e.g. pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. As part of 
the informed consent process, the patients will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the patient’s identity will remain confidential.
The investigator will maintain a list to enable patients to be identified.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  127 of 269
14.
Reference list
Reference list was updated by amendments 2 and 4. The numbering of the references was 
changed accordingly.
1.
Mesothelioma, Age-Adjusted SEER Cancer Incidence Rates, 1980-2012, By Race, 
Sex and Year of Diagnosis. Available online: 
http://seer.cancer.gov/csr/1975_2012/results_merged/sect_17_mesothelioma.pdf.
2.
Bianchi C, Bianchi T. Malignant mesothelioma: global incidence and relationship with 
asbestos. Ind Health. 2007;45(3):379-87.
3.
NCCN. Clinical Practice Guidelines in Oncology. Version 1.2015 Malignant Pleural 
Mesothelioma. Available online: 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (accessed 12 Mar 
2015).
4.
Stahel RA, Weder W, Lievens Y, Felip E, ESMO Guidelines Working Group. 
Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, 
treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v126-8.
5.
Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothelioma and asbestos 
exposure in the North Western Cape Province. Br J Ind Med. 1960;17:260-71.
6.
Thomson JG. Exposure to asbestos dust and diffuse pleural mesotheliomas. Br Med J. 
1963;1(5323):123.
7.
Peto J, Decarli A, La Vecchia C, Levi F, Negri E. The European mesothelioma 
epidemic. Br J Cancer. 1999;79(3-4):666-72.
8.
Kroidl D, Nowak D, Seysen U. Bewertung und Begutachtung in der Pneumologie. 
Empfehlungen der Deutschen Atemwegsliga und der Deutschen Gesellschaft für 
Pneumologie.Thieme Verlag Stuttgart pp 79. 2000.
9.
Manegold C, Schirren J, Dienemann H, Wannenmacher M. in Schmoll HJ, Höffken, K 
and Possinger, K , 2006, Kompedium Internistische Onkologie; Springer Medizin 
Verlag, Heidelberg pp 3644-45. 2006.
10.
Leung AN, Muller NL, Miller RR. CT in differential diagnosis of diffuse pleural 
disease. AJR American journal of roentgenology. 1990;154(3):487-92.
11.
NICE. Pemetrexed for the treatment of malignant pleural mesothelioma. Issued: 
January 2008. NICE technology appraisal guidance 135. Available online: 
https://www.nice.org.uk/guidance/ta135.
12.
Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. 
Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in 
patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21(14):2636-44.
13.
Zalcman G, Mazières J, Margery J, Greillier L, Audigier-Valette C, Moro-Sibilot D, et 
al. Bevacizumab 15mg/kg plus cisplatin-pemetrexed (CP) triplet versus CP doublet in 
Malignant Pleural Mesothelioma (MPM): Results of the IFCT-GFPC-0701 MAPS 
randomized phase 3 trial. J Clin Oncol. 2015;33(suppl; abstr 7500).
14.
Krug LM, et al. Vorinostat in patients with advanced malignant pleural mesothelioma 
who have failed prior pemetrexed and either cisplatin or carboplatin therapy: A phase 
III, randomized, double-blind, placebo-controlled trial. ECCO-ESMO 2011; Abstract 
3BA.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  128 of 269
15.
Gaafar RB, Favaretto AF, Gregorc V, Grossi F, Jassem J, Polychronis A, et al. Phase 
III trial (NGR015) with NGR-hTNF plus best investigator choice (BIC) versus 
placebo plus BIC in previously treated patients with advanced malignant pleural 
mesothelioma (MPM). J Clin Oncol. 2015;33(suppl; abstr 7501).
16.
Jassem J, Ramlau R, Santoro A, Schuette W, Chemaissani A, Hong S, et al. Phase III 
trial of pemetrexed plus best supportive care compared with best supportive care in 
previously treated patients with advanced malignant pleural mesothelioma. J Clin 
Oncol. 2008;26(10):1698-704.
17.
Stebbing J, Powles T, McPherson K, Shamash J, Wells P, Sheaff MT, et al. The 
efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma. 
Lung cancer. 2009;63(1):94-7.
18.
van Meerbeeck JP, Baas P, Debruyne C, Groen HJ, Manegold C, Ardizzoni A, 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(12):2577-82.
19.
Bera TK, Pastan I. Mesothelin is not required for normal mouse development or 
reproduction. Mol Cell Biol. 2000;20(8):2902-6.
20.
Golfier S, Kopitz C, Kahnert A, Heisler I, Schatz CA, Stelte-Ludwig B, et al. 
Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures 
tumors with heterogeneous target expression favored by bystander effect. Mol Cancer 
Ther. 2014;13(6):1537-48.
21.
Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in 
malignant pleural mesothelioma. Ann Oncol. 2004;15(2):257-60.
22.
The electronic Medicines Compendium (eMC) search results for vinorelbine. 
Available online: https://www.medicines.org.uk/emc/search/vinorelbine.
23.
Recommendations related to contraception and pregnancy testing in clinical trials. 
Available online: http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.
24.
Steele JP, Shamash J, Evans MT, Gower NH, Tischkowitz MD, Rudd RM. Phase II 
study of vinorelbine in patients with malignant pleural mesothelioma. J Clin Oncol. 
2000;18(23):3912-7.
25.
Muers MF, Stephens RJ, Fisher P, Darlison L, Higgs CM, Lowry E, et al. Active 
symptom control with or without chemotherapy in the treatment of patients with 
malignant pleural mesothelioma (MS01): a multicentre randomised trial. Lancet. 
2008;371(9625):1685-94.
26.
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 2006 
update of recommendations for the use of white blood cell growth factors: an 
evidence-based clinical practice guideline. J Clin Oncol. 2006;24(19):3187-205.
27.
NAVELBINE® (vinorelbine tartrate) label. Available online: 
http://www.fda.gov/ohrms/dockets/ac/04/briefing/4021b1_10_vinorelbine%20label.pd
f.
28.
Lung Cancer Symptom Scale (LCSS). Available online: http://www.lcss-
ql.com/index.htm.
29.
Oxnard GR, Armato SG, 3rd, Kindler HL. Modeling of mesothelioma growth 
demonstrates weaknesses of current response criteria. Lung cancer. 2006;52(2):141-8.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  129 of 269
30.
Plathow C, Klopp M, Thieke C, Herth F, Thomas A, Schmaehl A, et al. Therapy 
response in malignant pleural mesothelioma-role of MRI using RECIST, modified 
RECIST and volumetric approaches in comparison with CT. Eur Radiol. 
2008;18(8):1635-43.
31.
Hollen PJ, Gralla RJ, Liepa AM, Symanowski JT, Rusthoven JJ. Adapting the Lung 
Cancer Symptom Scale (LCSS) to mesothelioma: using the LCSS-Meso conceptual 
model for validation. Cancer. 2004;101(3):587-95.
32.
Hollen PJ, Gralla RJ, Liepa AM, Symanowski JT, Rusthoven JJ. Measuring quality of 
life in patients with pleural mesothelioma using a modified version of the Lung 
Cancer Symptom Scale (LCSS): psychometric properties of the LCSS-Meso. Support 
Care Cancer. 2006;14(1):11-21.
33.
Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 1958;53:457-81.
34.
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics. 1982;38:29-41.
35.
Cox DR, Oakes D. Analysis of Survival Data. New York: Chapman & Hall. 1984.
36.
EMA. Appendix 1 to the guideline on the evaluation of anticancer medicinal products 
in man, 2012. Available online: 
http://www.google.fi/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&uact
=8&ved=0ahUKEwi12K62sbbNAhUGbhQKHS-
BD5UQFggiMAA&url=http%3A%2F%2Fwww.ema.europa.eu%2Fema%2Fpages%2
Fincludes%2Fdocument%2Fopen_document.jsp%3FwebContentId%3DWC50013712
6&usg=AFQjCNEOUdPPE1LoZOiaWFaz_8VfRiM1mA.
37.
FDA. Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer 
Drugs and Biologics Guidance for Industry, April 2015. Available online: 
www.fda.gov/downloads/Drugs/.../Guidances/UCM259421.pdf.
38.
Lan K, DeMets D. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70:659–63.
39.
O’Brien P, Fleming T. A multiple testing procedure for clinical trials. Biometrics. 
1979;35:549–56.
40.
Agresti A. Categorical Data Analysis. Third Edition. New Jersey: John Wiley & Sons. 
2013.
41.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika. 1934;26: 404–13.
42.
Miller AC, Miettinen M, Schrump DS, Hassan R. Malignant mesothelioma and central 
nervous system metastases. Report of two cases, pooled analysis, and systematic 
review. Annals of the American Thoracic Society. 2014;11(7):1075-81.
43.
Yamagishi T, Fujimoto N, Miyamoto Y, Asano M, Fuchimoto Y, Wada S, et al. Brain 
metastases in malignant pleural mesothelioma. Clinical & experimental metastasis. 
2016;33(3):231-7.
44.
The Criteria Committee of the New York Heart Association.  Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. p. 1994: 253-256.
45.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-47.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  130 of 269
46.
U.S.Department of Health and Human Services. National Institutes of Health. 
National Cancer Institute. Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010).  Available 
online: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf 
47.
FDA. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers. Available online: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dru
gInteractionsLabeling/ucm093664.
48.
National Kidney Foundation. Calculators for Health Care Professionals. Available 
online: http://www.kidney.org/professionals/kdoqi/gfr_calculator.
49.
Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the 
context of other dry eye tests. Cornea. 2003;22(7):640-50.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  131 of 269
15.
Protocol amendments
15.1
Amendment 2
Amendment 2 is a global amendment dated 09 FEB 2016.
15.1.1
Overview of changes to the study
15.1.1.1
Modification 1: Change in OS analysis design
The study design was changed to increase the power of the OS analysis to 80%, with a 
corresponding increase in sample size and number of required OS events. The revised design 
also incorporates assumptions changes, including an increase in the accrual rate, more 
conservative PFS dropout assumptions, and a lower OS dropout assumption.
Sections affected by this modification: Section 2 Synopsis, Section 10.3.3.1 Secondary 
efficacy variables, Section 10.4 Determination of sample size, Section 10.4.2 Secondary 
endpoint overall survival
15.1.1.2
Modification 2: Changes in determination of sample size
Number of randomized patients was changed from 183 to 210 (total), from 122 to 140 
(anetumab ravtansine arm) and 61 to 70 (comparator arm). The sample size was increased to 
support the OS evaluation. Increased number of patients supports powering OS analysis at 
80%.
The accrual rate was increased to reflect improved assessment of accrual capabilities.
PFS dropout rate was increased to reflect provision for additional PFS dropouts afforded by 
larger number of patients. OS dropout rate was decreased to reflect improved OS follow-up 
effort.
As a result, the estimates of the times for patients to be accrued and to reach endpoint 
maturation were updated.
Information was updated on the estimated number of prescreened and screened patients 
needed to reach 210 randomized patients.
Sections affected by this modification: Section 2 Synopsis, Section 5.1 Design overview, 
Section 5.3 Justification of the design, Section 10.3.3.1 Secondary efficacy variables, Section 
10.4.1 Primary endpoint progression-free survival, Section 10.4.2 Secondary endpoint overall 
survival, Section 11.4 Missing data.
15.1.1.3
Modification 3: Pulmonary function evaluation removed
Pulmonary function evaluation by forced vital capacity measurement was removed from the 
secondary endpoints since spirometry schedule could be a significant burden for the patients.
Sections affected by this modification: Section 2 Synopsis, Section 3.1 Background, Section 4 
Study objectives, Section 5.1 Design overview, Section 6.3.1.2 Withdrawal criteria, Section 
9.1 Tabular schedule of evaluations, Section 9.2.2 Full screening period, Section 9.2.4 
Efficacy assessments, Section 9.2.5.2 Active follow-up, Section 9.4 Efficacy, Section 9.8 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  132 of 269
Appropriateness of procedures / measurements, Section 10.3.3.1 Secondary efficacy 
variables, Section 10.3.3.3 Safety variables, Section 11.4 Missing data, Section 14 Reference 
list
15.1.1.4
Modification 4: Clarification of progression as withdrawal criterion
Language in withdrawal criteria regarding duration of treatment after disease progression has 
been clarified.
Sections affected by this modification: Section 2 Synopsis, Section 5.1 Design overview, 
Section 6.3.1.2 Withdrawal criteria
15.1.1.5
Modification 5: Definition of corneal epitheliopathy introduced
“Corneal epitheliopathy” has been introduced throughout the protocol to replace other 
wordings “corneal toxicity”, “eye toxicity”, “corneal morphology changes”, “ocular adverse 
drug reactions”, and “corneal disorder” for consistency.
Sections affected by this modification: Section 5.3 Justification of the design, Section 6.3.1.2 
Withdrawal criteria, Section 7.4.2.1 Dose modifications of anetumab ravtansine, Section 
7.4.2.1.2 Non-hematological toxicities, Section 7.4.2.1.3 Miscellaneous toxicities, Section 9.1 
Tabular schedule of evaluations, Section 9.2.3.2 Treatment – Cycle 2 and higher, Section 9.5 
Pharmacokinetics / pharmacodynamics, Section 9.6.1.3 Assessments and documentation of 
adverse events, Section 9.6.1.6 Adverse events of special safety interest, Section 9.6.3.7 
Ophthalmologic examinations
15.1.1.6
Modification 6: Redefinition of mesothelin overexpression
Mesothelin overexpression was redefined as “moderate” and “stronger” and reference to the 
expression levels of ‘2+’ and ‘3+’ was removed for consistency with the language used by the 
central laboratory Ventana in their protocol and in their communication to Authorities.
Sections affected by this modification: Section 5.1 Design overview, Section 5.3 Justification 
of the design, Section 6.1.1 Eligibility criteria for prescreening, Section 6.1.2 Eligibility 
criteria for full study, Section 6.3.1.1.1 Prescreening failure, Section 9.2.3 Treatment period, 
Section 9.7.1 Biomarkers
15.1.1.7
Modification 7: Clarification of start of full study
Wording regarding the start of full study phase was updated for clarity by adding language on 
full study ICF to be signed prior to entering the screening phase.
Sections affected by this modification: Section 5.1 Design overview
15.1.1.8
Modification 8: Clarification of radiological eligibility
Radiological eligibility criterion (inclusion criterion number 4) was updated to allow 
inclusion of patients who have pleural non-measurable lesions per mRECIST but at the same 
have non-pleural measurable disease (per RECIST 1.1). This was done after consultation and 
approval of the Steering Committee.
Sections affected by this modification: Section 2 Synopsis, Section 6.1.2 Eligibility criteria 
for full study


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  133 of 269
15.1.1.9
Modification 9: Clarification of contraception duration and use
In the eligibility criteria for the full study, the duration of contraception was corrected from 
3 to 4 months after the last dose to provide consistency throughout the document. Advice on 
the use of additional contraception was strengthened in the protocol for male patients with a 
female partner of childbearing potential in line with the relevant EU Clinical Trial Facilitation 
Group (CTFG) guideline. Male patients with a female partner of childbearing potential must 
use a condom and ensure that an additional form of contraception is also used. Sperm 
conservation advice has been extended to all male patients (both arms) These changes were 
made due the request of the Medicines and Healthcare Products Regulatory Agency (MHRA) 
in United Kingdom (UK).
Sections affected by this modification: Section 6.1.2 Eligibility criteria for full study
15.1.1.10
Modification 10: Addition of optometrist as an alternative to 
ophthalmologist
Optometrist was added as an alternative to ophthalmologist as in some countries optometrist 
is licensed to perform the eye examinations requested in this Clinical Study Protocol. It was 
also clarified that the ophthalmologist/optometrist will be consulted by the investigator.
Sections affected by this modification: Section 6.2 Exclusion criteria, Section 7.4.2.1.3 
Miscellaneous toxicities, Section 9.1 Tabular schedule of evaluations, Section 9.2.3.2 
Treatment – Cycle 2 and higher, Section 9.6.3.7 Ophthalmologic examinations
15.1.1.11
Modification 11: Clarification of ocular eligibility
A note about low grades of superficial punctate keratitis was added to exclusion criterion 
number 5 to give appropriate guidance on ocular assessment during screening as a 
clarification.
Sections affected by this modification: Section 6.2 Exclusion criteria
15.1.1.12
Modification 12: Vinorelbine formulation corrected
The data about vinorelbine formulations available was corrected.
Sections affected by this modification: Section 7.2.2 Comparator - vinorelbine
15.1.1.13
Modification 13: Dose modification due to hypersensitivity corrected
Language on dose modification for anetumab ravtansine infusion-related reaction/other 
hypersensitivity events was corrected.
Sections affected by this modification: Section 7.4.2.1.2 Non-hematological toxicities, 
Section 7.4.2.1.3 Miscellaneous toxicities, Section 8.1 Prior and concomitant therapy
15.1.1.14
Modification 14: Clarification of reporting of AE of special interest
Language on reporting of AE of special interest updated for clarity.
Sections affected by this modification: Section 9.6.1.6 Adverse events of special safety 
interest


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  134 of 269
15.1.1.15
Modification 15: Clarification of blinded central review during 
screening
Language on blinded central review during screening was modified for completeness since 
during screening, blinded central review will not only check if at least 1 measurable lesion is 
present, but it will review the radiological eligibility in its entirety as defined in inclusion 
criterion number 4.
Sections affected by this modification: Section 2 Synopsis, Section 5.1 Design overview, 
Section 7.3 Treatment assignment, Section 9.2.3 Treatment period, Section 9.4.1 Radiological 
tumor assessments
15.1.1.16
Modification 16: Clarification of intra-patient dose escalation for 
study drugs
The language was modified (“for TEAE” added) to clarify that there can be no intra-patient 
dose escalation for study drugs when medication was previously reduced for TEAE. In case 
dose reduction occurred by mistake or logistical difficulty, this can be corrected in the 
following cycles.
Sections affected by this modification: Section 7.4.2.1.2 Non-hematological toxicities, 
Section 7.4.2.2 Dose modifications of vinorelbine
15.1.1.17
Modification 17: Clarification on follow-up of patients who are 
randomized but not treated
Clarification was added on follow-up of patients who are randomized but not treated. Change 
clarifies how to process patients who are randomized but received no treatment, clarifying 
that all ITT patients should be followed for efficacy to the extent feasible.
Sections affected by this modification: Section 6.3.1.2 Withdrawal criteria
15.1.1.18
Modification 18: Additional contact attempt added at the time of each 
survival sweep
A requirement for an additional contact attempt at the time of each survival sweep was added, 
to clarify that a further attempt should be made to contact patients previously lost to follow-
up.
Sections affected by this modification: Section 6.3.1.2 Withdrawal criteria
15.1.1.19
Modification 19: Time window between randomization and treatment 
start added
A time window between the IxRS transaction and the start of study drug has been introduced: 
start of treatment has to be within 24 hours after randomization call, provided the patient is 
seen at site prior to randomization, all in- and exclusion criteria are checked and patient is 
considered eligible before the randomization call is made. This change was introduced to fit in 
better with site logistical procedures.
Sections affected by this modification: Section 5.1 Design overview, Section 6.1.2 Eligibility 
criteria for full study, Section 6.2 Exclusion criteria, Section 9.1 Tabular schedule of 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  135 of 269
evaluations, Section 9.2.2 Full screening period, Section 9.2.3.1 Treatment – Cycle 1, Section 
9.4.1 Radiological tumor assessments, Section 9.2.4 Efficacy assessments
15.1.1.20
Modification 20: PROs schedule updated
PROs schedule was updated with MDASI-MPM questionnaires at C1D8, C1D15, C2D8, 
C2D15, C3D8 and C3D15. The reason for this change is to address the FDA/COA feedback 
on the PROs evidence and endpoint strategy.
In addition, it was clarified that MDASI-MPM and LCSS-Meso are to be completed before 
the patient meets with a clinician and before any examination or test is performed on that day.
Sections affected by this modification: Section 9.1 Tabular schedule of evaluations, Section 
9.2.2 Full screening period, Section 9.2.3.1 Treatment – Cycle 1, Section 9.2.3.2 Treatment – 
Cycle 2 and higher, Section 9.2.5.1 Safety follow-up, Section 9.2.5.2 Active follow-up, 
Section 9.4.3 Patient-reported outcomes
15.1.1.21
Modification 21: Inconsistency in dose re-escalation clarified
Inconsistency in dose re-escalation between dose modifications for non-hematological 
toxicities (Section 7.4.2.1.2 Non-hematological toxicities) and Table 7-6 (7.4.2.1.3 
Miscellaneous toxicities) was clarified. Accordingly, “dose increased” was added in the list of 
actions taken on study treatment to resolve the AE.
Sections affected by this modification: Section 7.4.2.1.2 Non-hematological toxicities, 
Section 7.4.2.2 Dose modifications of vinorelbine, Section 9.6.1.2.4 Action taken with study 
treatment
15.1.1.22
Modification 22: Clarification on start of treatment period
It was clarified that the start of treatment for efficacy purposes is defined as the 
randomization, and the start of treatment for safety purposes is defined as the first 
administration of study drug.
Sections affected by this modification: Section 5.1 Design overview
15.1.1.23
Modification 23: Clarification of the study background with data on 
probability of corneal epitheliopathy versus model-predicted drug 
exposure
The background of the study was clarified with data on probability of corneal epitheliopathy 
versus model-predicted drug exposure. In addition, the sentence in Section 5.3 Justification of 
the design referring to this data was clarified and a cross-reference added.
Sections affected by this modification: Section 3.1.2 Clinical experience, Section 5.3 
Justification of the design
15.1.1.24
Modification 24: Urine dipstick test removed from visit C1D1
Urine dipstick test removed from visit C1D1 because this test is already performed within 
7 days before C1D1.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  136 of 269
Sections affected by this modification: Section 9.1 Tabular schedule of evaluations, Section 
9.2.3.1 Treatment – Cycle 1
15.1.1.25
Modification 25: Appendix regarding response assessment updated
Appendix regarding the response assessment was updated to correctly reflect mRECIST 
criteria.
Sections affected by this modification: Section 16.3 Response assessment
15.1.1.26
Other modifications and corrections
In addition to the modifications specified above, there have been minor corrections for better 
clarity and consistency.

List of abbreviations has been updated. ICH was also updated in the text to 
International Council for Harmonization as it had changed the name. Sections affected 
by this modification: List of abbreviations, Section 9.6.3.1 Laboratory evaluations

Bayer corneal epitheliopathy grading system was referenced in additional sections in 
the text. Sections affected by this modification: Section 2 Synopsis, Section 5.1 
Design overview, Section 9.6.1.2.2 Intensity

A cross-reference to Section 9.8 Appropriateness of procedures / measurements was 
added in section 5.3 Justification of the design for clarity. Sections affected by this 
modification: Section 5.3 Justification of the design

It was clarified that the primary analysis will take place after 117 PFS events are 
observed rather than at that time. Sections affected by this modification: Section 5.5 
Primary completion

It was clarified that the eligibility criteria must be met and the exclusion criteria must 
be not met at the time of randomization call. Sections affected by this modification: 
Section 6.1.2 Eligibility criteria for full study, Section 6.2 Exclusion criteria

Cross-reference to Appendix 16.3 Response assessment was inserted instead of cross-
reference to Section 9.4.1 Radiological tumor assessments in inclusion criterion 
number 4. Sections affected by this modification: Section 6.1.2 Eligibility criteria for 
full study

It was clarified that if the anetumab ravtansine solution is frozen or stored above room 
temperature, it should be discarded. Sections affected by this modification: Section 
7.2.1 Test drug - anetumab ravtansine

As a clarification, the first withdrawal criterion for treatment with anetumab 
ravtansine in Figure 6-1 was divided into 2 criteria. In addition, the language regarding 
the exceptions to the withdrawal and to the treatment modification in Figure 6-1 and in 
subsection “Non-hematological toxicities requiring dose modification”, respectively, 
were removed as per request of French Authorities. Sections affected by this 
modification: Section 6.3.1.2 Withdrawal criteria, Section 7.4.2.1.2 Non-
hematological toxicities


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  137 of 269

IxRS transaction was added in the Study flow chart and visit descriptions at full 
screening -28 days as a correction. Sections affected by this modification: Section 9.1 
Tabular schedule of evaluations, Section 9.2.2 Full screening period

It was clarified that the extra survival sweep contacts will be conducted prior to PFS 
final analysis rather than at the time of PFS final analysis. Sections affected by this 
modification: Section 9.4.2 Survival

It was clarified that patients who sign the informed consent for prescreening will be 
included in the ENR. Sections affected by this modification: Section 10.2 Analysis 
sets

The location of the language “hazard ratio” was changed in the section describing the 
primary efficacy analysis to grammatically correct the sentence. Sections affected by 
this modification: Section 10.3.2 Primary efficacy variable

A sentence referring to SAP was added in the Section 10.3.3.1 Secondary efficacy 
variables for consistency with the Section 10.3.2 Primary efficacy variable. Sections 
affected by this modification: Section 10.3.3.1 Secondary efficacy variables

It was clarified that the sponsor will perform the interim analysis for OS. Sections 
affected by this modification: Section 10.5 Planned interim analyses

The sentence referring to the analysis methods described for PFS was removed from 
the paragraph describing the strategies to reduce the dropout rate for secondary 
endpoint OS for clarity. Sections affected by this modification: Section 11.4 Missing 
data

Reference list been updated. Sections affected by this modification: Section 14 
Reference list
15.1.2
Changes to the protocol text
In the sections on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version. As applicable, changes to the protocol text are highlighted as 
follows:

Addition of a whole new portion: Brief identification of the new portion

Removal of a whole portion: Complete display of the removed portion, formatted as 
crossed out

Editing of an existing portion: Comparative presentation of “old text” versus “new 
text”, with “old text” referring to the most recent previous protocol version. Deletions 
are crossed out in the “old text”. Additions are underlined in the “new text”.

Tables / figures: The term “amended” is added to the caption.

Terminological changes: Brief specification of the terminological change
Correction of typos or omissions are not highlighted.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  138 of 269
15.1.2.1
Section 2 Synopsis
Old text:
Study objective(s)
[…]
The secondary objectives of this study are to:

Test overall survival (OS)

Evaluate pulmonary function

Evaluate patient-reported outcomes (PROs) – symptom burden and 
health-related quality of life (QoL)

Evaluate other indicators of treatment efficacy (indicators of tumor 
response)

Evaluate safety
[…]
Test drug(s)
[…]
Anetumab ravtansine
Duration of treatment
Patients will continue on treatment until one of the following occurs:

Progressive disease (PD) as defined by modified Response Evaluation 
Criteria in Solid Tumors (mRECIST) for mesothelioma as assessed by 
blinded central radiology review

Clinical progression (continuation of treatment until centrally 
confirmed radiological PD could be allowed if in the investigator’s 
judgement this would provide clinical benefit to the patient)

Death

Any other criterion for withdrawal from study treatment.
Reference drug(s)
[…]
Vinorelbine
Duration of treatment
Patients will continue on treatment until one of the following occurs:

PD as defined by mRECIST for mesothelioma as assessed by blinded 
central radiology review

Clinical progression (continuation of treatment until centrally 
confirmed radiological PD could be allowed if in the investigator’s 
judgement this would provide clinical benefit to the patient)

Death

Any other criterion for withdrawal from study treatment.
[…]
Diagnosis and main criteria for 
inclusion /exclusion
Male or female patients (≥ 18 years of age) with unresectable locally 
advanced or metastatic MPM overexpressing mesothelin. Patients must 
have Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) of 0 or 1, a life expectancy of at least 3 months and at least 1 
measurable lesion per mRECIST per MPM as determined by the central 
reviewer. Patients must have received only 1 line of previous systemic 
anti-cancer treatment with platinum-pemetrexed with or without 
bevacizumab and must have no corneal epitheliopathy or any 
predisposing eye disorder.
Study design
A randomized, open-label, active-controlled, 2-arm, multicenter, Phase II 
study.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  139 of 269
Approximately 183 patients who meet the eligibility criteria will be 
randomly assigned in a 2:1 ratio to receive anetumab ravtansine or 
vinorelbine, respectively. Patients will be stratified at randomization 
according to geographic region and per time to progression (TTP) on 1st 
line treatment.
[…]
Methodology
Primary efficacy will be assessed based on radiological tumor evaluation 
by contrast-enhanced computed tomography (CT) or contrast-enhanced 
magnetic resonance imaging (MRI) of chest/abdomen/pelvis. The first 
tumor images will be obtained during full screening and will be sent to 
blinded central review to confirm that at least 1 measurable lesion is 
present prior to randomization. During treatment as well as active follow-
up, tumor imaging will be performed with the same modality every 
6 weeks during the first 6 months after the start of study treatment, every 
9 weeks until the end of year 2, and every 12 weeks thereafter until 
centrally confirmed radiological disease progression or end of study. 
Primary analysis results will be based on central review.
Determination of forced vital capacity (FVC) will be performed as a 
reproducible measure of pulmonary function, by a spirometry test until 
centrally confirmed radiological progression or end of study. 
Patients will be contacted to assess survival status every 3 months during 
long-term follow-up. In addition, extra survival sweep contacts will be 
conducted at the time of PFS final analysis and prior to OS final analysis 
to ensure that long-term follow-up data is current.
The effect of treatment on disease-specific health-related QoL and 
disease-specific symptoms will be assessed using the MD Anderson 
Symptom Inventory-Malignant Pleural Mesothelioma (MDASI-MPM) 
and the Lung Cancer Symptom Scale-Mesothelioma (LCSS-Meso) at full 
screening, at each cycle during treatment, at the safety follow-up visit, and 
during active follow-up.
Safety evaluations will be done at full screening, at each clinic visit during 
the treatment, and at the safety follow-up visit. The National Cancer 
Institute’s Common Terminology Criteria for Adverse Events (NCI-
CTCAE) version 4.03 will be used to grade severity of adverse events 
(AEs).
[…]
[…]
Number of patients
Approximately 183 patients will be randomized. Approximately 40% rate 
of screening failures is estimated, i.e. approximately 305 patients will be 
screened.
[…]
Plan for statistical analysis
[…]
Secondary efficacy variable OS will be tested using a 2-stage group-
sequential testing procedure with an overall 1-sided significance level of 
0.025 and 73% power. Each stage will utilize a 1-sided log-rank test 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  140 of 269
stratified by geographic region and per TTP on 1st line treatment. A Lan-
Demets alpha spending function with O’Brien-Fleming boundaries will be 
used. An interim analysis for OS will be performed at the same time as the 
final analysis for PFS, when approximately 85 OS events are expected to 
have been observed. The final analysis for OS will be performed after 
approximately 135 events have been observed.
Additional secondary variables include FVC response rate, objective 
response rate (ORR), disease control rate (DCR), duration of response 
(DOR), and analysis of the change in physical symptoms of MPM by 
PROs (as measured using the MDASI-MPM and LCSS-Meso). The final 
analysis for all these additional secondary variables will occur at the time 
of primary endpoint analysis.
The 183 randomized patients are estimated to be accrued in approximately 
20.4 months. Data for final PFS analysis are estimated to mature in 
23.9 months. Data for final OS analysis are estimated to mature in 
41.4 months.
New text:
Study objective(s)
[…]
The secondary objectives of this study are to:

Test overall survival (OS)

Evaluate patient-reported outcomes (PROs) – symptom burden and 
health-related quality of life (QoL)

Evaluate other indicators of treatment efficacy (indicators of tumor 
response)

Evaluate safety
[…]
Test drug(s)
[…]
Anetumab ravtansine
Duration of treatment
Patients will continue on treatment until one of the following occurs:

Progressive disease (PD) as defined by modified Response Evaluation 
Criteria in Solid Tumors (mRECIST) for mesothelioma as assessed by 
blinded central radiology review; however, treatment may be 
continued provided that the patient derives clinical benefit as 
determined by the treating physician.

Clinical progression

Death

Any other criterion for withdrawal from study treatment.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  141 of 269
Reference drug(s)
[…]
Vinorelbine
Duration of treatment
Patients will continue on treatment until one of the following occurs:

PD as defined by mRECIST for mesothelioma as assessed by blinded 
central radiology review; however, treatment may be continued 
provided that the patient derives clinical benefit as determined by the 
treating physician

Clinical progression

Death

Any other criterion for withdrawal from study treatment.
[…]
Diagnosis and main criteria for 
inclusion /exclusion
Male or female patients (≥ 18 years of age) with unresectable locally 
advanced or metastatic MPM overexpressing mesothelin. Patients must 
have Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) of 0 or 1, a life expectancy of at least 3 months and at least 1 
measurable lesion per mRECIST per MPM (i.e. pleural lesion(s) 
measured using mRECIST or extra-pleural lesion(s) measurable per 
RECIST 1.1) as determined by the central reviewer. Patients must have 
received only 1 line of previous systemic anti-cancer treatment with 
platinum-pemetrexed with or without bevacizumab and must have no 
corneal epitheliopathy or any predisposing eye disorder.
Study design
A randomized, open-label, active-controlled, 2-arm, multicenter, Phase II 
study.
Approximately 210 patients who meet the eligibility criteria will be 
randomly assigned in a 2:1 ratio to receive anetumab ravtansine or 
vinorelbine, respectively. Patients will be stratified at randomization 
according to geographic region and per time to progression (TTP) on 1st 
line treatment.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  142 of 269
Methodology
Primary efficacy will be assessed based on radiological tumor evaluation 
by contrast-enhanced computed tomography (CT) or contrast-enhanced 
magnetic resonance imaging (MRI) of chest/abdomen/pelvis. The first 
tumor images will be obtained during full screening and will be sent to 
blinded central review to confirm radiological eligibility prior to 
randomization. During treatment as well as active follow-up, tumor 
imaging will be performed with the same modality every 6 weeks during 
the first 6 months after the start of study treatment, every 9 weeks until the 
end of year 2, and every 12 weeks thereafter until centrally confirmed 
radiological disease progression or end of study. Primary analysis results 
will be based on central review.
Patients will be contacted to assess survival status every 3 months during 
long-term follow-up. In addition, extra survival sweep contacts will be 
conducted at the time of PFS final analysis and prior to OS final analysis 
to ensure that long-term follow-up data is current.
The effect of treatment on disease-specific health-related QoL and 
disease-specific symptoms will be assessed using the MD Anderson 
Symptom Inventory-Malignant Pleural Mesothelioma (MDASI-MPM) 
and the Lung Cancer Symptom Scale-Mesothelioma (LCSS-Meso) at full 
screening, at each cycle during treatment, at the safety follow-up visit, and 
during active follow-up.
Safety evaluations will be done at full screening, at each clinic visit during 
the treatment, and at the safety follow-up visit. The National Cancer 
Institute’s Common Terminology Criteria for Adverse Events (NCI-
CTCAE) version 4.03 will be used to grade severity of adverse events 
(AEs). In addition, a Bayer grading system will be used to assess corneal 
epitheliopathy.
[…]
[…]
Number of patients
Approximately 210 patients will be randomized. Approximately 40% rate 
of screening failures is estimated, i.e. approximately 350 patients will be 
prescreened.
[…]
Plan for statistical analysis
[…]
Secondary efficacy variable OS will be tested using a 2-stage group-
sequential testing procedure with an overall 1-sided significance level of 
0.025 and 80% power. Each stage will utilize a 1-sided log-rank test 
stratified by geographic region and per TTP on 1st line treatment. A Lan-
Demets alpha spending function with O’Brien-Fleming boundaries will be 
used. An interim analysis for OS will be performed at the same time as the 
final analysis for PFS, when approximately 80 OS events are expected to 
have been observed. The final analysis for OS will be performed after 
approximately 159 events have been observed 
Additional secondary variables include objective response rate (ORR), 
disease control rate (DCR), duration of response (DOR), and analysis of 
the change in physical symptoms of MPM by PROs (as measured using 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  143 of 269
the MDASI-MPM and LCSS-Meso). The final analysis for all these 
additional secondary variables will occur at the time of primary endpoint 
analysis.
The 210 randomized patients are estimated to be accrued in approximately 
19.8 months. Data for final PFS analysis are estimated to mature in 
21.2 months. Data for final OS analysis are estimated to mature in 
41.3 months.
15.1.2.2
List of abbreviations
Old text:
FVC
Forced vital capacity
[…]
ICH
International Conference on Harmonization
[…]
PFT
Pulmonary function test
New text:
CTFG
Clinical Trial Facilitation Group
[…]
FSH
Follicle stimulating hormone
[…]
ICH
International Council for Harmonization
[…]
MHRA
Medicines and Healthcare Products Regulatory Agency
[…]
PopPBPK
Population, physiologically-based pharmacokinetic
15.1.2.3
Section 3.1 Background
Old text:
[…]
Treatment of MPM
Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate 
management of disease, using a framework of radiotherapy, chemotherapy, surgery and 
symptom palliation with terminal care. However, few patients qualify for curative surgery, 
and the efficacy of radiotherapy is limited, hence the high need for effective systemic 
treatments. The combination of cisplatin and the antifolate pemetrexed proved superior to 
single cisplatin, respectively, in terms of overall survival (OS) (12.1 vs. 9.3 months), 
progression-free survival (PFS) (5.7 vs. 3.9 months), and response rate (41.3% vs. 16.7%) 
(12). The regimen also proved superior with respect to improvement in respiratory function. 
Results indicate that patients who had a tumor response had consistently better pulmonary 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  144 of 269
function tests (PFTs) than patients with stable disease (SD), and patients with SD had better 
PFTs than patients with progressive disease (PD) (12). […]
New text:
[…]
Treatment of MPM
Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate 
management of disease, using a framework of radiotherapy, chemotherapy, surgery and 
symptom palliation with terminal care. However, few patients qualify for curative surgery, 
and the efficacy of radiotherapy is limited, hence the high need for effective systemic 
treatments. The combination of cisplatin and the antifolate pemetrexed proved superior to 
single cisplatin, respectively, in terms of overall survival (OS) (12.1 vs. 9.3 months), 
progression-free survival (PFS) (5.7 vs. 3.9 months), and response rate (41.3% vs. 16.7%) 
(12). […]
15.1.2.4
Section 3.1.2 Clinical experience
Old text:
[…]
The safety finding of particular interest at the 6.5 mg/kg Q3W dose has been the corneal 
epitheliopathy and keratitis with and without blurred vision probably related to anetumab 
ravtansine: 11 of 38 patients (29%) developed corneal adverse events (AEs). None of these 
events affected the deep corneal stroma or were considered serious or led to drug 
discontinuation and all events were reversible.
[…]
New text:
[…]
The safety finding of particular interest at the 6.5 mg/kg Q3W dose has been the corneal 
epitheliopathy and keratitis with and without blurred vision probably related to anetumab 
ravtansine: 11 of 38 patients (29%) developed corneal adverse events (AEs). None of these 
events affected the deep corneal stroma or were considered serious or led to drug 
discontinuation and all events were reversible.
Furthermore, population, physiologically-based pharmacokinetic (PopPBPK) modeling of 
preliminary data from the FiH study 15051, combined with a probabilistic regression analysis 
provided evidence that the area under the ADC plasma concentration-time curve at steady 
state, AUC(ADC), is a descriptor for the occurrence of corneal epitheliopathy, as shown in 
Figure 3-1. Based on the on average linear PK of anetumab ravtansine (see above in this 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  145 of 269
section), it can be assumed that dose reduction will lead to a reduced total drug exposure, i.e. 
AUC(ADC), and thus, also to a reduced probability of corneal epitheliopathy (see Figure 3-1).
Figure 3-1
Probability of corneal epitheliopathy versus model-predicted drug exposure
5000
10000
15000
20000
25000
30000
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
AUC(ADC) [mgh/L]
Probability for corneal toxicity
ADC = Antibody-drug conjugate; AUC = Area under the curve; N = Number of patients; PopPBPK = Population, physiologically-
based pharmacokinetic; Q3W = Every 3 weeks
Drug exposure versus the probability of corneal toxicity relationship with AUC(ADC) equals the PopPBPK model-predicted area 
under the anetumab ravtansine plasma concentration-time curve at steady state.
The solid line indicates the median estimate and the thin lines represent the 90% confidence interval; data used for logistic 
regression model development are shown as diamonds. 
The box plots represent simulated AUC(ADC) distributions in a virtual population of N=1000 subjects receiving either 4.5 mg/kg 
(dotted box), 5.5 mg/kg (dashed box) or 6.5 mg/kg (solid box) anetumab ravtansine given Q3W.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  146 of 269
15.1.2.5
Section 4 Study objectives
Old text:
[…]
The secondary objectives of this study are to:

Test overall survival (OS)

Evaluate pulmonary function

Evaluate patient-reported outcomes (PROs) – symptom burden and health-related 
quality of life (QoL)

Evaluate other indicators of treatment efficacy (indicators of tumor response)

Evaluate safety
[…]
New text:
[…]
The secondary objectives of this study are to:

Test overall survival (OS)

Evaluate patient-reported outcomes (PROs) – symptom burden and health-related 
quality of life (QoL)

Evaluate other indicators of treatment efficacy (indicators of tumor response)

Evaluate safety
[…]
15.1.2.6
Section 5.1 Design overview
Old text:
[…]
At the time of the start of study treatment, the patients will have advanced or metastatic MPM 
recurrent/relapsing after a 1st line treatment with platinum in combination with pemetrexed 
with or without bevacizumab, and overexpressing mesothelin as determined by 
immunohistochemistry (IHC). Only patients who demonstrate mesothelin overexpression at 
the moderate (2+) and strong (3+) level by IHC in at least 30% of tumor cells can be 
randomized into the study.
[…]
The start of the study is defined by signing of the informed consent form (ICF) for 
prescreening. After meeting the eligibility criteria for prescreening and for full study (see 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  147 of 269
Sections 6.1 and 6.2), approximately 183 patients will be randomly assigned in a 2:1 ratio to 
receive anetumab ravtansine or vinorelbine, respectively. The anetumab ravtansine arm will 
consist of approximately 122 patients and the vinorelbine comparator arm of approximately 
61 patients. Patients will be stratified at randomization according to geographic region (Rest 
of the world [RoW] versus Asia) and per time to progression (TTP) on 1st line treatment 
(≥ 6 months versus < 6 months).
A graphical presentation of the overall study design is shown in Figure 5-2.
Figure 5-2
Overall study design
Stratification 
 Geographic 
region (RoW 
vs. Asia) 
 TTP on 1st line 
treatment        
(≥ 6 months vs.    
< 6 months)
Randomization
2:1
(N=183)
Anetumab 
ravtansine 
6.5 mg/kg Q3W 
Day 1 
of each 21-day Cycle
Vinorelbine 
30 mg/m2 QW
 Days 1, 8 and 15      
of each 21-day Cycle
Disease 
progression
Blinded central 
radiology review
Long-term
 follow-up
Active 
follow-up
N = Number of patients; Q3W = Every 3 weeks; QW = Once weekly; RoW = Rest of the world, TTP = Time to progression
The start of the treatment period is defined by first administration of study drug (anetumab 
ravtansine or vinorelbine). Patients in the anetumab ravtansine arm will receive anetumab 
ravtansine IV infusion at a dose of 6.5 mg/kg (recommended Phase II dose [RPIID]) on Day 1 
of a 21-day cycle. Patients in the comparator arm will receive vinorelbine 30 mg/m2 IV on 
Days 1, 8 and 15 of a 21-day cycle. Treatment will be continued until death or occurrence of 
PD as defined by Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for 
mesothelioma (21) and assessed by blinded central radiology review, or clinical progression, 
or until another criterion for withdrawal from the study is met. In case of clinical progression, 
however, continuation of treatment until centrally confirmed radiological PD could be 
allowed if in the investigator’s judgement this would provide clinical benefit to the patient.
[…]
Primary efficacy will be assessed based on radiological tumor evaluation by contrast-
enhanced CT or contrast-enhanced magnetic resonance imaging (MRI) of 
chest/abdomen/pelvis (see Section 9.4.1). The first tumor images will be obtained during full 
screening and will be sent to blinded central review to confirm that at least 1 measurable 
lesion is present prior to randomization. During treatment as well as active follow-up, tumor 
imaging will be performed with the same modality every 6 weeks during the first 6 months 
after the start of study treatment, every 9 weeks until the end of year 2, and every 12 weeks 
thereafter until centrally confirmed radiological disease progression or end of study. Primary 
analysis results will be based on central review.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  148 of 269
Determination of forced vital capacity (FVC) will be performed as a reproducible measure of 
pulmonary function, by a spirometry test as described in Section 9.4.2 until centrally 
confirmed radiological progression or end of study.
[…]
Safety evaluations will be done at full screening, at each clinic visit during the treatment, and 
at the safety follow-up visit as described in Section 9.6. The National Cancer Institute’s 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 will be used 
to grade severity of AEs.
New text:
[…]
At the time of the start of study treatment, the patients will have advanced or metastatic MPM 
recurrent/relapsing after a 1st line treatment with platinum in combination with pemetrexed 
with or without bevacizumab, and overexpressing mesothelin as determined by 
immunohistochemistry (IHC). Only patients who demonstrate mesothelin overexpression at 
the moderate and stronger level by IHC in at least 30% of tumor cells can be randomized into 
the study.
[…]
The start of the study is defined by signing of the informed consent form (ICF) for 
prescreening. After meeting the eligibility criteria for prescreening and signing the ICF for 
full study (see Sections 6.1 and 6.2), approximately 210 patients who meet all of the inclusion 
and none of the exclusion criteria will be randomly assigned in a 2:1 ratio to receive anetumab 
ravtansine or vinorelbine, respectively. The anetumab ravtansine arm will consist of 
approximately 140 patients and the vinorelbine comparator arm of approximately 70 patients. 
Patients will be stratified at randomization according to geographic region (Rest of the world 
[RoW] versus Asia) and per time to progression (TTP) on 1st line treatment (≥ 6 months 
versus < 6 months). An approximately 40% screen fail rate is anticipated (25% at 
prescreening and a subsequent 20% among biomarker expressers. Approximately 350 patients 
are estimated to be required for prescreening to yield approximately 263 biomarker-positive 
patients, resulting in 210 randomized eligible patients).
A graphical presentation of the overall study design is shown in Figure 5-2.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  149 of 269
Figure 5-2
Overall study design
Stratification 
 Geographic 
region (RoW 
vs. Asia) 
 TTP on 1st line 
treatment        
(≥ 6 months vs.    
< 6 months)
Randomization
2:1
(N=210)
Anetumab 
ravtansine 
6.5 mg/kg Q3W 
Day 1 
of each 21-day Cycle
Vinorelbine 
30 mg/m2 QW
 Days 1, 8 and 15      
of each 21-day Cycle
Disease 
progression
Blinded central 
radiology review
Long-term
 follow-up
Active 
follow-up
N = Number of patients; Q3W = Every 3 weeks; QW = Once weekly; RoW = Rest of the world, TTP = Time to progression
The start of the treatment period is defined for efficacy purposes by randomization to study 
drug (anetumab ravtansine or vinorelbine), and for safety purposes by first administration of 
study drug. Start of treatment has to be within 24 hours after the randomization call. Patients 
in the anetumab ravtansine arm will receive anetumab ravtansine IV infusion at a dose of 
6.5 mg/kg (recommended Phase II dose [RPIID]) on Day 1 of a 21-day cycle. Patients in the 
comparator arm will receive vinorelbine 30 mg/m2 IV on Days 1, 8 and 15 of a 21-day cycle. 
Treatment will be continued until death or occurrence of PD as defined by Modified Response 
Evaluation Criteria in Solid Tumors (mRECIST) for mesothelioma (21) and assessed by 
blinded central radiology review, or clinical progression, or until another criterion for 
withdrawal from the study is met. In case of radiological progression, however, treatment may 
be continued provided that the patient derives clinical benefit as determined by the treating 
physician.
[…]
Primary efficacy will be assessed based on radiological tumor evaluation by contrast-
enhanced CT or contrast-enhanced magnetic resonance imaging (MRI) of 
chest/abdomen/pelvis (see Section 9.4.1). The first tumor images will be obtained during full 
screening and will be sent to blinded central review to confirm radiological eligibility prior to 
randomization. During treatment as well as active follow-up, tumor imaging will be 
performed with the same modality every 6 weeks during the first 6 months after the start of 
study treatment, every 9 weeks until the end of year 2, and every 12 weeks thereafter until 
centrally confirmed radiological disease progression or end of study. Primary analysis results 
will be based on central review.
[…]
Safety evaluations will be done at full screening, at each clinic visit during the treatment, and 
at the safety follow-up visit as described in Section 9.6. The National Cancer Institute’s 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 will be used 
to grade severity of AEs. In addition, a Bayer grading system (see Table 7-6 and Table 7-7) 
will be used to assess corneal epitheliopathy.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  150 of 269
15.1.2.7
Section 5.3 Justification of the design
Old text:
Level of blinding. This Phase II study will be open-label (see Section 7.5), because a double-
blind, active-controlled study is not feasible due to different administration schedules, Q3W 
for anetumab ravtansine and QW for vinorelbine, and different safety profiles (e.g. corneal 
toxicity for the anetumab ravtansine arm and neutropenia for the comparator [vinorelbine] 
arm). The independent and central radiological review for the assessment of disease 
progression and other radiological imaging-based endpoints will be conducted in a blinded 
fashion.
Dosage. At the RPIID of 6.5 mg/kg Q3W, anetumab ravtansine has demonstrated very strong 
efficacy in advanced, unresectable or metastatic epithelial mesothelioma (best objective 
response 31% overall or 45% in the 2nd line setting, with very durable responses) (see 
Section 3.1.2). Moreover, no drug-related deaths, only 5 drug-related SAEs and a low rate of 
drug-related Grade 3/4 AEs were reported from clinical experience with anetumab ravtansine 
at the RPIID. Based on the on average linear PK of anetumab ravtansine, it can be assumed 
that dose reduction planned in this Phase II study will lead to a reduced total drug exposure 
and thus, to a reduced probability of corneal toxicity.
[…]
Study population. Objective responses or prolonged SD cases in the 15051 study of 
anetumab ravtansine occurred in patients with moderate to strong mesothelin expression (2+ 
and 3+). Because of the treatment’s surface mesothelin targeting MoA, no clinical efficacy is 
expected in MPM patients with little or no mesothelin cell surface expression. Patients with a 
sarcomatoid histology are not expected to have mesothelin overexpression and should not 
enter prescreening. Therefore, pre-selection based on mesothelin expression (see Section 
6.1.1) is intended during recruitment of this study.
[…]
Randomization. A 2:1 randomization ratio is used to provide an adequate safety database for 
evaluating anetumab ravtansine safety. This ratio also encourages study participation by 
providing an elevated probability of receiving experimental treatment. The sample size is 
adequate for efficacy, and the safety of vinorelbine is well-studied. The sample size includes a 
margin of 14.8% to address the possibility of dropouts (see Section 11.4).
For strategies to limit the amount and impact of missing data, see Section 11.4.
New text:
Level of blinding. This Phase II study will be open-label (see Section 7.5), because a double-
blind, active-controlled study is not feasible due to different administration schedules, Q3W 
for anetumab ravtansine and QW for vinorelbine, and different safety profiles (e.g. corneal 
epitheliopathy for the anetumab ravtansine arm and neutropenia for the comparator 
[vinorelbine] arm). The independent and central radiological review for the assessment of 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  151 of 269
disease progression and other radiological imaging-based endpoints will be conducted in a 
blinded fashion.
Dosage. At the RPIID of 6.5 mg/kg Q3W, anetumab ravtansine has demonstrated very strong 
efficacy in advanced, unresectable or metastatic epithelial mesothelioma (best objective 
response 31% overall or 45% in the 2nd line setting, with very durable responses) (see 
Section 3.1.2). Moreover, no drug-related deaths, only 5 drug-related SAEs and a low rate of 
drug-related Grade 3/4 AEs were reported from clinical experience with anetumab ravtansine 
at the RPIID. Based on the drug exposure corneal epitheliopathy relationship (see Section 
3.1.2 and Figure 3-1) and the average linear PK of anetumab ravtansine, it can be assumed 
that dose reduction planned in this Phase II study will lead to a reduced total drug exposure, 
and thus, to a reduced probability of corneal epitheliopathy.
[…]
Study population. Objective responses or prolonged SD cases in the 15051 study of 
anetumab ravtansine occurred in patients with moderate to stronger mesothelin expression. 
Because of the treatment’s surface mesothelin targeting MoA, no clinical efficacy is expected 
in MPM patients with little or no mesothelin cell surface expression. Patients with a 
sarcomatoid histology are not expected to have mesothelin overexpression and should not 
enter prescreening. Therefore, pre-selection based on mesothelin expression (see Section 
6.1.1) is intended during recruitment of this study.
[…]
Randomization. A 2:1 randomization ratio is used to provide an adequate safety database for 
evaluating anetumab ravtansine safety. This ratio also encourages study participation by 
providing an elevated probability of receiving experimental treatment. The sample size is 
adequate for efficacy, and the safety of vinorelbine is well-studied. The sample size includes a 
dropout rate of 3.4%/month (15.7% as of planned primary analysis) to address the possibility 
of dropouts (see Section 11.4).
For justification of study endpoints and measurements, see Section 9.8.
For strategies to limit the amount and impact of missing data, see Section 11.4.
15.1.2.8
Section 5.5 Primary completion
Old text:
Primary analysis will be performed when approximately 117 PFS events are observed by 
central review in the study.
[…]
New text:
Primary analysis will be performed after approximately 117 PFS events are observed by 
central review in the study.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  152 of 269
15.1.2.9
Section 6.1.1 Eligibility criteria for prescreening
Old text:
Overexpression of mesothelin at the moderate (2+) and strong (3+) level in at least 30% of 
tumor cells is a prerequisite to be eligible for this study. […]
New text:
Overexpression of mesothelin at the moderate and stronger level in at least 30% of tumor cells 
is a prerequisite to be eligible for this study. […]
15.1.2.10
Section 6.1.2 Eligibility criteria for full study
Old text:
The following inclusion criteria must be met at the time of full screening and on C1D1 unless 
otherwise specified.
1.
Written informed consent for full study.
2.
Histological documentation of MPM overexpressing mesothelin at the moderate (2+) 
and strong (3+) level in at least 30% of tumor cells as determined by centrally 
performed IHC.
[…]
4.
Patients must have at least 1 measurable lesion according to mRECIST for 
mesothelioma (specified in Section 9.4.1). This will be confirmed by central review of 
images before the patient can be randomized into the study.
Note: Patients with non-pleural disease as the only relapse site after a pleural surgery 
(e.g. subcutaneous lesions, nodal lesions, lung lesions etc.) will be eligible if at least 
1 measurable lesion according to RECIST 1.1 is present.
Note: In case the only site of disease was previously treated with radiotherapy, there 
should be evidence of unequivocal PD in this site: measurable pleural disease should be 
assessed on a contrast enhanced CT/MRI done at the minimum 4 weeks after the end of 
radiotherapy and compared with previous imaging; unequivocal progression should be 
judged by the investigator as per mRECIST per MPM.
[…]
7.
Women of childbearing potential (WOCBP) and fertile men must agree to use adequate 
contraception when sexually active from signing of the ICF for full study until at least 3 
months after the last study drug administration. Men being treated with vinorelbine are 
advised not to father a child during and up to 6 months after treatment; prior to 
treatment, advice should be sought for conserving sperm due to the chance of 
irreversible infertility as a consequence of treatment with vinorelbine (22)(.The 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  153 of 269
investigator or a designated associate is requested to advise the patient how to achieve 
highly effective birth control. Highly effective (failure rate of less than 1% per year) 
contraception methods (23) include:

Combined (estrogen and progesteron containing: oral, intravaginal, transdermal) 
and progesteron-only (oral, injectable, implantable) hormonal contraception 
associated with inhibition of ovulation.

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion or vasectomized partner (provided that partner is the sole 
sexual partner and has received medical assessment of the surgical success).

Sexual abstinence (reliability to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient).
Male patients should use a condom during treatment and until the end of relevant 
systemic exposure (this is 1 month after last study drug administration), plus a further 3 
months period, unless the female partner is permanently sterile. When a male study 
patient has a female partner of childbearing potential, contraception recommendations 
to the female partner should also be considered.
Note: a woman is considered WOCBP, i.e. fertile, following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include but are not limited to hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. A postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy. A man is considered 
fertile after puberty unless permanently sterile by bilateral orchiectomy.
[…]
New text:
The following inclusion criteria must be met at the time of randomization call and on C1D1 
unless otherwise specified.
1.
Written informed consent for full study.
2.
Histological documentation of MPM overexpressing mesothelin at the moderate and 
stronger level in at least 30% of tumor cells as determined by centrally performed IHC.
[…]
4.
Patients must have at least 1 measurable lesion according to mRECIST for 
mesothelioma (specified in Appendix 16.3) i.e. pleural lesion(s) measured using 
mRECIST or extra-pleural lesion(s) measurable per RECIST 1.1. This will be 
confirmed by central review of images before the patient can be randomized into the 
study.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  154 of 269
Note: In case the only site of disease was previously treated with radiotherapy, there 
should be evidence of unequivocal PD in this site: measurable pleural disease should be 
assessed on a contrast enhanced CT/MRI done at the minimum 4 weeks after the end of 
radiotherapy and compared with previous imaging; unequivocal progression should be 
judged by the investigator as per mRECIST per MPM.
[…]
7.
Women of childbearing potential (WOCBP) and fertile men must agree to use adequate 
contraception when sexually active from signing of the ICF for full study until at least 4 
months after the last study drug administration. Men being treated with vinorelbine are 
advised not to father a child during and up to 6 months after treatment; for all male 
patients, prior to treatment with either study drug, advice should be sought for 
conserving sperm due to the chance of irreversible infertility as a consequence of 
treatment (22). The investigator or a designated associate is requested to advise the 
patient how to achieve highly effective birth control. Highly effective (failure rate of 
less than 1% per year) contraception methods (23) include:

Combined (estrogen and progesteron containing: oral, intravaginal, transdermal) 
and progesteron-only (oral, injectable, implantable) hormonal contraception 
associated with inhibition of ovulation.

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion or vasectomized partner (provided that partner is the sole 
sexual partner and has received medical assessment of the surgical success).

Sexual abstinence (reliability to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient).
Male patients with a female partner of childbearing potential must use a condom and 
ensure that an additional form of contraception is also used during treatment and until 4 
months after last study drug administration.
Note: a woman is considered WOCBP, i.e. fertile, following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include but are not limited to hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. A postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy. A man is considered 
fertile after puberty unless permanently sterile by bilateral orchiectomy.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  155 of 269
15.1.2.11
Section 6.2 Exclusion criteria
Old text:
Patients who meet the following criteria at the time of full screening and on C1D1 will be 
excluded:
[…]
5.
Patients with corneal epitheliopathy or any eye disorder that may predispose the patients 
to this condition at the discretion of the ophthalmologist.
[…]
New text:
Patients who meet the following criteria at the time of randomization call and on C1D1 will 
be excluded:
5.
Patients with corneal epitheliopathy or any eye disorder that may predispose the patients 
to this condition at the discretion of the investigator in consultation with the 
ophthalmologist/optometrist.
Note: Low grades of superficial punctate keratitis, within the range seen in the normal 
population, should not lead to the exclusion of the patient.
15.1.2.12
Section 6.3.1.1.1 Prescreening failure
Old text:
A patient whose tumor tissue is centrally tested by IHC for mesothelin overexpression and 
whose result is not moderate (2+) and strong (3+) mesothelin overexpression in at least 30% 
of the tumor cells, or who fails to meet any of the other eligibility criteria for prescreening, is 
regarded as a “prescreening failure”. These patients should not undergo any further screening 
procedures.
New text:
A patient whose tumor tissue is centrally tested by IHC for mesothelin overexpression and 
whose result is not moderate and stronger mesothelin overexpression in at least 30% of the 
tumor cells, or who fails to meet any of the other eligibility criteria for prescreening, is 
regarded as a “prescreening failure”. These patients should not undergo any further screening 
procedures.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  156 of 269
15.1.2.13
Section 6.3.1.2 Withdrawal criteria
Old text:
Figure 6-1
Withdrawal criteria
PATIENTS MUST BE WITHDRAWN FROM THE STUDY TREATMENT IF ANY OF THE FOLLOWING 
OCCURS:
[…]

Centrally confirmed radiological PD as per mRECIST criteria.

Clinical progression, however continuation of treatment until centrally confirmed radiological PD could be allowed 
if in the investigator’s judgement this would provide clinical benefit to the patient.
[…]
Patients must be withdrawn from treatment with anetumab ravtansine if any of the following occurs:

CTCAE Grade 4 non-hematological AE and Bayer Grade 4 corneal toxicity (see Table 7-6) (except at the 
investigator’s discretion in case of certain Grade 4 abnormality of laboratory assessments, such as 
abnormal laboratory assessments without corresponding clinical symptoms, or abnormal laboratory 
assessments that can be easily clinically managed).
[…]
AE = Adverse event; ARDS = Acute respiratory distress syndrome; β-HCG = β subunit of human chorionic gonadotropin; 
CTCAE = Common Terminology Criteria for Adverse Events; FVC = Forced vital capacity; Hb = Hemoglobin; 
mRECIST = Modified Response Evaluation Criteria in Solid Tumors; PD = Progressive disease; Q3W = Every 3 weeks; 
QoL = Quality of life; SAE = Serious adverse event; TEAE = Treatment-emergent adverse event
Lost to follow-up patients
When a patient is lost to follow-up at any stage of the study, the site should try to contact the 
patient, the patient’s relatives, or another doctor treating the patient, unless prohibited by local 
regulations. All attempts to contact the patient or relatives should be documented and sites are 
expected to perform at least 5 attempts to contact the patient over the course of 3 months.
SAFETY FOLLOW-UP VISIT
All patients who discontinue study treatment must perform this visit, 30+7 days after the last administration of study 
treatment.
Patients ending treatment without centrally 
confirmed radiological PD as per mRECIST criteria
Patients ending treatment with centrally confirmed 
radiological PD as per mRECIST criteria
ACTIVE FOLLOW-UP
Imaging, QoL, and FVC assessment will continue until 
centrally confirmed PD is observed or they withdraw 
consent to active follow-up, are lost to follow-up or due 
to death.
LONG-TERM FOLLOW-UP
Patients who have centrally confirmed PD will have 
information on survival and new anti-cancer treatment 
collected.  
Patients must be withdrawn if they withdraw consent to 
long term follow-up, are lost to follow-up or due to death


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  157 of 269
New text:
Figure 6-1
Withdrawal criteria
PATIENTS MUST BE WITHDRAWN FROM THE STUDY TREATMENT IF ANY OF THE FOLLOWING 
OCCURS:
[…]

Centrally confirmed radiological PD as per mRECIST criteria; however, treatment may be continued provided 
that the patient derives clinical benefit as determined by the treating physician.

Clinical progression.
[…]
Patients must be withdrawn from treatment with anetumab ravtansine if any of the following occurs:

Bayer Grade 4 corneal epitheliopathy (see Table 7-6).

CTCAE Grade 4 non-hematological AE (see Table 7-5).

[…]
AE = Adverse event; ARDS = Acute respiratory distress syndrome; β-HCG = β subunit of human chorionic gonadotropin; 
CTCAE = Common Terminology Criteria for Adverse Events; Hb = Hemoglobin; mRECIST = Modified Response 
Evaluation Criteria in Solid Tumors; PD = Progressive disease; Q3W = Every 3 weeks; QoL = Quality of life; 
SAE = Serious adverse event; TEAE = Treatment-emergent adverse event
Patients randomized but not treated
In the event a patient is randomized but never treated, a withdrawal from treatment CRF 
should be filled out for the patient articulating the date of and reason for not treating the 
patient. The patient should receive efficacy follow-up, active follow-up if feasible, otherwise 
long-term follow-up. No safety follow-up is required.
Lost to follow-up patients
When a patient is lost to follow-up at any stage of the study, the site should try to contact the 
patient, the patient’s relatives, or another doctor treating the patient, unless prohibited by local 
regulations. All attempts to contact the patient or relatives should be documented and sites are 
expected to perform at least 5 attempts to contact the patient over the course of 3 months. An 
additional contact attempt should be made at the time of each survival sweep.
SAFETY FOLLOW-UP VISIT
All patients who discontinue study treatment must perform this visit, 30+7 days after the last administration of study 
treatment.
Patients ending treatment without centrally 
confirmed radiological PD as per mRECIST criteria
Patients ending treatment with centrally confirmed 
radiological PD as per mRECIST criteria
ACTIVE FOLLOW-UP
Imaging and QoL assessment will continue until 
centrally confirmed PD is observed or they withdraw 
consent to active follow-up, are lost to follow-up or due 
to death.
LONG-TERM FOLLOW-UP
Patients who have centrally confirmed PD will have 
information on survival and new anti-cancer treatment 
collected.  
Patients must be withdrawn if they withdraw consent to 
long term follow-up, are lost to follow-up or due to death


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  158 of 269
15.1.2.14
Section 7.2.1 Test drug - anetumab ravtansine
Old text:
Stability of the reconstituted solution
[…]
If frozen or stored above 25°C (77°F), the solution should be discarded.
[…]
Stability of the diluted solution
[…]
If frozen or stored above 25°C, the solution should be discarded.
[…]
New text:
Stability of the reconstituted solution
[…]
If frozen or stored above room temperature, the solution should be discarded.
[…]
Stability of the diluted solution
[…]
If frozen or stored above room temperature, the solution should be discarded.
[…]
15.1.2.15
Section 7.2.2 Comparator - vinorelbine
Old text:
Vinorelbine formulation is a concentrate for infusion solution. It is available as concentrate 
with 10 mg/mL or 50 mg/mL vinorelbine (as tartrate).
[…]
New text:
Vinorelbine formulation is a concentrate for infusion solution. It is available as concentrate 
with 10 mg/mL or 50 mg/5 mL vinorelbine (as tartrate).
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  159 of 269
15.1.2.16
Section 7.3 Treatment assignment
Old text:
[…]
Confirmation of adequate level of mesothelin overexpression will be obtained from the 
central lab. Confirmation of at least 1 measurable lesion present will be obtained from central 
radiological review. Confirmation of other inclusion and exclusion requirements will be 
obtained from the investigator. After confirmation of patient eligibility in IxRS, a 
randomization code will be assigned.
New text:
[…]
Confirmation of adequate level of mesothelin overexpression will be obtained from the 
central lab. Confirmation of radiological eligibility will be obtained from central radiological 
review. Confirmation of other inclusion and exclusion requirements will be obtained from the 
investigator. After confirmation of patient eligibility in IxRS, a randomization code will be 
assigned.
15.1.2.17
Section 7.4.2.1 Dose modifications of anetumab ravtansine
Old text:
The NCI-CTCAE v4.03 will be used to assess toxicities; in addition, a Bayer grading system 
(see Table 7-6 and Table 7-7) will be used to assess corneal toxicity.
[…]
New text:
The NCI-CTCAE v4.03 will be used to assess toxicities; in addition, a Bayer grading system 
(see Table 7-6 and Table 7-7) will be used to assess corneal epitheliopathy.
[…]
15.1.2.18
Section 7.4.2.1.2 Non-hematological toxicities
Old text:
Non-hematological toxicities requiring dose modification

CTCAE Grade ≥ 2 anetumab ravtansine infusion reaction or other CTCAE Grade ≥ 2 
hypersensitivity events

AST and/or ALT increase  5.0 x ULN (CTCAE Grade  3)

AST and/or ALT increase  3.0 x ULN (CTCAE Grade  2) with concomitant 
increase in total bilirubin  1.5 x ULN (CTCAE Grade  2)


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  160 of 269

Total bilirubin  3.0 x ULN (CTCAE Grade  3)

Bayer Grade ≥ 3 corneal toxicity (see below and Table 7-6)

Any other Grade ≥ 3 non-hematological toxicity that, in the investigator’s opinion, 
warrants treatment modification (see Table 7-5), excluding the following:
o
Nausea, vomiting, or diarrhea if manageable with anti-emetics or anti-
diarrheals within 7 days
o
Hair loss
o
Fatigue lasting ≤ 72 h
o
Certain asymptomatic laboratory assessments without a clear clinical correlate, 
if the investigator determines that this TEAE would not require treatment 
modification
[…]
Dose modifications for non-hematological toxicity
If treatment modification is required due to Grade ≥ 3 non-hematological TEAE, other than 
corneal toxicity and infusion reaction/hypersensitivity events, and the continuation of 
treatment is appropriate, the anetumab ravtansine dose will be either reduced or maintained as 
is at investigator’s discretion (see Table 7-5).
[…]
After dose reduction, there could be no intra-patient dose escalation irrespective of the type of 
TEAE that has led to dose reduction in this patient.
New text:
Non-hematological toxicities requiring dose modification

CTCAE Grade 2 anetumab ravtansine infusion-related reaction or other CTCAE 
Grade 2 hypersensitivity events (see Section 7.4.2.1.3)

AST and/or ALT increase  5.0 x ULN (CTCAE Grade  3)

AST and/or ALT increase  3.0 x ULN (CTCAE Grade  2) with concomitant 
increase in total bilirubin  1.5 x ULN (CTCAE Grade  2)

Total bilirubin  3.0 x ULN (CTCAE Grade  3)

Bayer Grade ≥ 3 corneal epitheliopathy (see below and Table 7-6)

Any other Grade ≥ 3 non-hematological toxicity that, in the investigator’s opinion, 
warrants treatment modification (see Table 7-5), excluding the following:
o
Nausea, vomiting, or diarrhea if manageable with anti-emetics or anti-
diarrheals within 7 days


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  161 of 269
o
Hair loss
o
Fatigue lasting ≤ 72 h
[…]
Dose modifications for non-hematological toxicity
If treatment modification is required due to Grade ≥ 3 non-hematological TEAE, other than 
corneal epitheliopathy and infusion-related reaction/hypersensitivity events, and the 
continuation of treatment is appropriate, the anetumab ravtansine dose will be either reduced 
or maintained as is at investigator’s discretion (see Table 7-5).
[…]
After dose reduction for TEAE, there could be no intra-patient dose re-escalation irrespective 
of the type of TEAE that has led to dose reduction in this patient with the exception of grade 3 
corneal epitheliopathy as per Table 7-6.
15.1.2.19
Section 7.4.2.1.3 Miscellaneous toxicities
Old text:
IV infusion reaction and other hypersensitivity events
If a patient experiences a CTCAE Grade ≥ 2 anetumab ravtansine infusion reaction or other 
CTCAE Grade ≥ 2 hypersensitivity event deemed at least possibly related to anetumab 
ravtansine, the infusion of anetumab ravtansine will be interrupted.
If treatment interruption is caused by a CTCAE Grade ≥ 2 anetumab ravtansine infusion 
reaction or other CTCAE Grade ≥ 2 hypersensitivity event deemed at least possibly 
related to anetumab ravtansine, treatment may be re-started at the time determined at the 
investigator’s discretion. Re-treatment should be at the infusion rate reduced by 50%, along 
with anti-allergic prophylaxis (e.g. anti-histamines, acetaminophen, and/or corticosteroids) 
chosen at the investigator’s discretion or according to the institutional guidelines.
Miscellaneous toxicities requiring dose modification
For any toxicity ≤ Grade 2 assessed as related to anetumab ravtansine by the investigator, 
dose modification should be considered. Such toxicities might be ≤ Grade 2 toxicities which 
interfere with the activities of daily life, such as long lasting fatigue, or anorexia, or corneal 
toxicity with vision impairment etc. A dose change might be necessary in order to ensure the 
patient’s compliance. These toxicities may be declared “TEAE requiring treatment 
modification” after consultation between the investigator and the sponsor.
Dose modifications for corneal toxicity
For the TEAE of corneal morphology changes and the best corrected visual acuity (BCVA) 
changes (blurred vision), the Bayer severity grading system (see Table 7-6 and Table 7-7) will 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  162 of 269
be used to assess the severity of TEAEs requiring modification of anetumab ravtansine 
treatment.
TEAE of corneal morphology changes deemed to be at least possibly related to anetumab 
ravtansine would require modification of anetumab ravtansine treatment (dose reduction or 
permanent discontinuation of treatment) according to the following principles (see Table 7-6).
Table 7-6
Bayer classification and management of corneal epitheliopathies
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Corneal 
morphology
No pathologic 
changes
Any stage of 
superficial 
punctate 
keratitis a
Epithelial 
opacities
Corneal ulcer 
without risk of 
acute rupture
Corneal ulcer more 
severe than Grade 3
Micro-cysts
Micro-deposits
Corneal erosion
Stromal opacity: 
non-central
Stromal opacity: 
central
Eye 
treatment b
Ocular 
lubricants at the 
discretion of 
investigator and 
ophthalmologist
Ocular 
lubricants; 
add topical 
steroids if 
superficial 
punctate 
keratitis 
shows 
treatment-
emergent 
progression 
by ≥ 2 SPK 
Grades
Intensive 
treatment with 
ocular lubricants 
enhanced with 
ointments; topical 
steroids; 
therapeutic 
contact lens may 
be considered at 
the discretion of 
investigator and 
ophthalmologist
Intensive therapy 
with ointments; 
topical steroids; 
therapeutic contact 
lens or occlusion 
recommended at 
the discretion of 
investigator and 
ophthalmologist
Intensive therapy with 
lubricants, ointments, 
topical steroids and 
antibiotics as needed; 
occlusion or 
therapeutic contact 
lens recommended; 
amniotic membrane 
transplant and other 
locally approved 
therapies to be 
considered at the 
discretion of 
investigator and 
ophthalmologist
Anetumab 
ravtansine c
No change
No change
Keep treatment 
dose level and 
schedule if the 
ophthalmological 
exam can be 
performed as 
needed; 
otherwise 
consider dose 
reduction by 
-1 dose level 
without dose 
schedule change 
at the discretion 
of investigator 
and 
ophthalmologist
1) Decrease dose 
to -1 dose level (or 
-2 dose level if 
event does not 
resolve to Grade 
≤ 2 at the -1 dose 
level within 
3 weeks) 
2) Re-start at the 
original dose level if 
the first Grade 3 
event resolves to 
Grade ≤ 2 within 
3 weeks and does 
not recur
3) If not resolved 
within 3 weeks 
continue at reduced 
-1 dose level (or 
-2 dose level)
Discontinue treatment
SPK = Superficial punctate keratitis
a
Oxford Schema must be used for grading SPK from stage 0 to VI.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  163 of 269
Table 7-6
Bayer classification and management of corneal epitheliopathies
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
b
Other remedial therapies for corneal epitheliopathy may be added or substituted at investigator's discretion 
or according to the institutional standards.
c
Treatment decisions are based on corneal morphology changes only, not on visual acuity changes.
[…]
Recommended measures in case of eye dryness and ocular hypertension
[…]
Changes in IOP should be managed by an ophthalmologist. The remedial therapy should be 
chosen at investigator’s discretion or according to the institutional standards; therapeutic 
measures can include modification of the type or posology of topical steroid eye drop, 
initiation of topical IOP lowering drugs and any other therapeutic options according to the 
local SoC. Ophthalmological monitoring should be maintained until the IOP has returned to 
normal values.
Reductions in tear production evaluated by the Schirmer test, while not being a part of the 
corneal epitheliopathy syndrome, are a risk factor for developing ocular surface disease 
including corneal epithelial defects. Therefore, the tear production will be evaluated in this 
study to determine if changes in this parameter may be helpful to identify patients at higher 
risk of developing the corneal epitheliopathy syndrome. Abnormal values in the Schirmer test 
should be evaluated and managed by an ophthalmologist to provide adequate protection to the 
corneal epithelium. The remedial therapy for the treatment-emergent changes in the 
Schirmer’s test (dry eye) should be chosen at investigator’s discretion or according to the 
institutional standards. These measures may include topical lubricants such as eye drops and 
ointments, punctual occlusion, use of therapeutic contact lenses and any other treatment 
approaches according to the local SoC.
New text:
IV infusion-related reaction and other hypersensitivity events
If a patient experiences a CTCAE Grade 2 anetumab ravtansine infusion-related reaction or 
other CTCAE Grade 2 hypersensitivity event deemed at least possibly related to anetumab 
ravtansine, the infusion of anetumab ravtansine will be interrupted.
If treatment interruption is caused by a CTCAE Grade 2 anetumab ravtansine infusion-
related reaction or other CTCAE Grade 2 hypersensitivity event deemed at least possibly 
related to anetumab ravtansine, treatment may be re-started at the time determined at the 
investigator’s discretion. Re-treatment should be at the infusion rate reduced by 50%, along 
with anti-allergic prophylaxis (e.g. anti-histamines, acetaminophen, and/or corticosteroids) 
chosen at the investigator’s discretion or according to the institutional guidelines.
In case of a CTCAE Grade ≥ 3 hypersensitivity and acute infusion reaction, treatment must be 
permanently withdrawn.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  164 of 269
Miscellaneous toxicities requiring dose modification
For any toxicity ≤ Grade 2 assessed as related to anetumab ravtansine by the investigator, 
dose modification should be considered. Such toxicities might be ≤ Grade 2 toxicities which 
interfere with the activities of daily life, such as long lasting fatigue, or anorexia, or corneal 
epitheliopathy with vision impairment etc. A dose change might be necessary in order to 
ensure the patient’s compliance. These toxicities may be declared “TEAE requiring treatment 
modification” after consultation between the investigator and the sponsor.
Dose modifications for corneal epitheliopathy
For the TEAE of corneal epitheliopathy and the best corrected visual acuity (BCVA) changes 
(blurred vision), the Bayer severity grading system (see Table 7-6 and Table 7-7) will be used 
to assess the severity of TEAEs requiring modification of anetumab ravtansine treatment.
TEAE of corneal epitheliopathy deemed to be at least possibly related to anetumab ravtansine 
would require modification of anetumab ravtansine treatment (dose reduction or permanent 
discontinuation of treatment) according to the following principles (see Table 7-6).
Table 7-6
Bayer classification and management of corneal epitheliopathy
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Corneal 
morphology
No pathologic 
changes
Any stage of 
superficial 
punctate 
keratitis a
Epithelial 
opacities
Corneal ulcer 
without risk of 
acute rupture
Corneal ulcer more 
severe than Grade 3
Micro-cysts
Micro-deposits
Corneal erosion
Stromal opacity: 
non-central
Stromal opacity: 
central
Eye 
treatment b
Ocular 
lubricants at the 
discretion of 
investigator in 
consultation 
with 
ophthalmologist
/optometrist
Ocular 
lubricants; 
add topical 
steroids if 
superficial 
punctate 
keratitis 
shows 
treatment-
emergent 
progression 
by ≥ 2 SPK 
Grades
Intensive 
treatment with 
ocular lubricants 
enhanced with 
ointments; topical 
steroids; 
therapeutic 
contact lens may 
be considered at 
the discretion of 
investigator in 
consultation with 
ophthalmologist/ 
optometrist
Intensive therapy 
with ointments; 
topical steroids; 
therapeutic contact 
lens or occlusion 
recommended at 
the discretion of 
investigator in 
consultation with 
ophthalmologist/ 
optometrist
Intensive therapy with 
lubricants, ointments, 
topical steroids and 
antibiotics as needed; 
occlusion or 
therapeutic contact 
lens recommended; 
amniotic membrane 
transplant and other 
locally approved 
therapies to be 
considered at the 
discretion of 
investigator in 
consultation with 
ophthalmologist/ 
optometrist
Anetumab 
ravtansine c
No change
No change
Keep treatment 
dose level and 
schedule if the 
ophthalmological 
exam can be 
performed as 
1) Decrease dose 
to -1 dose level (or 
-2 dose level if 
event does not 
resolve to Grade 
≤ 2 at the -1 dose 
Discontinue treatment


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  165 of 269
Table 7-6
Bayer classification and management of corneal epitheliopathy
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
needed; 
otherwise 
consider dose 
reduction by 
-1 dose level 
without dose 
schedule change 
at the discretion 
of investigator in 
consultation with 
ophthalmologist/ 
optometrist
level within 
3 weeks) 
2) Re-start at the 
original dose level if 
the first Grade 3 
event resolves to 
Grade ≤ 2 within 
3 weeks and does 
not recur
3) If not resolved 
within 3 weeks 
continue at reduced 
-1 dose level (or 
-2 dose level)
SPK = Superficial punctate keratitis
a
Oxford Schema must be used for grading SPK from stage 0 to VI.
b
Other remedial therapies for corneal epitheliopathy may be added or substituted at investigator's discretion 
or according to the institutional standards.
c
Treatment decisions are based on corneal epitheliopathy only, not on visual acuity changes.
[…]
Recommended measures in case of eye dryness and ocular hypertension
[…]
Changes in IOP should be managed by an ophthalmologist/optometrist. The remedial therapy 
should be chosen at investigator’s discretion or according to the institutional standards; 
therapeutic measures can include modification of the type or posology of topical steroid eye 
drop, initiation of topical IOP lowering drugs and any other therapeutic options according to 
the local SoC. Ophthalmological monitoring should be maintained until the IOP has returned 
to normal values.
Reductions in tear production evaluated by the Schirmer test, while not being a part of the 
corneal epitheliopathy syndrome, are a risk factor for developing ocular surface disease 
including corneal epithelial defects. Therefore, the tear production will be evaluated in this 
study to determine if changes in this parameter may be helpful to identify patients at higher 
risk of developing the corneal epitheliopathy syndrome. Abnormal values in the Schirmer test 
should be evaluated and managed by an ophthalmologist/optometrist to provide adequate 
protection to the corneal epithelium. The remedial therapy for the treatment-emergent changes 
in the Schirmer test (dry eye) should be chosen at investigator’s discretion or according to the 
institutional standards. These measures may include topical lubricants such as eye drops and 
ointments, punctual occlusion, use of therapeutic contact lenses and any other treatment 
approaches according to the local SoC.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  166 of 269
15.1.2.20
Section 7.4.2.2 Dose modifications of vinorelbine
Old text:
The following dose modifications for vinorelbine, based on the US label guidance (27), are 
provided below as a general recommendation. After dose reduction, there could be no intra-
patient dose escalation irrespective of the type of TEAE that has led to dose reduction in this 
patient. All label specific instructions for treatment with vinorelbine will apply. Please refer to 
the local full prescribing information for further guidance.
[…]
New text:
The following dose modifications for vinorelbine, based on the US label guidance (27), are 
provided below as a general recommendation. After dose reduction for TEAE, there could be 
no intra-patient dose re-escalation irrespective of the type of TEAE that has led to dose 
reduction in this patient. All label specific instructions for treatment with vinorelbine will 
apply. Please refer to the local full prescribing information for further guidance.
[…]
15.1.2.21
Section 8.1 Prior and concomitant therapy
Old text:
[…]
Table 8-2
Permitted concomitant therapies
Permitted concomitant therapies
Comments
Permitted for all patients
[…]
Institutional standards for the management of 
infusion reactions 
May be utilized at the discretion of the investigator.
[…] 
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  167 of 269
New text:
[…]
Table 8-2
Permitted concomitant therapies
Permitted concomitant therapies
Comments
Permitted for all patients
[…]
Institutional standards for the management of 
infusion-related reactions or other 
hypersensitivity events
May be utilized at the discretion of the investigator.
[…] 
[…]
15.1.2.22
Section 9.1 Tabular schedule of evaluations
Old text:
Schedule of procedures is presented in Table 9-1.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  168 of 269
Table 9-1
Study flow chart
Treatment
Pre-
screening
Full screening
(maximum days 
before C1D1)
Cycle 1
Cycle 2 and higher
Safety follow-up 
period / visit
Active 
follow-up a
Long-term 
follow-up a
Days
-28
- 7
D1
D8 
D15 
D1
D8 b
D15 b
+30 (after last 
dose)
Every 3 
months
Acceptable time window (in days)
(unless otherwise specified)
+/-1
+/-1
+/-1
+/-1
+/-1
+7
±14
Screening and enrollment
Written informed consent for 
prescreening c
X
Written informed consent for full 
study c
X
Demographics
X
Study disease characteristics d
X
X
Medical history d
X
Check eligibility criteria
X
X
X
IxRS transaction e
X
X
X
X
X
X
X
X
Safety
Toxicity / AE assessment f 
X f
X
X
X
X
X
X
X
X
X
X f
Concomitant medication
X f
X
X
X
X
X
X
X
X
X f
Complete physical examination
X
Brief physical examination g
X
X
X
X
X g
X g
X
Vital signs (BP, HR, RR, Temp)
X
X
X
X
X
X
X
X
X
Weight/height h
X h
X
X
X
X
X
X
X
12-Lead ECG i
X
X i
X i
X
ECOG PS assessment
X
X
X
X
X
EchoCG or MUGA scan j
X
X j
Ophthalmologic examination k
X
X 
X
Complete blood count
X
X
X
X
X
X
X
Electrolyte and chemistry panel
X
X l
X l
X
X l
X l
X
eGFR
X
X
X
Coagulation panel
X
X
X


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  169 of 269
Table 9-1
Study flow chart
Treatment
Pre-
screening
Full screening
(maximum days 
before C1D1)
Cycle 1
Cycle 2 and higher
Safety follow-up 
period / visit
Active 
follow-up a
Long-term 
follow-up a
Days
-28
- 7
D1
D8 
D15 
D1
D8 b
D15 b
+30 (after last 
dose)
Every 3 
months
Acceptable time window (in days)
(unless otherwise specified)
+/-1
+/-1
+/-1
+/-1
+/-1
+7
±14
Urine dipstick m
X
X
X
Serum pregnancy test (if applicable)
X n
X
Efficacy
Radiological tumor evaluation with 
contrast-enhanced CT/MRI o
X 
Every 6 weeks (first 6 months), every 9 
weeks (until end of year 2), every 12 
weeks thereafter o
X o
Forced vital capacity (FVC) o
X
In parallel with CT/MRI o
X o
Disease and survival status p
X
[…]
Patient-reported outcomes
LCSS-Meso y
X
X
X
X y
MDASI-MPM y
X
X
X
X y
[…]
AE = Adverse event; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; BP = Blood pressure; BM = Biomarker; C = Cycle; CT = Computed 
tomography; CYP2D6 = Cytochrome P450, family 2, subfamily D, polypeptide 6; D = Day; ECG = Electrocardiogram; EchoCG = Echocardiogram; ECOG PS 
= Eastern Cooperative Oncology Group Performance Status; eGFR = Estimated glomerular filtration rate; FVC = Forced vital capacity; HR = Heart rate; 
IHC = Immunohistochemistry; IM = Immunogenicity; IOP = Intraocular pressure; IV = Intravenous; IxRS = Interactive Voice / Web Response System; LCSS-
Meso = Lung Cancer Symptom Scale-Mesothelioma; MDASI-MPM = MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma; 
mRECIST = Modified Response Evaluation Criteria in Solid Tumors; MRI = Magnetic resonance imaging; MUGA = Multiple gated acquisition; OS = Overall 
survival; PD = Progressive disease; PFS = Progression-free survival; PGt = Pharmacogenetic; PK = Pharmacokinetic(s); PR = Partial response; RR = 
Respiratory rate; SAE = Serious adverse event; Temp = Body temperature.
[…]
e
IxRS transaction to register the patient in the system will be done at prescreening. IxRS transaction to randomize the patient will take place 
on the day of the first dose of study drug. IxRS transactions for medication dispensing will be done on Day 1 of each cycle for the anetumab 
ravtansine arm and on Day 1, Day 8, and Day 15 for the comparator arm. IxRS transaction to register the end of treatment will be done at the 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  170 of 269
safety follow-up visit.
[…]
k
A detailed ophthalmologic examination (visual acuity, IOP, Schirmer test and slit lamp) will be done for all patients during full screening within 
3 weeks before the start of study treatment. For patients treated in the anetumab ravtansine arm visual acuity and slit lamp exam will be 
repeated before infusion in every cycle except C1D1, and at safety follow-up visit, or more frequently at investigator’s and ophthalmologist’s 
discretion (important to refer to Table 7-6 and Table 7-7). IOP measurement is to be repeated during anetumab ravtansine therapy if the 
patient receives steroid eye drops as treatment for eye toxicity; dry eye (Schirmer) test may be repeated during treatment at investigator’s 
discretion (e.g. in case of eye dryness during anetumab ravtansine therapy). During treatment period, ophthalmologic examination can be 
done up to 7 days before anetumab ravtansine infusion.
[…]
o
Pre-study CT/MRI may be acceptable as a baseline scan if done within 28 days before randomization, if centrally evaluable for mRECIST 
and if performed according to the Imaging Acquisition Guidance provided in the Imaging Manual. During treatment period as well as active 
follow-up period, tumor scans (contrast-enhanced CT/MRI of chest/abdomen/pelvis) and FVC will be performed with the same modality every 
6 weeks during the first 6 months (24 weeks) after the start of study treatment, every 9 weeks until the end of year 2 (105 weeks), and every 
12 weeks thereafter until centrally confirmed radiological disease progression or end of study. MRI shall be performed instead of CT when 
local regulations do not permit the use of CT as requested per protocol schedule. Visit window of +/- 7 days is allowed.
[…]
r
PK sampling will be performed for patients in the anetumab ravtansine arm on C1D1, C1D8, C2D1, C3D1, C3D8, C3D15, C4D1, C6D1, 
C9D1 and on Day 1 of every 3 cycles thereafter. Unscheduled PK samples are requested at the next clinic visit after the initial onset of 
corneal toxicity and after the radiological assessment of the first PR (for details see Section 9.5).
[…]
y
MDASI-MPM and LCSS-Meso are to be completed before the patient meets with a clinician or before any examination or test is performed on 
that day. MDASI-MPM and LCSS-Meso are to be completed at full screening, on C2D1 and on Day 1 of every cycle thereafter (e.g. C3D1, 
C4D1 etc.), at safety follow-up visit, and during active follow-up period. During active follow-up period, MDASI-MPM and LCSS-Meso are to 
be taken in parallel with CT/MRI.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  171 of 269
New text:
Schedule of procedures is presented in Table 9-1.
Table 9-1
Study flow chart
Treatment
Pre-
screening
Full screening
(maximum days 
before C1D1)
Cycle 1
Cycle 2 and higher
Safety follow-up 
period / visit
Active 
follow-up a
Long-term 
follow-up a
Days
-28
- 7
D1
D8 
D15 
D1
D8 b
D15 b
+30 (after last 
dose)
Every 3 
months
Acceptable time window (in days)
(unless otherwise specified)
+/-1
+/-1
+/-1
+/-1
+/-1
+7
±14
Screening and enrollment
Written informed consent for 
prescreening c
X
Written informed consent for full 
study c
X
Demographics
X
Study disease characteristics d
X
X
Medical history d
X
Check eligibility criteria
X
X
Xz
IxRS transaction e
X
X
Xz
X
X
X
X
X
X
Safety
Toxicity / AE assessment f 
X f
X
X
Xz
X
X
X
X
X
X
X f
Concomitant medication
X f
X
Xz
X
X
X
X
X
X
X f
Complete physical examination
X
Brief physical examination g
Xz
X
X
X
X g
X g
X
Vital signs (BP, HR, RR, Temp)
X
X
Xz
X
X
X
X
X
X
Weight/height h
X h
Xz
X
X
X
X
X
X
12-Lead ECG i
X
X i
X i
X
ECOG PS assessment
X
X
Xz
X
X
EchoCG or MUGA scan j
X
X j
Ophthalmologic examination k
X
X 
X
Complete blood count
X
X
X
X
X
X
X


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  172 of 269
Table 9-1
Study flow chart
Treatment
Pre-
screening
Full screening
(maximum days 
before C1D1)
Cycle 1
Cycle 2 and higher
Safety follow-up 
period / visit
Active 
follow-up a
Long-term 
follow-up a
Days
-28
- 7
D1
D8 
D15 
D1
D8 b
D15 b
+30 (after last 
dose)
Every 3 
months
Acceptable time window (in days)
(unless otherwise specified)
+/-1
+/-1
+/-1
+/-1
+/-1
+7
±14
Electrolyte and chemistry panel
X
X l
X l
X
X l
X l
X
eGFR
X
X
X
Coagulation panel
X
X
X
Urine dipstick m
X
X
Serum pregnancy test (if applicable)
X n
X
Efficacy
Radiological tumor evaluation with 
contrast-enhanced CT/MRI o
X 
Every 6 weeks (first 6 months), every 9 
weeks (until end of year 2), every 12 
weeks thereafter o
X o
Disease and survival status p
X
[…]
Patient-reported outcomes
LCSS-Meso y
X
X
X
X y
MDASI-MPM y
X
X
X
Xy
X y
X y
X
X y
[…]
AE = Adverse event; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; BP = Blood pressure; BM = Biomarker; C = Cycle; CT = Computed 
tomography; CYP2D6 = Cytochrome P450, family 2, subfamily D, polypeptide 6; D = Day; ECG = Electrocardiogram; EchoCG = Echocardiogram; ECOG PS 
= Eastern Cooperative Oncology Group Performance Status; eGFR = Estimated glomerular filtration rate; HR = Heart rate; IHC = Immunohistochemistry; IM 
= Immunogenicity; IOP = Intraocular pressure; IV = Intravenous; IxRS = Interactive Voice / Web Response System; LCSS-Meso = Lung Cancer Symptom 
Scale-Mesothelioma; MDASI-MPM = MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma; mRECIST = Modified Response Evaluation Criteria 
in Solid Tumors; MRI = Magnetic resonance imaging; MUGA = Multiple gated acquisition; OS = Overall survival; PD = Progressive disease; 
PFS = Progression-free survival; PGt = Pharmacogenetic; PK = Pharmacokinetic(s); PR = Partial response; RR = Respiratory rate; SAE = Serious adverse 
event; Temp = Body temperature.
[…]
e
IxRS transaction to register the patient in the system will be done at prescreening. IxRS transaction to randomize the patient will take place 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  173 of 269
maximum 24 hours before the administration of first dose of study drug and can only be done after all inclusion and exclusion criteria are 
checked and eligibility is confirmed. IxRS transactions for medication dispensing will be done on Day 1 of each cycle for the anetumab 
ravtansine arm and on Day 1, Day 8, and Day 15 for the comparator arm. IxRS transaction to register the end of treatment will be done at the 
safety follow-up visit.
[…]
k
A detailed ophthalmologic examination (visual acuity, IOP, Schirmer test and slit lamp) will be done for all patients during full screening within 
3 weeks before the start of study treatment. For patients treated in the anetumab ravtansine arm visual acuity and slit lamp exam will be 
repeated before infusion in every cycle except C1D1, and at safety follow-up visit, or more frequently at investigator’s and 
ophthalmologist/optometrist’s discretion (important to refer to Table 7-6 and Table 7-7). IOP measurement is to be repeated during 
anetumab ravtansine therapy if the patient receives steroid eye drops as treatment for corneal epitheliopathy; dry eye (Schirmer) test may be 
repeated during treatment at investigator’s discretion (e.g. in case of eye dryness during anetumab ravtansine therapy). During treatment 
period, ophthalmologic examination can be done up to 7 days before anetumab ravtansine infusion.
[…]
o
Pre-study CT/MRI may be acceptable as a baseline scan if done within 28 days before randomization, if centrally evaluable for mRECIST 
and if performed according to the Imaging Acquisition Guidance provided in the Imaging Manual. During treatment period as well as active 
follow-up period, tumor scans (contrast-enhanced CT/MRI of chest/abdomen/pelvis) will be performed with the same modality every 6 weeks 
during the first 6 months (24 weeks) after the start of study treatment, every 9 weeks until the end of year 2 (105 weeks), and every 12 weeks 
thereafter until centrally confirmed radiological disease progression or end of study. MRI shall be performed instead of CT when local 
regulations do not permit the use of CT as requested per protocol schedule. Visit window of +/- 7 days is allowed.
[…]
r
PK sampling will be performed for patients in the anetumab ravtansine arm on C1D1, C1D8, C2D1, C3D1, C3D8, C3D15, C4D1, C6D1, 
C9D1 and on Day 1 of every 3 cycles thereafter. Unscheduled PK samples are requested at the next clinic visit after the initial onset of 
corneal epitheliopathy and after the radiological assessment of the first PR (for details see Section 9.5).
[…]
y
MDASI-MPM and LCSS-Meso are to be completed before the patient meets with a clinician and before any examination or test is performed 
on that day. MDASI-MPM and LCSS-Meso are to be completed at full screening, on C2D1 and on Day 1 of every cycle thereafter (e.g. C3D1, 
C4D1 etc.), at safety follow-up visit, and during active follow-up period. During active follow-up period, MDASI-MPM and LCSS-Meso are to 
be taken in parallel with CT/MRI. In addition, the MDASI-MPM only is performed on Day 8 and Day 15 during Cycles 1, 2 and 3.
z
Eligibility criteria check, IxRS transaction to randomize the patient, toxicity / AE assessment, concomitant medication review, brief physical 
examination, vital signs and weight measurement, and ECOG PS assessment can be done within 24 hours before administration of the first 
dose of study drug. Eligibility must be confirmed prior to randomizing the patient in IxRS.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  174 of 269
15.1.2.23
Section 9.2.2 Full screening period
Old text:
Within 28 days before the start of study treatment: 

Written informed consent for full study.

Updates of study disease characteristics and prior therapies for the study indication 
(see Section 9.3.3).

Medical history (see Section 9.3.2) and non-study-indication-related medications (see 
Section 9.3.3).

Check eligibility criteria for full study, and exclusion criteria (see Section 6.1.2 and 
6.2, respectively).

Radiological tumor evaluation with contrast-enhanced CT/MRI of 
chest/abdomen/pelvis (see Section 9.4.1). Pre-study CT/MRI may be acceptable as a 
baseline scan if done within 28 days before randomization, if centrally evaluable for 
mRECIST and if performed according to the Imaging Acquisition Guidance provided 
in the Imaging Manual.

FVC measurement (see Section 9.4.2).

Toxicity/AE assessment: any new finding or worsening of any ongoing medical 
history condition after the patient has signed the full study ICF must be recorded as an 
AE (see Section 9.6.1).
[…]
Within 7 days before the start of study treatment:

PROs (LCSS-Meso and MDASI-MPM) (see Section 9.4.4) before the patient meets 
with a clinician or before any examination or test is performed.
[…]
New text:
Within 28 days before the start of study treatment: 

Written informed consent for full study.

IxRS transaction to register the patient’s full screening (see Section 6.4) 

Updates of study disease characteristics and prior therapies for the study indication 
(see Section 9.3.3).

Medical history (see Section 9.3.2) and non-study-indication-related medications (see 
Section 9.3.3).

Check eligibility criteria for full study, and exclusion criteria (see Section 6.1.2 and 
6.2, respectively).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  175 of 269

Radiological tumor evaluation with contrast-enhanced CT/MRI of 
chest/abdomen/pelvis (see Section 9.4.1). Pre-study CT/MRI may be acceptable as a 
baseline scan if done within 28 days before start of study drug, if centrally evaluable 
for mRECIST and if performed according to the Imaging Acquisition Guidance 
provided in the Imaging Manual.

Toxicity/AE assessment: any new finding or worsening of any ongoing medical 
history condition after the patient has signed the full study ICF must be recorded as an 
AE (see Section 9.6.1).
[…]
Within 7 days before the start of study treatment:

PROs (LCSS-Meso and MDASI-MPM) (see Section 9.4.3) before the patient meets 
with a clinician and before any examination or test is performed.
[…]
15.1.2.24
Section 9.2.3 Treatment period
Old text:
After all screening assessments have been completed and the patient’s eligibility has been 
confirmed and documented (confirmation of mesothelin overexpression moderate [2+] and 
strong [3+] in at least 30% of tumor cells will be obtained from central lab and confirmation 
of at least 1 measurable lesion present will be obtained from central radiological review), the 
patient may begin treatment.
New text:
After all screening assessments have been completed and the patient’s eligibility has been 
confirmed and documented (confirmation of mesothelin overexpression moderate and 
stronger in at least 30% of tumor cells will be obtained from central lab and confirmation of 
radiological eligibility will be obtained from central radiological review), the patient may 
begin treatment.
15.1.2.25
Section 9.2.3.1 Treatment – Cycle 1
Old text:
The following procedures should be performed on C1D1 before receiving study treatment 
unless otherwise specified in the protocol:

Check eligibility criteria for full study, and exclusion criteria (see Section 6.1.2 and 
6.2, respectively).

IxRS transaction to randomize the patient (see Section 6.4) on the day of the first dose 
of study drug and for medication dispensing in both treatment arms (see Section 7.3).

Toxicity/AE assessment (see Section 9.6.1).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  176 of 269

Concomitant medication review (see Section 8.1).

Brief physical examination (see Section 9.6.3.2.2).

Vital signs (see Section 9.6.3.4).

Weight.

ECOG PS assessment (see Section 9.6.3.3).

Laboratory (see Section 9.6.3.1):

Urine dipstick. 

PK sampling (see Section 9.5):

In the anetumab ravtansine arm: Pre-infusion (within 1 h before the start of 
infusion), end of infusion (within 5 min after the end of infusion) and 
approximately 3 h (range: 2 to 4 h) after the start of infusion. 

In the comparator arm: Pre-infusion (within 1 h before the start of infusion), 
end of infusion (within 5 min after the end of infusion), approximately 3 h 
(range: 2 to 4 h) after the start of infusion. 
[…]
Cycle 1 Day 8
[…]
The following procedures should be performed on C1D8 before receiving study treatment 
unless otherwise specified in the protocol: 

IxRS transaction for medication dispensing in the comparator arm (see Section 7.3).
[…]
Cycle 1 Day 15
[…]
The following procedures should be performed on C1D15 before receiving study treatment 
unless otherwise specified in the protocol: 

IxRS transaction for medication dispensing in the comparator arm (see Section 7.3).
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  177 of 269
New text:
The following procedures should be performed on C1D1 before receiving study treatment 
unless otherwise specified in the protocol. Eligibility criteria check, IxRS transaction to 
randomize the patient, toxicity / AE assessment, concomitant medication review, brief 
physical examination, vital signs and weight measurement, and ECOG PS assessment can be 
done within 24 hours before administration of the first dose of study drug. Eligibility must be 
confirmed prior to randomizing the patient in IxRS.

Check eligibility criteria for full study, and exclusion criteria (see Section 6.1.2 and 
6.2, respectively).

IxRS transaction to randomize the patient (see Section 6.4) and for medication 
dispensing in both treatment arms (see Section 7.3).

Toxicity/AE assessment (see Section 9.6.1).

Concomitant medication review (see Section 8.1).

Brief physical examination (see Section 9.6.3.2.2).

Vital signs (see Section 9.6.3.4).

Weight.

ECOG PS assessment (see Section 9.6.3.3).

PK sampling (see Section 9.5):

In the anetumab ravtansine arm: Pre-infusion (within 1 h before the start of 
infusion), end of infusion (within 5 min after the end of infusion) and 
approximately 3 h (range: 2 to 4 h) after the start of infusion. 

In the comparator arm: Pre-infusion (within 1 h before the start of infusion), 
end of infusion (within 5 min after the end of infusion), approximately 3 h 
(range: 2 to 4 h) after the start of infusion. 
[…]
Cycle 1 Day 8
[…]
The following procedures should be performed on C1D8 before receiving study treatment 
unless otherwise specified in the protocol: 

PRO (MDASI-MPM) (see Section 9.4.3) before the patient meets with a clinician or 
before any examination and test is performed.

IxRS transaction for medication dispensing in the comparator arm (see Section 7.3).
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  178 of 269
Cycle 1 Day 15
[…]
The following procedures should be performed on C1D15 before receiving study treatment 
unless otherwise specified in the protocol: 

PRO (MDASI-MPM) (see Section 9.4.3) before the patient meets with a clinician and 
before any examination or test is performed.

IxRS transaction for medication dispensing in the comparator arm (see Section 7.3).
[…]
15.1.2.26
Section 9.2.3.2 Treatment – Cycle 2 and higher
Old text:
Cycle 2 and higher Day 1
[…]

PROs (LCSS-Meso and MDASI-MPM) (see Section 9.4.4) before the patient meets 
with a clinician or before any examination or test is performed.
[…]

Ophthalmologic examinations (visual acuity and slit lamp mandatory; IOP and 
Schirmer test optional) (see Section 9.6.3.7) for patients treated in the anetumab 
ravtansine arm in every cycle from C2D1 onwards, or more frequently at 
investigator’s and ophthalmologist’s discretion (important to refer to Table 7-6 and 
Table 7-7). To be performed within 7 days before anetumab ravtansine infusion.
[…]

PK sampling (see Section 9.5) for patients in the anetumab ravtansine arm will be 
done on C2D1, C3D1, C4D1, C6D1, C9D1 and on Day 1 of every 3 cycles thereafter:

C2D1: Pre-infusion (within 1 h before the start of infusion). 

C3D1: Pre-infusion (within 1 h before the start of infusion), end of infusion 
(within 5 min after the end of infusion) and approximately 3 h (range: 2 to 4 h) 
after the start of infusion. 

C4D1: Approximately 504 h after the start of C3D1 infusion (within 1 h before 
the start of infusion on C4D1). 

C6D1, C9D1 and on Day 1 of every 3 cycles thereafter: Pre-infusion (within 
1 h before the start of infusion) and end of infusion (within 5 min after the end 
of infusion). 
Unscheduled PK samples are requested at the next clinic visit after the initial onset of 
corneal toxicity and after the radiological assessment of the first PR (the first local 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  179 of 269
observation of at least a 30% reduction in the total tumor measurement according to 
mRECIST).
[…]
Cycle 2 and higher Day 8
[…]
The following procedures should be performed on Cycle 2 and higher, Day 8 before 
receiving study treatment unless otherwise specified in the protocol:

IxRS transaction for medication dispensing in the comparator arm (see Section 7.3).
[…]
Cycle 2 and higher Day 15
[…]
The following procedures should be performed on Cycle 2 and higher, Day 15 before 
receiving study treatment unless otherwise specified in the protocol:

IxRS transaction for medication dispensing in the comparator arm (see Section 7.3).
 […]
New text:
Cycle 2 and higher Day 1
[…]

PROs (LCSS-Meso and MDASI-MPM) (see Section 9.4.3) before the patient meets 
with a clinician and before any examination or test is performed.
[…]

Ophthalmologic examinations (visual acuity and slit lamp mandatory; IOP and 
Schirmer test optional) (see Section 9.6.3.7) for patients treated in the anetumab 
ravtansine arm in every cycle from C2D1 onwards, or more frequently at 
investigator’s and ophthalmologist/optometrist’s discretion (important to refer to 
Table 7-6 and Table 7-7). To be performed within 7 days before anetumab ravtansine 
infusion.
[…]

PK sampling (see Section 9.5) for patients in the anetumab ravtansine arm will be 
done on C2D1, C3D1, C4D1, C6D1, C9D1 and on Day 1 of every 3 cycles thereafter:

C2D1: Pre-infusion (within 1 h before the start of infusion). 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  180 of 269

C3D1: Pre-infusion (within 1 h before the start of infusion), end of infusion 
(within 5 min after the end of infusion) and approximately 3 h (range: 2 to 4 h) 
after the start of infusion. 

C4D1: Approximately 504 h after the start of C3D1 infusion (within 1 h before 
the start of infusion on C4D1). 

C6D1, C9D1 and on Day 1 of every 3 cycles thereafter: Pre-infusion (within 
1 h before the start of infusion) and end of infusion (within 5 min after the end 
of infusion). 
Unscheduled PK samples are requested at the next clinic visit after the initial onset of 
corneal epitheliopathy and after the radiological assessment of the first PR (the first 
local observation of at least a 30% reduction in the total tumor measurement according 
to mRECIST).
[…]
Cycle 2 and higher Day 8
[…]
The following procedures should be performed on Cycle 2 and higher, Day 8 before 
receiving study treatment unless otherwise specified in the protocol:

PRO (MDASI-MPM) (only C2D8 and C3D8, see Section 9.4.3) before the patient 
meets with a clinician and before any examination or test is performed.

IxRS transaction for medication dispensing in the comparator arm (see Section 7.3).
[…]
Cycle 2 and higher Day 15
[…]
The following procedures should be performed on Cycle 2 and higher, Day 15 before 
receiving study treatment unless otherwise specified in the protocol:

PRO (MDASI-MPM) (only C2D15 and C3D15, see Section 9.4.3) before the patient 
meets with a clinician and before any examination or test is performed.

IxRS transaction for medication dispensing in the comparator arm (see Section 7.3).
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  181 of 269
15.1.2.27
Section 9.2.4 Efficacy assessments
Old text:
Radiological tumor evaluations and forced vital capacity measurements
Radiological tumor evaluation with contrast-enhanced CT/MRI of chest/abdomen/pelvis and 
FVC measurement will be performed at the following intervals (for further details, see 
Sections 9.4.1 and 9.4.2, respectively).
Full screening (baseline):

Within 28 days before the start of study treatment and randomization.
[…]
New text:
Radiological tumor evaluations
Radiological tumor evaluation with contrast-enhanced CT/MRI of chest/abdomen/pelvis will 
be performed at the following intervals (for further details, see Section 9.4.1).
Full screening (baseline):

Within 28 days before the start of study treatment.
[…]
15.1.2.28
Section 9.2.5.1 Safety follow-up
Old text:
[…]

PROs (LCSS-Meso and MDASI-MPM) (see Section 9.4.4) before the patient meets 
with a clinician or before any examination or test is performed.
[…]
New text:
[…]

PROs (LCSS-Meso and MDASI-MPM) (see Section 9.4.3) before the patient meets 
with a clinician and before any examination or test is performed.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  182 of 269
15.1.2.29
Section 9.2.5.2 Active follow-up
Old text:
Patients who discontinue study treatment due to any other reason than centrally confirmed 
radiological PD will continue clinic visits during active follow-up for efficacy assessments 
including tumor response, FVC and QoL. These assessments will continue until disease 
progression, consent withdrawal, lost to follow-up or end of study.

PROs (LCSS-Meso and MDASI-MPM) (see Section 9.4.4) before the patient meets 
with a clinician or before any examination or test is performed. During active follow-
up period MDASI-MPM and LCSS-Meso are to be taken in parallel with CT/MRI.
[…]

FVC measurement (see Section 9.4.2), in parallel with CT/MRI.

Toxicity/AE assessment (see Section 9.6.1), in parallel with CT/MRI. During active 
follow-up period, only AEs and SAEs that are related to study-specific procedures are 
mandatory to be reported. However, at the investigator’s discretion, SAEs may be 
reported if considered potentially relevant. In such cases, the SAEs will be processed 
by the sponsor according to all applicable regulations.
[…]
New text:
Patients who discontinue study treatment due to any other reason than centrally confirmed 
radiological PD will continue clinic visits during active follow-up for efficacy assessments 
including tumor response and QoL. These assessments will continue until disease 
progression, consent withdrawal, lost to follow-up or end of study.

PROs (LCSS-Meso and MDASI-MPM) (see Section 9.4.3) before the patient meets 
with a clinician and before any examination or test is performed. During active follow-
up period MDASI-MPM and LCSS-Meso are to be taken in parallel with CT/MRI.
[…]

Toxicity/AE assessment (see Section 9.6.1), in parallel with CT/MRI. During active 
follow-up period, only AEs and SAEs that are related to study-specific procedures are 
mandatory to be reported. However, at the investigator’s discretion, SAEs may be 
reported if considered potentially relevant. In such cases, the SAEs will be processed 
by the sponsor according to all applicable regulations.
[…]
15.1.2.30
Section 9.4.1 Radiological tumor assessments
Old text:
The first radiological (contrast-enhanced CT/MRI of chest/abdomen/pelvis) tumor evaluation 
will be conducted during full screening within 28 days before the start of study treatment (see 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  183 of 269
flow chart in Section 9.1). Pre-study CT/MRI may be acceptable as a baseline scan if done 
within 28 days before randomization, if centrally evaluable for mRECIST and if performed 
according to the Imaging Acquisition Guidance provided in the Imaging Manual. Baseline 
CT/MRI should be obtained prior to randomization. A sole positron emission tomography 
(PET) scan without a diagnostic CT/MRI is not acceptable for radiological evaluation of 
target lesions; findings must be confirmed by CT or MRI. Although PET scan findings may 
be used as supportive evidence of tumor assessment, the CT or MRI results will be the 
definitive and documented data for the study. All subsequent scans should be done with the 
identical method and technique (e.g. slice thickness, field of view) to those obtained at 
baseline. These screening images will be provided to blinded central review to assess 
radiological eligibility (central confirmation of at least 1 measurable lesion required before 
randomization). If focal neurological symptoms are present at screening, a CT scan or MRI of 
the brain is required to rule out brain metastasis by the investigator. All additional suspected 
sites of disease should be imaged (e.g. cervical lymph nodes, bone etc.).
[…]
New text:
The first radiological (contrast-enhanced CT/MRI of chest/abdomen/pelvis) tumor evaluation 
will be conducted during full screening within 28 days before the start of study treatment (see 
flow chart in Section 9.1). Pre-study CT/MRI may be acceptable as a baseline scan if done 
within 28 days before start of study drug, if centrally evaluable for mRECIST and if 
performed according to the Imaging Acquisition Guidance provided in the Imaging Manual. 
Baseline CT/MRI should be obtained prior to randomization. A sole positron emission 
tomography (PET) scan without a diagnostic CT/MRI is not acceptable for radiological 
evaluation of target lesions; findings must be confirmed by CT or MRI. Although PET scan 
findings may be used as supportive evidence of tumor assessment, the CT or MRI results will 
be the definitive and documented data for the study. All subsequent scans should be done with 
the identical method and technique (e.g. slice thickness, field of view) to those obtained at 
baseline. These screening images will be provided to blinded central review to assess 
radiological eligibility (central confirmation of radiological eligibility required before 
randomization). If focal neurological symptoms are present at screening, a CT scan or MRI of 
the brain is required to rule out brain metastasis by the investigator. All additional suspected 
sites of disease should be imaged (e.g. cervical lymph nodes, bone etc.).
[…]
15.1.2.31
Section 9.4 Efficacy
Old text:
9.4.2 Pulmonary function assessment
Forced vital capacity (FVC) as a measure of pulmonary function in chemotherapy pre-treated 
patients will be evaluated by a spirometry machine at full screening within 28 days before the 
start of study treatment (see flow chart in Section 9.1). During treatment period as well as 
active follow-up period FVC will be performed in parallel with tumor scans i.e. with the same 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  184 of 269
modality every 6 weeks during the first 6 months after the start of study treatment, every 
9 weeks until the end of year 2, and every 12 weeks thereafter until centrally confirmed 
radiological disease progression or end of study. Visit window of +/- 7 days is allowed.
New text:
Section 9.4.2 Pulmonary function assessment removed by amendment 2; numbering of the 
following sections changed accordingly
15.1.2.32
Section 9.4.2 Survival
Old text:
Patients will be contacted for survival every 3 months (±14 days) during long-term follow-up 
until data maturation for the OS final analysis is reached, death, withdrawal of consent, lost to 
follow-up or the end of study, whichever occurs first (see flow chart in Section 9.1). In 
addition, extra survival sweep contacts will be conducted at the time of PFS final analysis and 
prior to OS final analysis to ensure that long-term follow-up data is current.
New text:
Patients will be contacted for survival every 3 months (±14 days) during long-term follow-up 
until data maturation for the OS final analysis is reached, death, withdrawal of consent, lost to 
follow-up or the end of study, whichever occurs first (see flow chart in Section 9.1). In 
addition, extra survival sweep contacts will be conducted prior to PFS final analysis and prior 
to OS final analysis to ensure that long-term follow-up data is current.
15.1.2.33
Section 9.4.3 Patient-reported outcomes
Old text:
[…]
The LCSS-Meso and MDASI-MPM questionnaires will be completed at full screening 
(within 7 days before the start of study treatment), on C2D1 and on Day 1 of every cycle 
thereafter (i.e. C3D1, C4D1 etc.), at safety follow-up visit and during active follow-up period. 
During active follow-up period, MDASI-MPM and LCSS-Meso are to be taken in parallel 
with tumor scans i.e. with the same modality every 6 weeks during the first 6 months after the 
start of study treatment, every 9 weeks until the end of year 2, and every 12 weeks thereafter 
until centrally confirmed radiological disease progression or end of study. MDASI-MPM and 
LCSS-Meso are to be completed before the patient meets with a clinician or before any 
examination or test is performed on that day. A PRO information sheet will be provided and 
completed by the study personnel for each questionnaire at each visit at which the LCSS-
Meso and the MDASI-MPM are to be administered, regardless of whether or not the LCSS-
Meso or the MDASI-MPM are completed by the patient.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  185 of 269
New text:
[…]
The MDASI-MPM questionnaires will be completed at full screening (within 7 days before 
the start of study treatment), on C1D8, C1D15, C2D1, C2D8, C2D15, C3D1, C3D8, C3D15 
and on Day 1 of every cycle thereafter (i.e. C4D1, C5D1 etc.), at safety follow-up visit and 
during active follow-up period. The LCSS-Meso questionnaires will be completed at full 
screening (within 7 days before the start of study treatment), C2D1 and on Day 1 of every 
cycle thereafter (i.e. C3D1, C4D1 etc.), at safety follow-up visit and during active follow-up 
period. During active follow-up period, MDASI-MPM and LCSS-Meso are to be taken in 
parallel with tumor scans i.e. with the same modality every 6 weeks during the first 6 months 
after the start of study treatment, every 9 weeks until the end of year 2, and every 12 weeks 
thereafter until centrally confirmed radiological disease progression or end of study. MDASI-
MPM and LCSS-Meso are to be completed before the patient meets with a clinician and 
before any examination or test is performed on that day. A PRO information sheet will be 
provided and completed by the study personnel for each questionnaire at each visit at which 
the LCSS-Meso and the MDASI-MPM are to be administered, regardless of whether or not 
the LCSS-Meso or the MDASI-MPM are completed by the patient.
[…]
15.1.2.34
Section 9.5 Pharmacokinetics / pharmacodynamics
Old text:
Anetumab ravtansine arm
[…]
Unscheduled PK samples are requested at the next clinic visit after the initial onset of corneal 
toxicity and after the radiological assessment of the first PR (the first local observation of at 
least a 30% reduction in the total tumor measurement according to mRECIST). The date and 
actual clock time of this unscheduled PK sample and of the last dose of anetumab ravtansine 
has to be recorded on the CRF as an Unscheduled Procedure.
[…]
New text:
Anetumab ravtansine arm
[…]
Unscheduled PK samples are requested at the next clinic visit after the initial onset of corneal 
epitheliopathy and after the radiological assessment of the first PR (the first local observation 
of at least a 30% reduction in the total tumor measurement according to mRECIST). The date 
and actual clock time of this unscheduled PK sample and of the last dose of anetumab 
ravtansine has to be recorded on the CRF as an Unscheduled Procedure.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  186 of 269
15.1.2.35
Section 9.6.1.2.2 Intensity
Old text:
The intensity of an AE should be documented using the NCI-CTCAE v4.03. For events not 
listed in the NCI-CTCAE, the following scale will be used:
[…]
New text:
The intensity of an AE should be documented using the NCI-CTCAE v4.03 or by the Bayer 
grading system (see Table 7-6 and Table 7-7) for corneal epitheliopathy. For events not listed 
in the NCI-CTCAE, the following scale will be used:
[…]
15.1.2.36
Section 9.6.1.2.4 Action taken with study treatment
Old text:
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.

Drug withdrawn

Drug interrupted

Dose reduced

Dose not changed

Not applicable

Unknown
New text:
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.

Drug withdrawn

Drug interrupted

Dose reduced

Dose not changed

Dose increased

Not applicable

Unknown


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  187 of 269
15.1.2.37
Section 9.6.1.3 Assessments and documentation of adverse events
Old text:
AEs observed, mentioned upon open questioning by a member of the investigator team or 
spontaneously reported by the patient will be documented in the patient’s records and on the 
appropriate CRF. AEs will be documented in an event-based manner, using NCI-CTCAE 
version 4.03 guidelines. In addition, since the NCI-CTCAE may not adequately capture the 
severity of new corneal epitheliopathy, an alternative severity grading system for ocular 
adverse drug reactions will be used (see Table 7-6 and Table 7-7).
[…]
New text:
AEs observed, mentioned upon open questioning by a member of the investigator team or 
spontaneously reported by the patient will be documented in the patient’s records and on the 
appropriate CRF. AEs will be documented in an event-based manner, using NCI-CTCAE 
version 4.03 guidelines. In addition, since the NCI-CTCAE may not adequately capture the 
severity of new corneal epitheliopathy, an alternative severity grading system for corneal 
epitheliopathy will be used (see Table 7-6 and Table 7-7).
[…]
15.1.2.38
Section 9.6.1.6 Adverse events of special safety interest
Old text:
[…]
Corneal disorders are considered as AEs of special interest. Specific dose modification 
schemes are defined in Section 7.4.2.1. An alternative severity grading system for ocular 
adverse drug reactions will be used in addition to NCI-CTCAE version 4.03 criteria, since the 
NCI-CTCAE may not adequately capture the severity of these novel adverse reactions (see 
Table 7-6 and Table 7-7).
There is no need to report corneal toxicities as SAEs unless they meet the criteria for an SAE 
as defined in Section 9.6.1.1; however these events will need to be closely monitored and 
reviewed, and documented timely and accurately both in source data and on the CRF. Details 
of ophthalmologic examination will be documented on the “ophthalmologic examination” and 
“slit lamp” CRF pages and in case AEs occur, also on “AE” CRF page, ensuring the reporting 
terminology used on those pages matches and reflects the source.
New text:
[…]
Corneal epitheliopathy is considered as AE of special interest. Specific dose modification 
schemes are defined in Section 7.4.2.1. An alternative severity grading system for corneal 
epitheliopathy will be used in addition to NCI-CTCAE version 4.03 criteria, since the NCI-


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  188 of 269
CTCAE may not adequately capture the severity of these novel adverse reactions (see Table 
7-6 and Table 7-7).
There is no need for expedited reporting or use of complementary pages to report corneal 
epitheliopathy, unless it meets the criteria for an SAE as defined in Section 9.6.1.1; however 
these events will need to be closely monitored and reviewed, and documented timely and 
accurately both in source data and on the CRF. Details of ophthalmologic examination will be 
documented on the “ophthalmologic examination” and “slit lamp” CRF pages and in case 
AEs occur, also on “AE” CRF page, ensuring the reporting terminology used on those pages 
matches and reflects the source.
15.1.2.39
Section 9.6.3.1 Laboratory evaluations
Old text:
[…]
An isolated laboratory abnormality that meets the criteria for a CTCAE Grade 4 classification 
is not reportable as an SAE, unless the investigator assesses that the event meets standard 
International Conference on Harmonization (ICH) criteria for an SAE (see SAE definition in 
Section 9.6.1.1). All laboratory abnormalities, including CTCAE Grade 4 abnormalities, will 
be documented on the laboratory CRF.
New text:
[…]
An isolated laboratory abnormality that meets the criteria for a CTCAE Grade 4 classification 
is not reportable as an SAE, unless the investigator assesses that the event meets standard 
International Council for Harmonization (ICH) criteria for an SAE (see SAE definition in 
Section 9.6.1.1). All laboratory abnormalities, including CTCAE Grade 4 abnormalities, will 
be documented on the laboratory CRF.
15.1.2.40
Section 9.6.3.7 Ophthalmologic examinations
Old text:
Corneal toxicity has been identified as a TEAE of special interest for which a causal 
relationship with anetumab ravtansine has been deemed probable by the investigators in Phase 
I trial. A detailed ophthalmologic examination (visual acuity [BCVA according to ETDRS, or 
Snellen, or Landolt C or other charts], IOP, dry eye test [Schirmer test] and slit lamp) will be 
done for all patients during full screening within 3 weeks before the start of study treatment 
(see flow chart in Section 9.1). For patients treated in the anetumab ravtansine arm, visual 
acuity test and slit lamp examination will be repeated before infusion in every cycle except 
C1D1, and at safety follow-up visit, or more frequently at investigator’s and 
ophthalmologist’s discretion (important to refer to Table 7-6 and Table 7-7). IOP 
measurement is to be repeated during anetumab ravtansine therapy if the patient receives 
steroid eye drops as treatment for eye toxicity; dry eye (Schirmer) test may be repeated during 
treatment at investigator’s discretion (e.g. in case of eye dryness during anetumab ravtansine 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  189 of 269
therapy). During treatment, ophthalmologic examination can be done up to 7 days before 
anetumab ravtansine infusion.
New text:
Corneal epitheliopathy has been identified as a TEAE of special interest for which a causal 
relationship with anetumab ravtansine has been deemed probable by the investigators in Phase 
I trial. A detailed ophthalmologic examination (visual acuity [BCVA according to ETDRS, or 
Snellen, or Landolt C or other charts], IOP, dry eye test [Schirmer test] and slit lamp) will be 
done for all patients during full screening within 3 weeks before the start of study treatment 
(see flow chart in Section 9.1). For patients treated in the anetumab ravtansine arm, visual 
acuity test and slit lamp examination will be repeated before infusion in every cycle except 
C1D1, and at safety follow-up visit, or more frequently at investigator’s and 
ophthalmologist/optometrist’s discretion (important to refer to Table 7-6 and Table 7-7). 
IOP measurement is to be repeated during anetumab ravtansine therapy if the patient receives 
steroid eye drops as treatment for corneal epitheliopathy; dry eye (Schirmer) test may be 
repeated during treatment at investigator’s discretion (e.g. in case of eye dryness during 
anetumab ravtansine therapy). During treatment, ophthalmologic examination can be done up 
to 7 days before anetumab ravtansine infusion.
In certain countries, an optometrist or equivalent specialist may be licensed to perform the eye 
examinations as detailed above; as per ICH-GCP, at the Principal Investigator’s discretion, a 
chosen specialist can perform required eye exams.
15.1.2.41
Section 9.7.1 Biomarkers
Old text:
Preclinical and Phase I evidence suggests that mesothelin expression (or expression level 
above a certain threshold) in human tumors may be required for binding, internalization, and 
anti-tumor activity of anetumab ravtansine. All patients will have formalin-fixed, paraffin-
embedded (FFPE) tumor samples available for IHC determination of mesothelin expression at 
prescreening as a potential predictive biomarker (see also flow chart in Section 9.1). In the 
absence of archival tissue, fresh biopsies may be used if deemed safe by the investigator and 
there is no additional risk for the patient in the investigator’s judgement. Only patients whose 
tumors express mesothelin at staining intensity of moderate (2+) and strong (3+) in at least 
30% of tumor cells will participate further in this study. Mesothelin levels will be determined 
using a validated IHC assay (clone SP74).
[…]
New text:
Preclinical and Phase I evidence suggests that mesothelin expression (or expression level 
above a certain threshold) in human tumors may be required for binding, internalization, and 
anti-tumor activity of anetumab ravtansine. All patients will have formalin-fixed, paraffin-
embedded (FFPE) tumor samples available for IHC determination of mesothelin expression at 
prescreening as a potential predictive biomarker (see also flow chart in Section 9.1). In the 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  190 of 269
absence of archival tissue, fresh biopsies may be used if deemed safe by the investigator and 
there is no additional risk for the patient in the investigator’s judgement. Only patients whose 
tumors express mesothelin at staining intensity of moderate and stronger in at least 30% of 
tumor cells will participate further in this study. Mesothelin levels will be determined using a 
validated IHC assay (clone SP74).
[…]
15.1.2.42
Section 9.8 Appropriateness of procedures / measurements
Old text:
[…]
Appropriateness of mRECIST criteria. RECIST 1.1 criteria, designed to assess spherically 
shaped solid tumors, may be an unreliable method in the context of the lens/crescent-shaped 
pleural lesions found in MPM (29). mRECIST criteria were designed and validated to 
measure the specific context of MPM (21, 30). Accordingly, mRECIST criteria are 
appropriate for the study context.
Appropriateness of FVC. The degree of improvement of pulmonary function assessed by 
FVC has been chosen as surrogate measure of patient benefit and parameter to demonstrate 
validity of mRECIST. Pulmonary function tests (PFT) correlate with tumor response: in the 
cisplatin-pemetrexed Phase III trial, patients who had a tumor response had consistently better 
PFT than patients with SD, and patients with SD had better PFTs than patients with PD 
(12).The FVC test has already been used and validated in the Phase III VANTAGE trial (31) 
and previously by Nowak et al. (32), as mentioned by Byrne in the mRECIST criteria (21).
[…]
New text:
Appropriateness of mRECIST criteria. RECIST 1.1 criteria, designed to assess spherically 
shaped solid tumors, may be an unreliable method in the context of the lens/crescent-shaped 
pleural lesions found in MPM (29). mRECIST criteria were designed and validated to 
measure the specific context of MPM (21, 30). Accordingly, mRECIST criteria are 
appropriate for the study context.
[…]
15.1.2.43
Section 10.2 Analysis sets
Old text:
[…]
Enrolled set (ENR). All patients who signed the informed consent for any portion of the 
study. Enrolled patients will be used for patient disposition.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  191 of 269
New text:
[…]
Enrolled set (ENR). All patients who signed the informed consent for any portion of the 
study including prescreening. Enrolled patients will be used for patient disposition.
[…]
15.1.2.44
Section 10.3.2 Primary efficacy variable
Old text:
[…]
Assuming true median PFS of 3.6 months under vinorelbine treatment and constant hazards, 
the study primary hypothesis test is designed to detect a 100% prolongation of true PFS 
(median 7.2 months) in the anetumab ravtansine arm in comparison to the comparator arm 
with 90% power with a 1-sided significance level of 0.0125 (hazard ratio 0.5).
[…]
New text:
[…]
Assuming true median PFS of 3.6 months under vinorelbine treatment and constant hazards, 
the study primary hypothesis test is designed to detect a 100% prolongation of true PFS 
(median 7.2 months) in the anetumab ravtansine arm in comparison to the comparator arm 
(hazard ratio 0.5) with 90% power with a 1-sided significance level of 0.0125.
[…]
15.1.2.45
Section 10.3.3.1 Secondary efficacy variables
Old text:
Overall survival (OS), defined as time from randomization until death from any cause. 
Patients lost to follow-up or alive at the time of analysis will be censored at the last known 
alive date.
Forced vital capacity (FVC) response rate: An improvement of ≥ 30% FVC is defined as 
PR, an improvement of < 30% to a deterioration of < 20% is defined as no change (NC), and 
a deterioration of ≥ 20% is defined as PD (30). A patient is a responder if the patient has a 
best spirometrically-evaluated FVC improvement on-study of PR, as determined by the 
investigator. No confirmation of FVC response is required. The FVC response rate in each 
arm is the number of responders divided by the number of randomized patients.
Objective response rate (ORR): A patient is a responder if the patient has a confirmed tumor 
response on-study of CR or PR, as determined by the central radiological reviewer per 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  192 of 269
mRECIST criteria. The ORR in each arm is the number of responders divided by the number 
of randomized patients.
[…]
Secondary efficacy analysis
[…]
Assuming true median OS of 9.6 months under vinorelbine treatment and constant hazards, 
the 2-stage group sequential hypothesis test is designed to detect a 60% prolongation of true 
OS (median 15.4 months) in the anetumab ravtansine arm in comparison to the comparator 
arm with an overall 73% power and an overall 1-sided significance level of 0.025 (hazard 
ratio 0.625).
The interim OS analysis will be performed at the time of the final primary endpoint (PFS) 
analysis, when an estimated 85 OS events will be observed. If the study is not stopped for 
superiority at the interim analysis, the final OS analysis will occur when approximately 
135 OS events have been observed. A Lan-Demets alpha spending function (38) with 
O’Brien-Fleming boundaries (39) will be used, based on actual events at the time of the 
interim analysis. Approximately 0.005 alpha is estimated to be spent at the interim analysis 
and 0.020 at the final if 85 OS events are observed at the interim analysis. The actual alpha 
levels will be based on the actual number of events included in the interim analysis. The 
group sequential testing procedure is further described in Section 10.4, and additional details 
will be described in the SAP.
[…]
Response rate variables (FVC response rate, ORR, DCR) will be summarized by treatment 
arm including number of patients (N), response rates, and Clopper-Pearson (40) exact 
binomial confidence intervals. In addition, each response category will be summarized. FVC 
response rate will be tested for association with treatment using a 1-sided Fisher’s Exact Test 
(41, 42) with significance level of 0.025. Further details will be described in the SAP.
[…]
New text:
Additional details, including additional censoring rules for time-to-event variables, will be 
described in the SAP.
Overall survival (OS), defined as time from randomization until death from any cause. 
Patients lost to follow-up or alive at the time of analysis will be censored at the last known 
alive date.
Objective response rate (ORR): A patient is a responder if the patient has a confirmed tumor 
response on-study of CR or PR, as determined by the central radiological reviewer per 
mRECIST criteria. The ORR in each arm is the number of responders divided by the number 
of randomized patients.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  193 of 269
Secondary efficacy analysis
[…]
Assuming true median OS of 9.6 months under vinorelbine treatment and constant hazards, 
the 2-stage group sequential hypothesis test is designed to detect a 60% prolongation of true 
OS (median 15.4 months) in the anetumab ravtansine arm in comparison to the comparator 
arm with an overall 80% power and an overall 1-sided significance level of 0.025 (hazard 
ratio 0.625).
The interim OS analysis will be performed at the time of the final primary endpoint (PFS) 
analysis, when an estimated 80 OS events will be observed. If the study is not stopped for 
superiority at the interim analysis, the final OS analysis will occur when approximately 
159 OS events have been observed. A Lan-Demets alpha spending function (36) with 
O’Brien-Fleming boundaries (37) will be used, based on actual events at the time of the 
interim analysis. Approximately 0.00158 alpha is estimated to be spent at the interim analysis 
and 0.02342 at the final if 80 OS events are observed at the interim analysis. The actual alpha 
levels will be based on the actual number of events included in the interim analysis. The 
group sequential testing procedure is further described in Section 10.4, and additional details 
will be described in the SAP.
[…]
Response rate variables (ORR, DCR) will be summarized by treatment arm including number 
of patients (N), response rates, and Clopper-Pearson (38) exact binomial confidence intervals. 
In addition, each response category will be summarized. Further details will be described in 
the SAP.
[…]
15.1.2.46
Section 10.3.3.3 Safety variables
Old text:
Safety variables will include AEs, laboratory changes (hematology, clinical chemistry and 
clinical urinalysis), abnormal findings in physical examination, changes in ECOG PS, 
changes in vital signs (weight, blood pressure, heart rate, respiratory rate, and body 
temperature), changes in FVC, changes in ECG, changes in cardiac function test (EchoCG or 
MUGA scan) and changes in ophthalmologic examinations (visual acuity and slit lamp 
examination, IOP and Schirmer test if repeated). […]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  194 of 269
New text:
Safety variables will include AEs, laboratory changes (hematology, clinical chemistry and 
clinical urinalysis), abnormal findings in physical examination, changes in ECOG PS, 
changes in vital signs (weight, blood pressure, heart rate, respiratory rate, and body 
temperature), changes in ECG, changes in cardiac function test (EchoCG or MUGA scan) and 
changes in ophthalmologic examinations (visual acuity and slit lamp examination, IOP and 
Schirmer test if repeated). […]
15.1.2.47
Section 10.4 Determination of sample size
Old text:
The sample size is primarily designed to support hypothesis test of the primary endpoint PFS. 
Statistical power for the analysis of the secondary endpoint of OS is also evaluated.
[…]
New text:
The sample size is primarily designed to support hypothesis test of the primary endpoint PFS, 
and to provide a limited formal evaluation of secondary endpoint OS.
[…]
15.1.2.48
Section 10.4.1 Primary endpoint progression-free survival
Old text:
[…]
Assuming median PFS of 3.6 months under vinorelbine treatment and constant hazards and a 
2:1 treatment:comparator randomization, a 100% prolongation of PFS in the anetumab 
ravtansine arm in comparison to the comparator arm can be detected at a 1-sided significance 
level of 0.0125 with 90% power, with a single-stage trial with approximately 117 PFS events 
(hazard ratio 0.5). Assuming a maximum accrual rate of 10.5 patients/month (17.5 patients/ 
month screened with 40% overall screening failure rate) with 8-month linear accrual ramp-up, 
and a 2.7%/month dropout (loss to follow-up and unevaluable for tumor assessment) rate, 
183 patients be will accrued in approximately 20.4 months and reach endpoint maturation of 
117 events in approximately 23.9 months. The total number of unevaluable/dropout patients 
over the duration of the study through final PFS analysis is estimated at 27 (14.8%).
New text:
[…]
Assuming median PFS of 3.6 months under vinorelbine treatment and constant hazards and a 
2:1 treatment:comparator randomization, a 100% prolongation of PFS in the anetumab 
ravtansine arm in comparison to the comparator arm can be detected at a 1-sided significance 
level of 0.0125 with 90% power, with a single-stage trial with approximately 117 PFS events 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  195 of 269
(hazard ratio 0.5). Assuming a maximum accrual rate of 12.5 patients/month (20.83 patients/ 
month screened with 40% overall screening failure rate) with 6-month linear accrual ramp-up, 
and a 3.4%/month dropout (loss to follow-up and unevaluable for tumor assessment) rate, 
210 patients be will accrued in approximately 19.8 months and reach endpoint maturation of 
117 events in approximately 22.0 months. The total number of unevaluable/dropout patients 
over the duration of the study through final PFS analysis is estimated at 33 (15.7%).
15.1.2.49
Section 10.4.2 Secondary endpoint overall survival
Old text:
The sample size is also evaluated for testing the following hypotheses in secondary endpoint 
OS:
[…]
Assuming true median OS of 9.6 months under vinorelbine treatment and constant hazards, a 
60% prolongation of true OS (median 15.4 months) in the anetumab ravtansine arm in 
comparison to the comparator arm (median 9.6 months) can be detected with an overall 73% 
power and an overall 1-sided significance level of 0.025 (hazard ratio 0.625), with a 2-stage 
group sequential test with a total of 135 events.
The OS analysis assumes the same accrual as for primary endpoint PFS, with 183 patients 
accrued in approximately 20.4 months. A 0.5% per month loss to OS follow-up rate is 
assumed. An interim OS analysis will be performed at the time of the final primary endpoint 
(PFS) analysis at an estimated 23.9 months from first patient randomized, when an estimated 
85 OS events will have been observed. If the study is not stopped for superiority at the OS 
interim analysis, the final OS analysis will occur after approximately 135 OS events have 
been observed, at approximately 41.4 months from first patient randomized. A Lan-Demets 
alpha spending function (38) with O’Brien-Fleming boundaries (39) will be used, based on 
actual events at the time of the interim analysis. Under the null hypothesis of no anetumab 
ravtansine OS superiority, approximately 0.005 alpha is estimated to be spent at the interim 
analysis and 0.020 at the final (0.025 alpha overall). Under the alternative hypothesis of 60% 
OS improvement under anetumab ravtansine treatment, the chance of finding superiority is 
estimated at 29.4% at the interim analysis and 43.6% at the final analysis (73% power 
overall). The total number of patients lost to OS follow-up over the duration of the study 
through final OS analysis is estimated at 13 (7.1%)
New text:
The sample size is also designed to test the following hypotheses in secondary endpoint OS:
[…]
Assuming true median OS of 9.6 months under vinorelbine treatment and constant hazards, a 
60% prolongation of true OS (median 15.4 months) in the anetumab ravtansine arm in 
comparison to the comparator arm (median 9.6 months) can be detected with an overall 80% 
power and an overall 1-sided significance level of 0.025 (hazard ratio 0.625), with a 2-stage 
group sequential test with a total of 159 events.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  196 of 269
The OS analysis assumes the same accrual as for primary endpoint PFS, with 210 patients 
accrued in approximately 19.8 months. A 0.3% per month loss to OS follow-up rate is 
assumed. An interim OS analysis will be performed at the time of the final primary endpoint 
(PFS) analysis at an estimated 22 months from first patient randomized, when an estimated 80 
OS events will have been observed. If the study is not stopped for superiority at the OS 
interim analysis, the final OS analysis will occur after approximately 159 OS events have 
been observed, at approximately 41.3 months from first patient randomized. A Lan-Demets 
alpha spending function (36) with O’Brien-Fleming boundaries (37) will be used, based on 
actual events at the time of the interim analysis. Under the null hypothesis of no anetumab 
ravtansine OS superiority, approximately 0.00158 alpha is estimated to be spent at the interim 
analysis and 0.02342 at the final (0.025 alpha overall). Under the alternative hypothesis of 
60% OS improvement under anetumab ravtansine treatment, the chance of finding superiority 
is estimated at 16.9% at the interim analysis and 63.2% at the final analysis (80% power 
overall). The total number of patients lost to OS follow-up over the duration of the study 
through final OS analysis is estimated at 10 (4.8%).
15.1.2.50
Section 10.5 Planned interim analyses
Old text:
An interim analysis for OS will be performed at the same time as the final primary endpoint 
analysis, as described in Section 10.4.
[…]
New text:
An interim analysis for OS will be performed, by the sponsor, at the same time as the final 
primary endpoint analysis, as described in Section 10.4.
[…]
15.1.2.51
Section 11.4 Missing data
Old text:
[…]
Strategies to reduce the dropout rate for secondary endpoints include:

For OS, every effort will be made to continue contacting study patients in long-term 
follow-up and to determine death status and dates. A survival sweep contact will be 
conducted at the time of PFS final analysis and prior to OS final analysis to ensure that 
long-term follow-up data is current. Analysis methods as described for PFS help 
mitigate the impact of missing data.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  197 of 269
Strategies to reduce impact of missing data when present include:

Time-to-event analysis approaches maximize available data and reduce impact of 
censoring, with unbiased results when censoring is uninformative.

Study is powered assuming a ~15% total dropout rate (3% per month) for PFS and a 
0.5% per month dropout rate for OS, ensuring a moderate dropout rate will not 
degrade reliability of study results.

Analyses will ensure conservative treatment of missing values. For tumor and FVC 
response endpoints, missing assessments will count as non-responders. For non-time-
to-event QoL endpoints, time point analysis will include patients present both at 
baseline and at the time point, mitigating survivorship bias.
New text:
[…]
Strategies to reduce the dropout rate for secondary endpoints include:

For OS, every effort will be made to continue contacting study patients in long-term 
follow-up and to determine death status and dates. A survival sweep contact will be 
conducted at the time of PFS final analysis and prior to OS final analysis to ensure that 
long-term follow-up data is current.
[…]
Strategies to reduce impact of missing data when present include:

Time-to-event analysis approaches maximize available data and reduce impact of 
censoring, with unbiased results when censoring is uninformative.

Study is powered assuming a ~16% total dropout rate (3.4% per month) for PFS and a 
~5% total (0.3% per month) dropout rate for OS, ensuring a moderate dropout will not 
degrade reliability of study results.

Analyses will ensure conservative treatment of missing values. For tumor response 
endpoints, missing assessments will count as non-responders. For non-time-to-event 
QoL endpoints, time point analysis will include patients present both at baseline and at 
the time point, mitigating survivorship bias.
15.1.2.52
Section 14 Reference list
Old text:
31.
Krug LM, Arduino JM, Sun X, Kindler HL, Manegold C, Fennell D, et al. Forced vital 
capacity (FVC) as a reproducible measure of pulmonary function (PF) in 
chemotherapy-pretreated patients with malignant pleural mesothelioma (MPM). J Clin 
Oncol. 2011;29(suppl; abstr 7028).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  198 of 269
32.
Nowak AK, Byrne MJ, Williamson R, Ryan G, Segal A, Fielding D, et al. A 
multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. 
Br J Cancer. 2002;87(5):491-6.
41.
Fisher RA. Statistical Methods for Research Workers. Edinburgh: Oliver and Boyd. 
1954.
42.
Agresti A. Categorical Data Analysis. Third Edition. New Jersey: John Wiley & Sons. 
2013.
New text:
Reference list was updated by amendment 2. The numbering of the references was changed 
accordingly.
15.1.2.53
Section 16.3 Response assessment
Old text:
Tumor response will be evaluated in this study using the mRECIST criteria for MPM (21).
At baseline, the pleural disease to be measured should have a short-axis diameter of at least 
1 cm for each of the 6 measurements, as lesions < 1 cm are considered non-measurable.
Uni-dimensional measurements of tumor thickness perpendicular to the chest wall or 
mediastinum should be performed, measured in 2 sites (or positions) at 3 separate levels on 
transverse cuts of contrast-enhanced CT scan (or MRI). The sum of the 6 measurements 
defines a pleural unidimensional measure: sum of 6 pleural thickness measurements = 
1 univariate diameter. 
[…]
Nodal, subcutaneous and other bidimensionally measurable lesions (e.g. lung) are measured 
unidimensionally as per the RECIST 1.1 criteria. Unidimensional measurements are added to 
obtain the total tumor measurement.
New text:
Tumor response will be evaluated in this study using the mRECIST criteria for MPM (21).
At baseline, the pleural disease to be measured should have a short-axis diameter of at least 
1 cm for at minimum one of the 6 measurements, as lesions < 1 cm are considered non-
measurable.
Unidimensional measurements of tumor thickness perpendicular to the chest wall or 
mediastinum should be performed, measured in 2 sites (or positions) at 3 separate levels on 
transverse cuts of contrast-enhanced CT scan (or MRI). The sum of the measurements which 
meet the definition of measurable disease defines a pleural unidimensional measure: sum of 
up to 6 pleural thickness measurements = 1 univariate diameter. 
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  199 of 269
Nodal, subcutaneous and other bidimensionally measurable non-pleural lesions (e.g. lung) are 
measured unidimensionally as per the RECIST 1.1 criteria. Unidimensional measurements are 
added to obtain the total tumor measurement.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  200 of 269
15.2
Amendment 4
Amendment 4 is a global amendment dated 11 AUG 2016.
15.2.1
Overview of changes to the study
15.2.1.1
Modification 1: Addition of durable response rate (DRR) as a 
secondary variable
Durable response rate was added as a secondary variable as it could be a key in the context of 
the regulatory environment surrounding this trial.
Sections affected by this modification: Section 2 Synopsis, Section 10.3.3.1 Secondary 
efficacy variables
15.2.1.2
Modification 2: Change in the number of patients planned to be 
prescreened
The screen failure rate was increased from 40% to 50% based on current data. Subsequently, 
the number of patients planned to be prescreened was increased from 350 to 420 and the 
number of patients to be prescreened / month from 20.83 to 25.
Sections affected by this modification: Section 2 Synopsis, Section 5.1 Design overview, 
Section 10.4.1 Primary endpoint progression-free survival
15.2.1.3
Modification 3: Change in inclusion/exclusion criteria: Amendment of 
time window for prior participation in another clinical study
The option for 5 drug half lives was removed from the time window for prior treatment with 
platinum in combination with pemetrexed before start of study treatment (full study inclusion 
criterion 3). This was done due to the short half life of pemetrexed (3.5 hours) as one of the 
first line therapies to allow for any toxicities to resolve before the start of study treatment.
Sections affected by this modification: Section 6.1.2 Eligibility criteria for full study, Section 
8.1 Prior and concomitant therapy
15.2.1.4
Modification 4: Change in exclusion criteria: Exclusion of prior 
experimental device therapy
Patients having received prior device therapy were excluded in order to have a homogenous 
first line population (exclusion criterion 4). There is no internal or literature data available 
explaining how signaling pathways are modified after treatment with devices, and particularly 
whether patients may respond differentially after treatment with these devices in combination 
with standard of care compared to standard of care alone.
Sections affected by this modification: Section 6.2 Exclusion criteria
15.2.1.5
Modification 5: Change in exclusion criteria: Exclusion of patients 
with CNS metastasis
Patients with CNS metastasis were excluded from the study population for this trial since the 
incidence of brain metastases is very low in pleural mesothelioma population (42, 43) and 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  201 of 269
prognosis for patients with existing brain or other CNS metastases is generally poor 
(exclusion criterion 16).
Sections affected by this modification: Section 6.2 Exclusion criteria, Section 9.1 Tabular 
schedule of evaluations, Section 9.2.2 Full screening period, Section 9.4.1 Radiological tumor 
assessments
15.2.1.6
Modification 6: Clarification on re-screening criteria
Clarification was added around the circumstances where re-screening would be permitted to 
align with other studies in the program.
Sections affected by this modification: Section 6.3.1.1.3 Re-screening
15.2.1.7
Modification 7: Removal of details around reconstitution and dilution 
of anetumab ravtansine
Information about reconstitution and dilution of the anetumab ravtansine solution and the 
associated stability information was removed from the protocol and included in a standalone 
document. This update was made to provide the investigational sites with the most current 
guidance in the most effective and efficient way.
Sections affected by this modification: Section 7.2.1 Test drug – anetumab ravtansine
15.2.1.8
Modification 8: Changes to dose modifications of anetumab 
ravtansine

Previous Tables 7-3 (Dose adjustments in response to neutrophil and platelet nadir 
counts of the previous cycle) and 7-4 (Dose adjustments in response to pre-infusion 
values) were combined into one table (Table 7-3) for clarity and ease of use and to 
align with other studies in the program. The numbering of the subsequent tables in the 
Section 7 was changed accordingly.

In Table 7-3, criteria for dose modification based on platelet nadir count of the 
previous cycle were modified to be in line with other studies in the program (for 
≥ 7 days added for platelets < 25,000 mm3 and < 50,000/mm3 with clinically 
significant bleeding instead of ≥ 25,000/mm3).

Requirement of dose reduction for ANC < 1,000/mm3 and/or platelets < 75,000/mm3 
was replaced with requirement to adjust dose by nadir counts in previous cycle.

The following were removed from the section non-hematological toxicities requiring 
dose modification for clarity and to remove duplication in line with other studies in the 
program:
o
AST and/or ALT increase > 5.0 x ULN (CTCAE Grade ≥ 3) – this is 
duplication of information in Table 7-4.
o
Total bilirubin > 3.0 x ULN (CTCAE Grade ≥ 3) – this is duplication of 
information in Table 7-4.
o
Hair loss CTCAE Grade ≥ 3 as alopecia grade 3 does not exist.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  202 of 269

In Table 7-4 an inconsistency between a footnote and the table was corrected i.e. 
treatment should be interrupted/delayed unless TEAE resolves to Grade ≤ 2. This was 
corrected also in Figure 6-1.

Paracetamol was added as an example of anti-allergic prophylaxis for infusion-related 
reaction or other hypersensitivity event. This is in line with guidance used in other 
studies in the program.
Sections affected by this modification: Section 6.3.1.2 Withdrawal criteria, Section 7.4.2.1.1 
Hematological toxicities, Section 7.4.2.1.2 Non-hematological toxicities, Section 7.4.2.1.3 
Miscellaneous toxicities
15.2.1.9
Modification 9: Addition of Oxford Schema
Oxford Schema and the respective reference were added as an appendix for completeness. 
A cross-reference to the appendix was added in Table 7-5. Oxford Schema is used for the 
grading of superficial punctate keratitis if observed during the slit lamp examination.
Sections affected by this modification: Section 7.4.2.1.3 Miscellaneous toxicities, Section 
16.9 Grading staining: Oxford Schema (new addition)
15.2.1.10
Modification 10: Corrections to prior and concomitant therapies

Acute steroids were removed from prohibited prior and concomitant therapies 
(Table 8-1) since the use of these medications for conditions such as pain control, 
dyspnea and nausea was more widely spread than anticipated after a determination 
was made that there were no pharmacokinetic, safety or medical concerns. The use of 
chronic steroids was added to the permitted concomitant therapies (Table 8-2).

Concomitant live attenuated virus vaccines (e.g. yellow fever) were added as 
prohibited for patients in both arms rather than just in the vinorelbine arm within 
2 weeks before the start of study treatment as the treatment assignment is only 
performed at randomization. After C1D1, these therapies are only prohibited for 
patients in the vinorelbine arm.
Sections affected by these modifications: Section 8.1 Prior and concomitant therapy
15.2.1.11
Modification 11: Addition of collection of optional archival tumor 
tissue for exploratory analysis
Optional collection of archival tumor tissue for patients who consent post randomization was 
added in order to perform the analysis of changes in the genomic and expression profile (e.g. 
mesothelin expression) in tumor tissue over time on drug treatment. This may elucidate the 
underlying molecular mechanism of drug response and intrinsic and acquired resistance to 
anetumab ravtansine.
Sections affected by this modification: Section 2 Synopsis, Section 5.1 Design overview, 
Section 9.1 Tabular schedule of evaluations, Section 9.2.3.1 Treatment – Cycle 1, Section 
9.7.1 Biomarkers


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  203 of 269
15.2.1.12 Modification 12: Clarification regarding central review for 
determination of progressive disease
Language to state that only patients who have not undergone central review for PD 
confirmation will undergo retrospective central blinded review was added for clarity.
Sections affected by this modification: Section 9.4.1 Radiological tumor assessments
15.2.1.13
Modification 13: Clarification to PK validity criteria
Language was added in the description of the analysis set “PK set” for clarity.
Sections affected by this modification: Section 10.2 Analysis sets
15.2.1.14
Modification 14: Timing of analysis of DRR, DOR and updated PFS 
Because the PFS analysis is expected to mature shortly after accrual ends, it may not be 
sufficiently mature to assess duration of response or the newly added durable response rate 
endpoint. Accordingly, final analysis of this newly added endpoint is deferred until the final 
OS analysis to permit greater data maturity.
Following patients for tumor assessments through OS analysis to obtain duration of response 
makes an updated analysis of PFS and of DOR at time of OS analysis appropriate. 
Sections affected by this modification: Section 10.3.2 Primary efficacy variable, Section 
10.3.3.1 Secondary efficacy variables
15.2.1.15
Modification 15: Addition of mention of sensitivity analyses and 
citations
Addition of mention of sensitivity analyses and site to 2012 EU and 2015 FDA guidances for 
primary variable PFS. This change is to ensure that the study design is up to date with the 
FDA and EU guidance for conducting the primary variable PFS analysis.
Sections affected by this modification: Section 10.3.2 Primary efficacy variable
15.2.1.16
Modification 16: Addition of further details to the analysis of the 
patient-reported outcomes
In response to FDA feedback and scientific advice from MD Anderson Cancer Center, the 
MDASI-MPM developer, the definitions of the PRO endpoints were modified and further 
details surrounding the analysis of the PROs were added. Based on feedback from MD 
Anderson Cancer Center, radiological progression was decoupled from PRO endpoint 
definitions. To enable this Phase II study to be used both to help validate the MDASI-MPM 
and perform hypothesis testing on MDASI-MPM-based endpoints, an independent blinded 
PRO review committee is being established to perform validation-related analyses and 
determine key endpoint details based on blinded analyses of pooled data, including the degree 
of change from baseline constituting clinically meaningful improvement and worsening in 
symptoms and pain.
Sections affected by this modification: Section 5.3 Justification of the design, Section 7.5 
Blinding, Section 10.3.3.1 Secondary efficacy variables


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  204 of 269
15.2.1.17
Modification 17: Clarification of patient-reported outcomes 
instrument use
Clarification was added referring to the LCSS-Meso as a disease-related QoL or HRQoL 
assessment instrument, and referring to the MDASI-MPM as a disease-related symptom 
assessment instrument.
Sections affected by this modification: Section 2 Synopsis, Section 5.1 Design overview, 
Section 9.2.5.2 Active follow-up, Section 9.4.3 Patient-reported outcomes, Section 10.2 
Analysis sets, Section 11.4 Missing data
15.2.1.18
Modification 18: Addition of hypothesis tests and hierarchy for 
selected secondary variables
Hypothesis tests and hierarchy for selected secondary variables including addressing the 
timing were added. Regulatory guidance and feedback requires formal hypothesis tests and 
establishing a gatekeeping strategy for secondary variables to ensure control of overall study 
Type I error. A hierarchy was specified. Language was added to clarify analysis timing. 
Although additional secondary variables will be analyzed at primary endpoint analysis, the 
Type I error control strategy requires that secondary variables ranking below OS in the 
hierarchy to wait until the OS analysis completes to determine superiority.
Sections affected by this modification: Section 2 Synopsis, Section 10.3.3.1 Secondary 
efficacy variables
15.2.1.19
Other modifications and corrections
In addition to the modifications specified above, there have been minor corrections for better 
clarity and consistency.

Due to sponsor name change, sponsor information and sponsor logo were changed. In 
addition, Bayer HealthCare Pharmaceuticals Inc. was added as a sponosr for US 
territory since it is and has at any time been the sponsor for the US territory for this 
trial as set forth in FDA IND form 1571. Sections affected by this modification: 
Section 1 Title page

Study acronym (ARCS-M2L) was added. Sections affected by this modification: 
Section 1 Title page

Study medical expert was changed. Sections affected by this modification: Section 1 
Title page, Section 13.1 Investigator(s) and other study personnel

A sentence about Data Monitoring Committee was added in the protocol synopsis for 
consistency with the rest of the document. Sections affected by this modification: 
Section 2 Synopsis

List of abbreviations was updated. Sections affected by this modification: List of 
abbreviations

Limitation of data was clarified based on a Phase I expansion cohort. Sections affected 
by this modification: Section 3.2 Rationale of the study


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  205 of 269

A clarification was added to the exclusion criterion 4 to make it clear that only patients 
with more than 1 line of previous systemic anti-cancer therapy for MPM are excluded. 
Sections affected by this modification: Section 6.2 Exclusion criteria

Dose omission, infusion interruption and change in infusion rate were added as 
options for anetumab ravtansine dose modifications for consistency with the rest of the 
section. In addition, wording “temporary treatment interruption” was changed to “dose 
delay”. Sections affected by this modification: Section 7.4.2.1 Dose modifications of 
anetumab ravtansine

A column for ophthalmologic examination within 21 days before the start of study 
treatment was added to the Study flow chart for ease of use and clarity. In addition, a 
separate section was created for the respective bullet point in the Visit description 
section. Sections affected by this modification: Section 9.1 Tabular schedule of 
evaluations, Section 9.2.2 Full screening period

Vitals signs was removed from the -28 day prior to screening time window as this was 
a duplication and should only be in the – 7 day prior to screening time window. 
Sections affected by this modification: Section 9.1 Tabular schedule of evaluations, 
Section 9.2.2 Full screening period

Time window for lipase testing at Cycle 2 Day 1 and higher Day 1 visits was 
increased as due to logistical issues in different countries with national or referral 
laboratory turnaround times, it is not always possible to obtain lipase analysis results 
prior to dosing within the 1 day window for Cycle 2 and higher Day 1. A safety risk 
assessment was performed and it was determined that there will be no additional risk 
to the patient by referring to lipase analysis results which are up to 8 days old before 
dosing. Therefore the time window for lipase testing on Cycle 2 and higher Day 1 was 
extended to 8 days before administration of the study treatment. Sections affected by 
this modification: Section 9.1 Tabular schedule of evaluations, Section 9.2.3.2 
Treatment – Cycle 2 and higher

Time window for cardiac function testing during treatment was increased to 7 days 
due to logistical issues in different countries where due to availability of the 
appointments for these tests, it is not always possible to obtain the results prior to 
dosing within the 1 day window for on treatment visits. A safety risk assessment was 
performed and it was determined that there will be no additional risk to the patient by 
referring to cardiac function results which are up to 7 days old before administration 
of the study treatment. Sections affected by this modification are: Section 9.1 Tabular 
schedule of evaluations, Section 9.2.3.2 Treatment – Cycle 2 and higher, Section 
9.6.3.6 Cardiac function

A time window of +/- 5 min was added for 12-lead ECG on C1D1 at 30 min post-dose 
to allow flexibility at the site level. Sections affected by this modification: Section 
9.2.3.1 Treatment – Cycle 1


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  206 of 269

Language was added to specify in which situation pregnancies should be reported as 
SAEs (i.e. only those with abnormal outcome). Sections affected by this modification: 
Section 9.6.2 Pregnancies

Red blood cell count was added to the list of laboratory assessments as this had been 
mistakenly omitted. Sections affected by this modification: Section 9.6.3.1 Laboratory 
evaluations

Specification of calcium type collected was added to the list of laboratory assessment 
as CTCAE 4.03 requires specification of calcium type to grade hypercalcemia and 
hypocalcemia severity. Sections affected by this modification: Section 9.6.3.1 
Laboratory evaluations

Definition of disease control rate was clarified to define patients with disease control. 
Sections affected by this modification: Section 10.3.3.1 Secondary efficacy variables

Infusion-related reactions (IRRs) were added to the list of safety variables to clarify 
separate reporting of infusion-related reactions and associated symptoms. Sections 
affected by this modification: Section 10.3.3.3 Safety variables

It was added that biomarker analyses may be specified in a separate document. 
Sections affected by this modification: Section 10.3.4.2 Biomarker variables

“Disease characteristics” was added to the data required from prescreening and full 
screening failures for consistency with Section 9.1 Tabular schedule of evaluations. 
Sections affected by this modification: Section 11.1 Data recording

Reference list was updated. Sections affected by this modification: Section 14 
Reference list
15.2.2
Changes to the protocol text
In the sections on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version. As applicable, changes to the protocol text are highlighted as 
follows:

Addition of a whole new portion: Brief identification of the new portion

Removal of a whole portion: Complete display of the removed portion, formatted as 
crossed out

Editing of an existing portion: Comparative presentation of “old text” versus “new 
text”, with “old text” referring to the most recent previous protocol version. Deletions 
are crossed out in the “old text”. Additions are underlined in the “new text”.

Tables / figures: The term “amended” is added to the caption.

Terminological changes: Brief specification of the terminological change
Correction of typos or omissions are not highlighted.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  207 of 269
15.2.2.1
Section 1 Title page
Old text:
[…]
Phase II anetumab ravtansine as 2nd line treatment for malignant pleural mesothelioma 
(MPM)
Test drug:
BAY 94-9343 / anetumab ravtansine
[…]
Sponsor:
Bayer HealthCare AG, D-51368 Leverkusen, Germany
Sponsor’s medical expert:
Telephone no.: 
Mobile:
[…]
New text:
[…]
Phase II anetumab ravtansine as 2nd line treatment for malignant pleural mesothelioma 
(MPM)
ARCS-M2L (Anetumab Ravtansine Clinical Studies – Mesothelioma 2nd Line)
Test drug:
BAY 94-9343 / anetumab ravtansine
[…]
Sponsor:
Non-US: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer HealthCare Pharmaceuticals Inc., 
100 Bayer Boulevard, P.O. Box 915, 
Whippany NJ 07981-0915, USA
Sponsor’s medical expert:
Telephone no.: 
Mobile: 
[…]
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  208 of 269
15.2.2.2
Section 2 Synopsis
Old text:
[…]
Methodology
[…]
The effect of treatment on disease-specific health-related QoL 
and disease-specific symptoms will be assessed using the MD 
Anderson Symptom Inventory-Malignant Pleural 
Mesothelioma (MDASI-MPM) and the Lung Cancer 
Symptom Scale-Mesothelioma (LCSS-Meso) at full 
screening, at each cycle during treatment, at the safety 
follow-up visit, and during active follow-up.
[…]
Obligatory biomarker sampling will be performed on all 
patients to measure mesothelin expression levels in tumor 
material at prescreening. In addition, plasma levels of soluble 
mesothelin will be studied to evaluate whether plasma 
mesothelin levels may correlate with response rate and be of 
predictive value. Biomarker plasma will be collected to 
analyze circulating tumor DNA, too. Exploratory biomarker 
analysis may also be performed using additional fresh tumor 
tissue to determine alterations in tumor-associated genes and 
to perform gene expression analysis.
[…]
Number of patients
Approximately 210 patients will be randomized. 
Approximately 40% rate of screening failures is estimated, 
i.e. approximately 350 patients will be prescreened.
[…]
Plan for statistical analysis
[…]
Additional secondary variables include objective response 
rate (ORR), disease control rate (DCR), duration of response 
(DOR), and analysis of the change in physical symptoms of 
MPM by PROs (as measured using the MDASI-MPM and 
LCSS-Meso). The final analysis for all these additional 
secondary variables will occur at the time of primary 
endpoint analysis.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  209 of 269
New text:
[…]
Methodology
[…]
The effect of treatment on disease-specific symptoms and 
disease-specific health-related QoL will be assessed using the 
MD Anderson Symptom Inventory-Malignant Pleural 
Mesothelioma (MDASI-MPM) and the Lung Cancer 
Symptom Scale-Mesothelioma (LCSS-Meso), respectively, at 
full screening, at each cycle during treatment, at the safety 
follow-up visit, and during active follow-up.
[…]
Obligatory biomarker sampling will be performed on all 
patients to measure mesothelin expression levels in tumor 
material at prescreening. In addition, plasma levels of soluble 
mesothelin will be studied to evaluate whether plasma 
mesothelin levels may correlate with response rate and be of 
predictive value. Biomarker plasma will be collected to 
analyze circulating tumor DNA, too. Exploratory biomarker 
analysis may also be performed using additional fresh or 
archival tumor tissue to determine alterations in tumor-
associated genes and to perform gene expression analysis.
An independent Data Monitoring Committee will periodically 
monitor patient safety.
[…]
Number of patients
Approximately 210 patients will be randomized. 
Approximately 50% rate of screening failures is estimated, 
i.e. approximately 420 patients will be prescreened.
[…]
Plan for statistical analysis
[…]
Additional secondary variables include objective response 
rate (ORR), disease control rate (DCR), duration of response 
(DOR), durable response rate (DRR) and analysis of the 
change in physical symptoms of MPM by PROs (as measured 
using the MDASI-MPM and LCSS-Meso). In the event 
primary PFS and secondary OS hypothesis tests succeed, key 
secondary PRO variables will be tested at 1-sided 
significance level using an alpha-preserving hierarchy. A 
stratified log-rank test will be used for time-to-event 
endpoints, and a Cochran-Mantel-Haenszel test will be used 
for rate endpoints. 
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  210 of 269
15.2.2.3
List of abbreviations
Old text:
[…]
USP
United States Pharmacopeia
[…]
New text:
[…]
DRR
Durable response rate
[…]
EMA
European Medicines Agency
[…]
RBC
Red blood cell count
[…]
15.2.2.4
Section 3.2 Rationale of the study
Old text:
At the MTD of 6.5 mg/kg Q3W, anetumab ravtansine has demonstrated very strong efficacy 
in advanced, unresectable or metastatic epithelial mesothelioma (best objective response 31% 
overall or 45% in the 2nd line setting, with very durable responses). Such high response rate 
and long lasting responses would translate to the potential for anetumab ravtansine to impart 
large clinical benefit as the 2nd line treatment for advanced mesothelioma, which represents an 
indication of high unmet medical need for effective treatment options, as currently no 
approved SoC exists.
New text:
At the MTD of 6.5 mg/kg Q3W, anetumab ravtansine has demonstrated very strong efficacy 
in advanced, unresectable or metastatic epithelial mesothelioma (best objective response 31% 
overall or 45% in the 2nd line setting, with very durable responses) in a Phase I expansion 
cohort. Such high response rate and long lasting responses, if repeatable, would translate to 
the potential for anetumab ravtansine to impart large clinical benefit as the 2nd line treatment 
for advanced mesothelioma, which represents an indication of high unmet medical need for 
effective treatment options, as currently no approved SoC exists.
15.2.2.5
Section 5.1 Design overview
Old text:
[…]
An approximately 40% screen fail rate is anticipated (25% at prescreening and a subsequent 
20% among biomarker expressers. Approximately 350 patients are estimated to be required 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  211 of 269
for prescreening to yield approximately 263 biomarker-positive patients, resulting in 
210 randomized eligible patients).
[…]
The effect of treatment on disease-specific health-related QoL and disease-specific symptoms 
will be assessed using the MD Anderson Symptom Inventory-Malignant Pleural 
Mesothelioma (MDASI-MPM) and the Lung Cancer Symptom Scale-Mesothelioma (LCSS-
Meso) at full screening, at each cycle during treatment, at the safety follow-up visit, and 
during active follow-up as per Section 9.4.3.
[…]
Exploratory biomarker analysis may also be performed using additional fresh tumor tissue to 
determine alterations in tumor-associated genes and to perform gene expression analysis.
New text:
[…]
An approximately 50% screen fail rate is anticipated (25% at prescreening and a subsequent 
33% among biomarker expressers. Approximately 420 patients are estimated to be required 
for prescreening to yield approximately 263 biomarker-positive patients, resulting in 
210 randomized eligible patients).
[…]
The effect of treatment on disease-specific symptoms and disease-specific health-related QoL 
will be assessed using the MD Anderson Symptom Inventory-Malignant Pleural 
Mesothelioma (MDASI-MPM) and the Lung Cancer Symptom Scale-Mesothelioma (LCSS-
Meso), respectively, at full screening, at each cycle during treatment, at the safety follow-up 
visit, and during active follow-up as per Section 9.4.3.
[…]
Exploratory biomarker analysis may also be performed using additional fresh or archival 
tumor tissue to determine alterations in tumor-associated genes and to perform gene 
expression analysis.
15.2.2.6
Section 5.3 Justification of the design
Old text:
Level of blinding. […] The independent and central radiological review for the assessment of 
disease progression and other radiological imaging-based endpoints will be conducted in a 
blinded fashion.
[…]
New text:
Level of blinding. […] The independent and central radiological review for the assessment of 
disease progression and other radiological imaging-based endpoints will be conducted in a 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  212 of 269
blinded fashion. In addition, an independent PRO review committee of PRO, statistical, and 
psychometric experts, will conduct analyses in a blinded fashion to support validation of the 
MDASI-MPM instrument and determine endpoint definitional details. 
[…]
15.2.2.7
Section 6.1.2 Eligibility criteria for full study
Old text:
[…]
3. Unresectable locally advanced or metastatic MPM after locally confirmed unequivocal 
progression on 1st line treatment with platinum (both cis- or carbo-platinum) in 
combination with pemetrexed. Last dose of previous therapy must be at least 5 drug half-
lives or 28 days, whichever is shorter, before the start of study treatment.
[…]
New text:
[…]
3.
Unresectable locally advanced or metastatic MPM after locally confirmed unequivocal 
progression on 1st line treatment with platinum (both cis- or carbo-platinum) in 
combination with pemetrexed. Last dose of previous therapy must be at least 28 days 
before the start of study treatment.
[…]
15.2.2.8
Section 6.2 Exclusion criteria
Old text:
[…]
4.
 More than 1 previous systemic anti-cancer therapy line (even if therapy used as 
neoadjuvant or adjuvant treatment).
Note: Patients pre-treated with systemic therapy other than platinum, pemetrexed, 
bevacizumab (13) (e.g. other cytotoxic drugs, immunotherapy, targeted therapy, 
hormonal therapy, or any other experimental or approved therapy) are not to be enrolled.
[…]
16. Symptomatic brain metastases or meningeal tumors or other uncontrolled metastases in 
the central nervous system (CNS) unless the patient

Is > 6 months from definitive therapy,

Has a negative imaging study within 4 weeks before study entry (ICF signature for 
full study) and


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  213 of 269

Is clinically stable with respect to the tumor at the time of study entry.
[…]
New text:
[…]
4.
 More than 1 previous systemic anti-cancer therapy line for MPM (even if therapy used 
as neoadjuvant or adjuvant treatment).
Note: Patients pre-treated with systemic therapy other than platinum, pemetrexed, 
bevacizumab (13) (e.g. other cytotoxic drugs, immunotherapy, targeted therapy, 
hormonal therapy, or any other experimental or approved therapy or device) are not to be 
enrolled.
[…]
16. Brain metastases or meningeal tumors or other metastases in the central nervous system 
(CNS). Patients with neurological symptoms must undergo a contrast CT scan or MRI of 
the brain and/or other areas of the CNS as applicable within 28 days before the start of 
study treatment to exclude metastastic disease in the CNS.
[…]
15.2.2.9
Section 6.3.1.1.3 Re-screening
Old text:
Re-starting the defined set of screening procedures to enable the “screening failure” patient’s 
participation at a later time point is not allowed – with the following exceptions:

The patient had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule.

Initial screening occurred too early to complete the required washout period after prior 
therapy.

The in- / exclusion criteria preventing the patient’s initial attempt to participate have 
been changed (via protocol amendment).

Equivocal screening results require further testing for clarification even if, for 
logistical reasons, the further testing cannot be performed within the allocated time 
window (e.g. equivocal laboratory creatinine clearance requiring formal creatinine 
clearance measurement).
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the patient to an unjustifiable health risk. Also, for re-screening, the patient has to re-
sign the ICF, even if it was not changed after the patient’s previous screening.
Re-testing for mesothelin expression after obtaining an initial negative result is not allowed.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  214 of 269
A patient can only be re-screened once and for all re-screening requests, the sponsor needs to 
be contacted to discuss before re-screening the patient.
New text:
Re-screening is defined as re-starting the defined set of screening procedures following 
“screening failure” to allow a patient to participate at a later time point. This is not allowed 
except in the following circumstances:

Equivocal screening test results that require repeat or further testing for 
clarification, which cannot for logistical reasons be performed within the screening 
period.

Initial screening occurred too early to complete the required washout period after prior 
therapy.

The in- / exclusion criteria preventing the patient’s initial attempt to participate have 
been changed (via protocol amendment).

The patient had successfully passed the screening procedures, but could not be 
randomized on schedule and the allocated time window for these tests has expired.
During re-screening, all expired tests must be repeated to fall within the protocol-defined time 
window.
The investigator has to ensure that the repeated screening procedures do not expose the 
patient to an unjustifiable health risk. Also, for re-screening, the patient has to re-sign the ICF, 
even if it was not changed after the patient’s previous screening and a new patient 
identification number has to be requested via Interactive Voice / Web Response System 
(IxRS).
A patient can only be re-screened once and for all re-screening requests, the sponsor needs to 
be contacted to discuss before re-screening the patient.
Re-testing for mesothelin expression after obtaining an initial negative result is not allowed.
15.2.2.10
Section 6.3.1.2 Withdrawal criteria
Old text:
[…]
Withdrawal from study treatment, active follow-up and long-term follow-up
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  215 of 269
Figure 6-1
Withdrawal criteria 
[…]
Patients must be withdrawn from treatment with anetumab ravtansine if any of the following occurs:
[…]

If any type of TEAE requiring dose modification does not resolve to Grade ≤ 1 (or Hb ≥ 9 g/dL in case of 
anemia) within 6 weeks after the last dose of anetumab ravtansine.
[…]
[…]
New text:
[…]
Withdrawal from study treatment, active follow-up and long-term follow-up
[…]
Figure 6-1
Withdrawal criteria 
[…]
Patients must be withdrawn from treatment with anetumab ravtansine if any of the following occurs:
[…]

If any type of TEAE requiring dose modification does not resolve to Grade ≤ 2(or Hb ≥ 9 g/dL in case of 
anemia) within 6 weeks after the last dose of anetumab ravtansine.
 […]
[…]
15.2.2.11
Section 7.2.1 Test drug – anetumab ravtansine
Old text:
[…]
The drug product is to be stored at 2°C to 8°C (36°F to 46°F).
Reconstitution
The drug product should be reconstituted and processed under aseptic conditions (i.e. 
qualified laminar flow unit and trained personnel) to preclude microbial contamination.
Using a sterile syringe, gently add 11.9 mL of water for injection through the middle of the 
stopper to the freeze-dried product into the 30 mL injection vial to obtain a solution 
(approximate reconstituted volume is 12.5 mL). During reconstitution, make sure that the 
needle does not come into contact with the cake or resulting solution; avoid shaking. The 
lyophilizate should dissolve completely.
The reconstituted lyophilizate may be diluted only after the solution is clear.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  216 of 269
Dilution of the reconstituted solution
Dilution of the reconstituted solution with 0.9% sodium chloride solution (normal saline) 
should be done under aseptic conditions (i.e. qualified laminar flow unit and trained 
personnel) to preclude microbial contamination. A slight turbidity may occur during the 
dilution which does not affect the quality of the drug product.
Stability of the reconstituted solution
Exposure to bright light should be avoided; standard room illumination does not necessitate 
any precautions.
The reconstituted solution is physically and chemically stable for 24 h at room temperature 
and between 2°C and 8°C. However, unless administered immediately, for microbiologic 
consideration, the reconstituted solution should be stored between 2°C and 8°C and used 
within 6 h according to USP 797 “Pharmaceutical Compounding – Sterile preparations”.
If not reconstituted under aseptic conditions, the solution should be used immediately or 
stored at 2°C to 8°C and used within 1 h, according to USP 797.
If frozen or stored above room temperature, the solution should be discarded.
Stability of the diluted solution
Exposure to bright light should be avoided; standard room illumination does not necessitate 
any precautions.
Stability investigations have shown that if diluted under aseptic conditions, concentrations 
between 0.1 and 3.0 mg/mL are stable for the period of use (24 h) at room temperature and 
between 2°C and 8°C. However, unless administered immediately, for microbiologic 
consideration, diluted solution should be stored between 2°C and 8°C and used within 6 h 
according to USP 797 “Pharmaceutical Compounding – Sterile preparations”.
If not diluted under aseptic conditions, the solution should be used immediately or stored at 
2°C to 8°C and used within 1 h, according to USP 797.
If frozen or stored above room temperature, the solution should be discarded.
Refer to IB for anetumab ravtansine for details regarding drug properties and formulation.
New text:
[…]
The drug product is to be stored at 2°C to 8°C (36°F to 46°F).
The reconstitution and dilution of the anetumab ravtansine solution and the associated 
stability information is described in detail in a separate manual “15743 Anetumab ravtansine 
storage and handling instructions” that will be maintained in the trial master file (TMF) and in 
each center’s investigator site file.
Refer to IB for anetumab ravtansine for details regarding drug properties and formulation.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  217 of 269
15.2.2.12
Section 7.4.2.1 Dose modifications of anetumab ravtansine
Old text:
[…]
TEAE requiring dose modification (temporary treatment interruption, dose reduction, or 
permanent discontinuation of treatment) will be defined as any of the events described below 
that is possibly, probably, or definitely related to anetumab ravtansine and occurs anytime 
during the study (not only in Cycle 1).
[…]
New text:
[…]
TEAE requiring dose modification (dose omission, infusion interruption, change in infusion 
rate, dose delay, dose reduction, or permanent discontinuation of study drug) will be defined 
as any of the events described below that is possibly, probably, or definitely related to 
anetumab ravtansine and occurs anytime during the study (not only in Cycle 1).
[…]
15.2.2.13
Section 7.4.2.1.1 Hematological toxicities
Old text:
Dose modifications for hematological toxicity

If treatment modification is required due to a hematological TEAE, and the 
continuation of treatment is appropriate, the anetumab ravtansine dose will be adjusted 
as described in Table 7-3 and Table 7-4 below.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  218 of 269
Table 7-3
Dose adjustments in response to neutrophil and platelet nadir a counts of 
the previous cycle
Absolute 
neutrophil nadir 
count of the 
previous cycle 
(/mm3)
Platelet nadir count of the previous 
cycle (/mm3)
Anetumab 
ravtansine dose 
adjustment b
≥ 500 or < 500 for 
< 7 days
and
≥ 25,000
No change
< 500 for ≥ 7 days
and/or
< 25,000 regardless of the presence of 
active bleeding (or ≥ 25,000 with 
clinically significant bleeding, i.e. 
bleeding requiring platelet transfusion)
Decrease 1 dose 
level b
Febrile 
neutropenia c
and/or
< 25,000 regardless of the presence of 
active bleeding (or ≥ 25,000 with 
clinically significant bleeding, i.e. 
bleeding requiring platelet transfusion)
Decrease 1 dose 
level b
ANC = Absolute neutrophil count; C = Cycle; CBC = Complete blood count; D = Day; Q3W = Every 3 
weeks
a
Site visits and blood test for CBC (and biochemistry) on D8 and D15 will be performed on C1, C2 and 
C3 only. From Cycle 4 onwards, visits and procedures on D8 and D15 are no longer required.
b
Dose reduction by 1 dose level translates to a change from 6.5 mg/kg Q3W to 5.5 mg/kg Q3W, or 
from 5.5 mg/kg Q3W to 4.5 mg/kg Q3W. Not more than 2 dose reductions from the starting dose 
level are permitted.
c
Febrile neutropenia is defined as ANC < 1000/mm3 and fever (a single body temperature reading of 
> 38.3°C [101°F] or a sustained body temperature of ≥ 38°C [100.4°F] for more than 1 hour).
Table 7-4
Dose adjustments in response to pre-infusion values
Absolute 
neutrophil 
count (/mm3)
Platelets 
(/mm3)
Hemoglobin 
(g/dL)
Timing
Anetumab ravtansine 
dose adjustment
≥ 1,000
and
≥ 75,000
Treat on time
Adjust dose by nadir a 
counts in previous cycle 
per investigator’s 
discretion 
< 1,000
and/
or
< 75,000
Delay until 
ANC ≥ 1.0 
and platelets 
≥ 75,000 b
Decrease by 1 dose 
level c 
< 8
Delay until 
Hb ≥ 8 b
Re-start at the same 
dose or decrease by 
1 dose level c (at 
investigator’s discretion)
ANC = Absolute neutrophil count; C = Cycle; CBC = Complete blood count; D = Day; Hb = Hemoglobin; 
Q3W = Every 3 weeks; TEAE = Treatment-emergent adverse event
a
Site visits and blood test for CBC (and biochemistry) on D8 and D15 will be performed on C1, C2 and 
C3 only. From Cycle 4 onwards, visits and procedures on D8 and D15 are no longer required.
b
Treatment will be discontinued if the TEAE fails to resolve to Grade ≤ 1 (or Hb ≥ 9 g/dL in case of 
anemia) within 6 weeks after the last dose of anetumab ravtansine.
c
Dose reduction by 1 dose level translates to a change from 6.5 mg/kg Q3W to 5.5 mg/kg Q3W, or 
from 5.5 mg/kg Q3W to 4.5 mg/kg Q3W. Not more than 2 dose reductions from the starting dose 
level are permitted.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  219 of 269
New text:
Dose modifications for hematological toxicity

If treatment modification is required due to a hematological TEAE, and the 
continuation of treatment is appropriate, the anetumab ravtansine dose will be adjusted 
as described in Table 7-3 below.
[…]
Table 7–3
Dose modifications for anetumab ravtansine in response to hematological 
toxicities a for neutrophil and platelet nadir b counts – table added
Dose modifications
Blood count
Start new cycle only if 
platelet count is
≥ 75,000 (Grade ≤1) (pre-infusion)
< 25,000 (Grade 4) for ≥ 7 days (nadir b)
Platelet 
count
(/mm3)
Dose reduce by 1 dose 
level c
< 50,000 (Grade 3) for ≥ 7 days with bleeding d 
(nadir b)
Start new cycle only if 
ANC is
≥ 1000 (Grade ≤ 2) (pre-infusion)
< 500 (Grade 4) for 7 days (nadir b)
Absolute 
neutrophil 
count
(/mm3)
Dose reduce by 1 dose 
level c
Febrile neutropenia (Grade 3) e (during previous 
cycle)
Start new cycle only if 
hemoglobin is
Hb ≥ 8 (pre-infusion)
Hemoglobin 
(g/dL)
Re-start at the same dose 
or dose reduce by 1 dose 
level c (at investigator’s 
discretion)
< 8 (nadir b)
Any
Discontinue
Grade 3 or 4 toxicity after 2 dose reductions
ANC = Absolute neutrophil count; C = Cycle; CBC = Complete blood count; D = Day; Hb = Hemoglobin; 
Q3W = Every 3 weeks
a
For any toxicity ≤ Grade 2 assessed as related to study drug(s) by the investigator, dose modification 
may be considered if investigator feels this is in the patients best interest. Such toxicities might be 
≤ Grade 2 toxicities which interfere with the activities of daily life.
b
Nadir: lowest value measured in previous cycle or pre-infusion. Site visits and blood test for CBC on D8 
and D15 are mandatory for C1, C2 and C3 only. From C4 onwards, visits and procedures on D8 and D15 
are no longer required.
c
Dose reduction by 1 dose level translates to a change from 6.5 mg/kg Q3W to 5.5 mg/kg Q3W, or from 
5.5 mg/kg Q3W to 4.5 mg/kg Q3W. Not more than 2 dose reductions from the starting dose level are 
permitted.
d
Clinically significant bleeding, i.e. bleeding requiring platelet transfusion.
e
Febrile neutropenia is defined as ANC < 1000/mm3 and fever (a single body temperature reading of 
> 38.3°C [101°F] or a sustained body temperature of ≥ 38°C [100.4°F] for more than 1 hour).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  220 of 269
15.2.2.14
Section 7.4.2.1.2 Non-hematological toxicities
Old text:
Non-hematological toxicities requiring dose modification

CTCAE Grade 2 anetumab ravtansine infusion-related reaction or other CTCAE 
Grade 2 hypersensitivity events (see Section 7.4.2.1.3)

AST and/or ALT increase  5.0 x ULN (CTCAE Grade  3)

AST and/or ALT increase  3.0 x ULN (CTCAE Grade  2) with concomitant 
increase in total bilirubin  1.5 x ULN (CTCAE Grade  2)

Total bilirubin  3.0 x ULN (CTCAE Grade  3)

Bayer Grade ≥ 3 corneal epitheliopathy (see below and Table 7-6)

Any other Grade ≥ 3 non-hematological toxicity that, in the investigator’s opinion, 
warrants treatment modification (see Table 7-5), excluding the following:
o
Nausea, vomiting, or diarrhea if manageable with anti-emetics or anti-
diarrheals within 7 days
o
Hair loss
o
Fatigue lasting ≤ 72 h

Any other toxicity irrespective of the type or severity that represents a clinically 
significant risk to patient in the investigator’s opinion.
Dose modifications for non-hematological toxicity
[…]
Table 7-5
Dose adjustments in response to non-hematologic toxicities
CTCAE v4.03 
grade
Anetumab ravtansine dose 
delay / interruption
Anetumab ravtansine dose 
modification
[…]
[…]
1st appearance: Delay/Interruption 
until Grade ≤ 2 b
2nd appearance: 
Delay/Interruption until Grade ≤ 2b
[…]
[…]
[…]
[…]
b
Treatment will be discontinued if the TEAE fails to resolve to Grade ≤ 1 within 6 weeks after the last 
dose of anetumab ravtansine.
[…]
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  221 of 269
New text:
Non-hematological toxicities requiring dose modification

CTCAE Grade 2 anetumab ravtansine infusion-related reaction or other CTCAE 
Grade 2 hypersensitivity events (see Section 7.4.2.1.3)

AST and/or ALT increase  3.0 x ULN (CTCAE Grade  2) with concomitant 
increase in total bilirubin  1.5 x ULN (CTCAE Grade  2)

Bayer Grade ≥ 3 corneal epitheliopathy (see below and Table 7-5)

Any other Grade ≥ 3 non-hematological toxicity that, in the investigator’s opinion, 
warrants treatment modification (see Table 7-4), excluding the following:
o
Nausea, vomiting, or diarrhea if manageable with anti-emetics or anti-
diarrheals within 7 days
o
Fatigue lasting ≤ 72 

Any other toxicity irrespective of the type or severity that represents a clinically 
significant risk to patient in the investigator’s opinion.
Dose modifications for non-hematological toxicity
[…]
Table 7-4
Dose adjustments in response to non-hematologic toxicities
CTCAE v4.03 
grade
Anetumab ravtansine dose 
delay / interruption
Anetumab ravtansine dose 
modification
[…]
1st appearance: Delay/Interruption 
until Grade ≤ 2 b
2nd appearance: 
Delay/Interruption until Grade ≤ 2b
[…]
[…]
[…]
b
Treatment will be discontinued if the TEAE fails to resolve to Grade ≤ 2 within 6 weeks after the last 
dose of anetumab ravtansine.
[…]
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  222 of 269
15.2.2.15
Section 7.4.2.1.3 Miscellaneous toxicities
Old text:
IV infusion-related reaction and other hypersensitivity events
[…]
Re-treatment should be at the infusion rate reduced by 50%, along with anti-allergic 
prophylaxis (e.g. anti-histamines, acetaminophen, and/or corticosteroids) chosen at the 
investigator’s discretion or according to the institutional guidelines.
[…]
Dose modifications for corneal epitheliopathy
[…]
Table 7-6
Bayer classification and management of corneal epitheliopathy
[…]
[…]
a
Oxford Schema must be used for grading SPK from stage 0 to VI.
[…]
[…]
New text:
IV infusion-related reaction and other hypersensitivity events
[…]
Re-treatment should be at the infusion rate reduced by 50%, along with anti-allergic 
prophylaxis (e.g. anti-histamines, paracetamol, acetaminophen, and/or corticosteroids) chosen 
at the investigator’s discretion or according to the institutional guidelines.
[…]
Dose modifications for corneal epitheliopathy
[…]
Table 7-5
Bayer classification and management of corneal epitheliopathy
[…]
[…]
a
Oxford Schema must be used for grading SPK from stage 0 to VI (see Section 16.9).
[…]
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  223 of 269
15.2.2.16
Section 7.5 Blinding
Old text:
This is an open-label study except for the independent and central radiological review for 
the assessment of disease progression and other radiological imaging based endpoints, 
which will be conducted in a blinded fashion.
New text:
This is an open-label study except for: 

The independent and central radiological review for the assessment of disease 
progression and other radiological imaging based endpoints, which will be conducted 
in a blinded fashion.

The independent blinded PRO review committee which will conduct analyses to 
support validation of the MDASI-MPM instrument and determine endpoint 
definitional details.
15.2.2.17
Section 8.1 Prior and concomitant therapy
Old text:
[…]
Table 8-1
Prohibited prior and concomitant therapies
Prohibited prior and 
concomitant therapy 
(see also Section 6.2)
Time period when 
prohibited
Comments
Prohibited for all patients
[…]
Platinum/pemetrexed/ 
bevacizumab
Within 5 drug half-lives or 
28 days, whichever is 
shorter, before the start 
of study treatment until 
safety follow-up visit
[…]
Anti-arrhythmic therapy other 
than beta blockers or digoxin
Acute steroid therapy or 
taper
Chronic steroid therapy is acceptable, provided that 
the dose is stable for 1 month before the start of 
study treatment and thereafter.
Radiotherapy
Within 4 weeks before 
the start of screening for 
full study
Except for pain control, see below in Table 8-2. […]
Drugs with known bone 
marrow toxicity
Strong inhibitors and strong 
inducers of CYP3A4 (listed 
in Appendix 16.6), including:
- Herbal preparations 
Within 2 weeks before 
the start of study 
treatment until the safety 
follow-up visit
DM4 and vinorelbine are substrates of CYP3A4.
During study treatment, moderate and weak CYP3A4 
inducers should be used with caution as decrease in 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  224 of 269
Table 8-1
Prohibited prior and concomitant therapies
Prohibited prior and 
concomitant therapy 
(see also Section 6.2)
Time period when 
prohibited
Comments
containing CYP3A4 inducers 
(e.g. St John’s Wort)
- Grapefruit and grapefruit 
juice (CYP3A4 inhibitor)
plasma concentrations of DM4 cannot be ruled out.
Prohibited for patients in the comparator (vinorelbine) arm
Concomitant live attenuated 
virus vaccines (e.g. yellow 
fever) 
Within 2 weeks before 
the start of study 
treatment until the safety 
follow-up visit
Contraindicated due to risk of generalized vaccine 
disease, possibly fatal
ASCO = American Society of Clinical Oncology; CSF = Colony stimulating factor; CT = Computed tomography; 
CYP3A4 = Cytochrome P450, family 3, subfamily A, polypeptide 4; DM4 = Derivatives of maytansine 4; G-
CSF = Granulocyte-colony stimulating factor; IV = Intravenous; MPM = Malignant pleural mesothelioma; 
mRECIST = Modified Response Evaluation Criteria in Solid Tumors; MRI = Magnetic resonance imaging; 
PD = Progressive disease; RT = Radiotherapy
Table 8-2
Permitted concomitant therapies 
Permitted concomitant therapies
Comments
Permitted for all patients
[…]
Institutional standards for the management of 
infusion-related reactions or other 
hypersensitivity events 
May be utilized at the discretion of the investigator.
Palliative radiotherapy for pain control
Allowed provided that:
- In the opinion of the investigator, the patient does not have PD,
[…]
[…]
[…]
New text:
[…]
Table 8-1
Prohibited prior and concomitant therapies
Prohibited prior and 
concomitant therapy 
(see also Section 6.2)
Time period when 
prohibited
Comments
Prohibited for all patients
[…]
Platinum/pemetrexed/ 
bevacizumab
Within 28 days before the 
start of study treatment 
until safety follow-up visit


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  225 of 269
Table 8-1
Prohibited prior and concomitant therapies
Prohibited prior and 
concomitant therapy 
(see also Section 6.2)
Time period when 
prohibited
Comments
[…]
Anti-arrhythmic therapy other 
than beta blockers or digoxin
Radiotherapy
Within 4 weeks before 
the start of screening for 
full study
Except for pain control, see below in Table 8-2. […]
Drugs with known bone 
marrow toxicity
Strong inhibitors and strong 
inducers of CYP3A4 (listed 
in Appendix 16.6), including:
- Herbal preparations 
containing CYP3A4 inducers 
(e.g. St John’s Wort)
- Grapefruit and grapefruit 
juice (CYP3A4 inhibitor)
Within 2 weeks before 
the start of study 
treatment until the safety 
follow-up visit
DM4 and vinorelbine are substrates of CYP3A4.
During study treatment, moderate and weak CYP3A4 
inducers should be used with caution as decrease in 
plasma concentrations of DM4 cannot be ruled out.
Concomitant live attenuated 
virus vaccines (e.g. yellow 
fever) 
Within 2 weeks before 
the start of study 
treatment (for all patients, 
during screening, then 
from C1D1 until the 
safety follow-up visit for 
patients in vinorelbine 
arm only)
Contraindicated due to risk of generalized vaccine 
disease, possibly fatal
ASCO = American Society of Clinical Oncology; C=Cycle; CSF = Colony stimulating factor; CT = Computed 
tomography; CYP3A4 = Cytochrome P450, family 3, subfamily A, polypeptide 4; D=Day; 
DM4 = Derivatives of maytansine 4; G-CSF = Granulocyte-colony stimulating factor; IV = Intravenous; 
MPM = Malignant pleural mesothelioma; mRECIST = Modified Response Evaluation Criteria in Solid 
Tumors; MRI = Magnetic resonance imaging; PD = Progressive disease; RT = Radiotherapy
Table 8-2
Permitted concomitant therapies 
Permitted concomitant therapies
Comments
Permitted for all patients
[…]
Institutional standards for the management of 
infusion-related reactions or other 
hypersensitivity events 
May be utilized at the discretion of the investigator.
Chronic steroid therapy
Permitted provided that the dose is stable for one month prior to 
start of study drug.
Palliative radiotherapy for pain control
Allowed provided that:
- In the opinion of the investigator, the patient does not have PD,
[…]
[…]
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  226 of 269
15.2.2.18
Section 9.1 Tabular schedule of evaluations
Old text:
Table 9-1
Study flow chart 
Treatment
Pre-
screening
Full 
screening
(maximum 
days before 
C1D1)
Cycle 1
Cycle 2 and higher
Safety follow-up 
period / visit
Active 
follow-up a
Long-term 
follow-up a
Days
-28
- 7
D1
D8 
D15 
D1
D8 b
D15 b
+30 (after last 
dose)
Every 3 
months
Acceptable time window (in days)
(unless otherwise specified)
+/-1
+/-1
+/-1
+/-1
+/-1
+7
±14
[…]
Safety
[…]
Vital signs (BP, HR, RR, Temp)
X
X
X z
X
X
X
X
X
X
[…]
Ophthalmologic examination k
X
X 
X
[…]
Electrolyte and chemistry panel
X
X l
X l
X
X l
X l
X
[…]
Efficacy
Radiological tumor evaluation with 
contrast-enhanced CT/MRI o
X 
Every 6 weeks (first 6 months), every 9 
weeks (until end of year 2), every 12 
weeks thereafter o
X o
[…]
Biomarker sampling
BM archival or fresh biopsy tissue u
X v
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  227 of 269
Table 9-1
Study flow chart 
Treatment
Pre-
screening
Full 
screening
(maximum 
days before 
C1D1)
Cycle 1
Cycle 2 and higher
Safety follow-up 
period / visit
Active 
follow-up a
Long-term 
follow-up a
Days
-28
- 7
D1
D8 
D15 
D1
D8 b
D15 b
+30 (after last 
dose)
Every 3 
months
Acceptable time window (in days)
(unless otherwise specified)
+/-1
+/-1
+/-1
+/-1
+/-1
+7
±14
[…]
j
Cardiac function test is required during full screening and pre-dose C2D1, pre-dose C4D1, and afterwards at the investigator’s 
discretion based on clinical need. EchoCG shall be performed instead of MUGA when local regulations do not permit the use of MUGA 
as requested per protocol schedule.
[…]
u
Fresh tumor tissue collection is optional after a local assessment of partial or complete response.
[…]
z
Eligibility criteria check, IxRS transaction to randomize the patient, toxicity / AE assessment, concomitant medication review, brief 
physical examination, vital signs and weight measurement, and ECOG PS assessment can be done within 24 hours before 
administration of the first dose of study drug. Eligibility must be confirmed prior to randomizing the patient in IxRS.
New text:


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  228 of 269
Table 9-1
Study flow chart 
Treatment
Pre-
screening
Full screening
(maximum days 
before C1D1)
Cycle 1
Cycle 2 and higher
Safety follow-up 
period / visit
Active 
follow-up a
Long-term 
follow-up a
Days
-28
-21
- 7
D1
D8 
D15 
D1
D8 b
D15 b
+30 (after last 
dose)
Every 3 
months
Acceptable time window (in days)
(unless otherwise specified)
+/-1
+/-1
+/-1
+/-1
+/-1
+7
±14
[…]
Safety
[…]
Vital signs (BP, HR, RR, Temp)
X
X z
X
X
X
X
X
X
[…]
Ophthalmologic examination k
X
X 
X
[…]
Electrolyte and chemistry panel
X
X l
X l
X aa
X l
X l
X
[…]
Efficacy
Radiological tumor evaluation with 
contrast-enhanced CT/MRI o
X bb
Every 6 weeks (first 6 months), every 9 
weeks (until end of year 2), every 12 
weeks thereafter o
X o
[…]
Biomarker sampling
BM archival or fresh biopsy tissue u
X v
X u
[…]
[…]
j
Cardiac function test is required during full screening and pre-dose C2D1, pre-dose C4D1, and afterwards at the investigator’s discretion 
based on clinical need. During treatment, cardiac function test can be done up to 7 days before study drug administration. EchoCG shall be 
performed instead of MUGA when local regulations do not permit the use of MUGA as requested per protocol schedule.
[…]
u
If additional archival tissue is available, optional archival tissue should be collected for patients who consent and sent when possible after 
C1D1. Fresh tumor tissue collection is optional after a local assessment of partial or complete response.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  229 of 269
Table 9-1
Study flow chart 
Treatment
Pre-
screening
Full screening
(maximum days 
before C1D1)
Cycle 1
Cycle 2 and higher
Safety follow-up 
period / visit
Active 
follow-up a
Long-term 
follow-up a
Days
-28
-21
- 7
D1
D8 
D15 
D1
D8 b
D15 b
+30 (after last 
dose)
Every 3 
months
Acceptable time window (in days)
(unless otherwise specified)
+/-1
+/-1
+/-1
+/-1
+/-1
+7
±14
z
Eligibility criteria check, IxRS transaction to randomize the patient, toxicity / AE assessment, concomitant medication review, brief physical 
examination, vital signs and weight measurement, and ECOG PS assessment can be done within 24 hours before administration of the first 
dose of study drug. Eligibility must be confirmed prior to randomizing the patient in IxRS.
aa Lipase testing on Cycle 2 and higher Day 1 can be performed within 8 days before administration of the study treatment.
bb Patients with neurological symptoms at screening must undergo a contrast CT or MRI scan of the brain and/or other areas of the CNS as 
applicable within 28 days before the start of study treatment to exclude metastastic disease in the CNS.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  230 of 269
15.2.2.19
Section 9.2.2 Full screening period
Old text:
[…]
Within 28 days before the start of study treatment: 
[…]

Radiological tumor evaluation with contrast-enhanced CT/MRI of 
chest/abdomen/pelvis (see Section 9.4.1). Pre-study CT/MRI may be acceptable as a 
baseline scan if done within 28 days before start of study drug, if centrally evaluable 
for mRECIST and if performed according to the Imaging Acquisition Guidance 
provided in the Imaging Manual.
[…]

Complete physical examination (see Section 9.6.3.2.1).

Vital signs (see Section 9.6.3.4).

Weight and height.
[…]

A detailed ophthalmologic examination (visual acuity, IOP, Schirmer test and slit 
lamp) (see Section 9.6.3.7) will be done within 3 weeks before the start of study 
treatment.
[…]
New text:
[…]
Within 28 days before the start of study treatment: 
[…]

Radiological tumor evaluation with contrast-enhanced CT/MRI of 
chest/abdomen/pelvis (see Section 9.4.1). Pre-study CT/MRI may be acceptable as a 
baseline scan if done within 28 days before start of study drug, if centrally evaluable 
for mRECIST and if performed according to the Imaging Acquisition Guidance 
provided in the Imaging Manual. Patients with neurological symptoms at screening 
must undergo a contrast CT or MRI scan within 28 days before the start of study 
treatment to exclude brain metastases
[…]

Complete physical examination (see Section 9.6.3.2.1).

Weight and height.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  231 of 269
Within 21 days before the start of study treatment:

A detailed ophthalmologic examination (visual acuity, IOP, Schirmer test and slit 
lamp) (see Section 9.6.3.7)
[…]
15.2.2.20
Section 9.2.3.1 Treatment – Cycle 1
Old text:
Cycle 1 Day 1
[…]

12-lead ECG (see Section 9.6.3.5), 30 min post-dose.
New text:
Cycle 1 Day 1
[…]

12-lead ECG (see Section 9.6.3.5), 30 min (+/- 5 min) post-dose.
For patients who consent to provide optional additional archival tissue, this should be 
collected and sent to the central laboratory at any time post randomization.
15.2.2.21
Section 9.2.3.2 Treatment – Cycle 2 and higher
Old text:
Cycle 2 and higher Day 1
[…]

EchoCG or MUGA scan (see Section 9.6.3.6) on C2D1, C4D1, and afterwards at the 
investigator’s discretion based on clinical need.
[…]

Laboratory (see Section 9.6.3.1).
[…]

Electrolyte and chemistry panel.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  232 of 269
New text:
Cycle 2 and higher Day 1
[…]

EchoCG or MUGA scan (see Section 9.6.3.6) on C2D1, C4D1, and afterwards at the 
investigator’s discretion based on clinical need. During treatment, cardiac function test 
can be done up to 7 days before study drug administration.
[…]

Laboratory (see Section 9.6.3.1).
[…]

Electrolyte and chemistry panel (lipase testing can be performed within 8 days 
before administration of the study treatment).
[…]
15.2.2.22
Section 9.2.5.2 Active follow-up
Old text:
Patients who discontinue study treatment due to any other reason than centrally confirmed 
radiological PD will continue clinic visits during active follow-up for efficacy assessments 
including tumor response and QoL.
[…]
New text:
Patients who discontinue study treatment due to any other reason than centrally confirmed 
radiological PD will continue clinic visits during active follow-up for efficacy assessments 
including tumor response, disease-related-symptoms, and QoL.
[…]
15.2.2.23
Section 9.4.1 Radiological tumor assessments
Old text:
[…]
If focal neurological symptoms are present at screening, a CT scan or MRI of the brain is 
required to rule out brain metastasis by the investigator. All additional suspected sites of 
disease should be imaged (e.g. cervical lymph nodes, bone etc.).
[…]
The final evaluation of treatment response will be done by central blinded review 
retrospectively.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  233 of 269
[…]
New text:
[…]
If focal neurological symptoms are present at screening, a CT scan or MRI of the brain and/or 
other areas of the CNS as applicable is required to rule out metastastic disease in the CNS 
within 28 days before the start of study treatment by the investigator. All additional suspected 
sites of disease should be imaged (e.g. cervical lymph nodes, bone etc.)
[…]
The final evaluation of treatment response for those patients not undergoing central review for 
PD confirmation will be done by central blinded review retrospectively.
[…]
15.2.2.24
Section 9.4.3 Patient-reported outcomes
Old text:
The effect of treatment on disease-specific health-related quality of life (QoL) and disease-
specific symptoms will be assessed using the MD Anderson Symptom Inventory-Malignant 
Pleural Mesothelioma (MDASI-MPM) and the Lung Cancer Symptom Scale-Mesothelioma 
(LCSS-Meso).
The LCSS-Meso will be used to assess change in thoracic cancer symptoms. In addition to the 
LCSS-Meso, the MDASI-MPM will be used to assess change in thoracic cancer symptoms 
and interference of these symptoms with daily activities.
[…]
New text:
The effect of treatment on disease-related symptoms and disease-specific health-related 
quality of life (QoL) will be assessed using the MD Anderson Symptom Inventory-Malignant 
Pleural Mesothelioma (MDASI-MPM) and the Lung Cancer Symptom Scale-Mesothelioma 
(LCSS-Meso), respectively.
The LCSS-Meso will be used to assess change in thoracic cancer symptoms and health-related 
Quality of Life (HRQoL). In addition to the LCSS-Meso, the MDASI-MPM will be used to 
assess change in thoracic cancer symptoms and interference of these symptoms with daily 
activities.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  234 of 269
15.2.2.25
Section 9.6.2 Pregnancies
Old text:
[…]
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE.
New text:
[…]
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE.
Only those pregnancies with abnormal outcome need to be reported as SAEs. All pregnancies 
must be reported on additional pregnancy report forms provided to the site.
15.2.2.26
Section 9.6.3.1 Laboratory evaluations
Old text:
Safety laboratory analyses will be performed locally according to the schedule summarized in 
the flow chart of Section 9.1.

Complete blood count: Hemoglobin, hematocrit, platelet count, white blood cell count 
(WBC). WBC must include differential including neutrophil, lymphocyte, monocyte, 
basophil, and eosinophil counts.

Electrolyte and chemistry panel: sodium, potassium, chloride, calcium, phosphorus, 
glucose (fasting or random/unspecified), AST, ALT, gamma-glutamyl transferase 
(GGT), bilirubin (total and direct), ALP, uric acid, total protein, albumin, lipase, 
amylase, lactic dehydrogenase (LDH), blood urea nitrogen (BUN) or urea, and 
creatinine.
[…]
New text:
Safety laboratory analyses will be performed locally according to the schedule summarized in 
the flow chart of Section 9.1.

Complete blood count: Hemoglobin, hematocrit, platelet count, red blood cell count 
(RBC), white blood cell count (WBC). WBC must include differential including 
neutrophil, lymphocyte, monocyte, basophil, and eosinophil counts.

Electrolyte and chemistry panel: sodium, potassium, chloride, calcium (total, 
corrected, or ionized), phosphorus, glucose (fasting or random/unspecified), AST, 
ALT, gamma-glutamyl transferase (GGT), bilirubin (total and direct), ALP, uric acid, 
total protein, albumin, lipase, amylase, lactic dehydrogenase (LDH), blood urea 
nitrogen (BUN) or urea, and creatinine.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  235 of 269
[…]
15.2.2.27
Section 9.6.3.6 Cardiac function
Old text:
Cardiac function test is mandatory. It will be measured by EchoCG or MUGA scan at full 
screening and on C2D1, C4D1, and afterwards at the investigator’s discretion based on 
clinical need (see flow chart in Section 9.1). EchoCG shall be performed instead of MUGA 
when local regulations do not permit the use of MUGA as requested per protocol schedule.
New text:
Cardiac function test is mandatory. It will be measured by EchoCG or MUGA scan at full 
screening and on C2D1, C4D1, and afterwards at the investigator’s discretion based on 
clinical need (see flow chart in Section 9.1). During treatment, cardiac function test can be 
done up to 7 days before study drug administration. EchoCG shall be performed instead of 
MUGA when local regulations do not permit the use of MUGA as requested per protocol 
schedule.
15.2.2.28
Section 9.7.1 Biomarkers
Old text:
[…]
Exploratory biomarker analysis may also be performed using additional fresh tumor tissue to 
determine alterations in tumor-associated genes and to perform gene expression analysis. 
Fresh tumor tissue should be collected after a local assessment of response (complete 
response [CR] or partial response [PR]) for patients who consent to this procedure. The 
exploratory biomarkers may include, but are not limited to, DNA sequencing of tumor-
associated genes and gene expression profiling. Next generation sequencing (NGS), and 
RNA, protein or miRNA expression analysis may be performed.
[…]
New text:
[…]
For patients who provide optional consent, exploratory biomarker analysis may also be 
performed using additional fresh or archival tumor tissue to determine alterations in tumor-
associated genes and to perform gene expression analysis. If additional archival tissue is 
available after randomization, tissue should be sent for analysis to the central laboratory. 
Fresh tumor tissue should be collected after a local assessment of response (complete 
response [CR] or partial response [PR]) for patients who consent to this procedure. The 
exploratory biomarkers may include, but are not limited to, DNA sequencing of tumor-
associated genes and gene expression profiling. Next generation sequencing (NGS), and 
RNA, protein or miRNA expression analysis may be performed. The analysis of changes in 
the genomic and expression profile (e.g. mesothelin expression) in tumor tissue over time on 
drug treatment may elucidate the underlying molecular mechanism of drug response and 
intrinsic and acquired resistance to anetumab ravtansine.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  236 of 269
[…]
15.2.2.29
Section 10.2 Analysis sets
Old text:
[…]
PK set. All patients with valid PK profile for anetumab ravtansine will be included in the 
analysis set for the anetumab ravtansine PK analysis. All patients with valid PK profile for 
vinorelbine will be included in the analysis set for the PK analysis of vinorelbine.
[…]
Quality of life set (QOL). All randomized patients with a non-missing QoL evaluation at 
baseline will be included in the QOL dataset. Patients in this set will be reported by treatment 
arm as randomized. The QOL set will be used for QoL evaluations.
[…]
New text:
[…]
PK set. All patients with at least one valid PK sample for anetumab ravtansine will be 
included in the analysis set for the anetumab ravtansine PK analysis. All patients with at least 
one valid PK sample for vinorelbine will be included in the analysis set for the PK analysis of 
vinorelbine. PK samples will be considered valid under the following conditions: known dose, 
known duration of treatment, known time of sample collection.
[…]
Quality of life set (QOL). All randomized patients with a non-missing LCSS-Meso 
evaluation at baseline will be included in the QOL dataset. Patients in this set will be reported 
by treatment arm as randomized. The QOL set will be used for QoL evaluations.
[…]
15.2.2.30
Section 10.3.2 Primary efficacy variable
Old text:
[…]
Primary efficacy analysis
[…]
Sensitivity analyses will be performed, including analyses to assess the impact of missing data 
and the possibility of survivorship and selection biases. Further details will be described in the 
SAP.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  237 of 269
New text:
[…]
Primary efficacy analysis
[…]
Assumption-checking and sensitivity analyses will be performed, consistent with regulatory 
guidance on progression-free survival endpoints including Appendix 1 to the EMA guideline 
on the evaluation of anti-cancer medicinal products in man (36) and the FDA guidance on 
clinical trial endpoints for the approval of non-small cell lung cancer drugs and biologics (37), 
including analyses to assess the impact of missing data; the possibility of informative 
censoring, survivorship, and selection biases; the proportional hazards assumption; and the 
impact of clinical progression and subsequent therapy. Investigator progression will be 
evaluated as a sensitivity analysis, and concordance between investigator and independent 
central review determinations will be evaluated. Details will be described in the SAP.
An updated analysis of PFS will be performed at the time of the final Overall Survival 
analysis (See Section 10.3.3.1). Details will be described in the SAP.
15.2.2.31
Section 10.3.3.1 Secondary efficacy variables
Old text:
[…]
Disease control rate (DCR), defined as proportion of patients achieving CR, PR, or SD per 
mRECIST criteria, as determined by the central radiological reviewer.
Duration of response (DOR) is defined in responders as the time from documentation of 
tumor response to disease progression or death without documented progression, as 
determined by the central radiological reviewer.
Patient-reported outcomes
Time to worsening of symptoms characteristic of mesothelioma, as measured by the 
MDASI-MPM questionnaire total score of the subset of symptoms. Patients will be 
considered as “censored” at the date of their last tumor evaluation, if the reason for stopping 
treatment is not related to PD. Patients dropping out due to progression-related reason or 
experiencing a PD event or death due to any reason will be considered as having had their 
deterioration in symptoms at the date of their last tumor evaluation.
Time to worsening of pain based on a 1 or 2 point increase in the “pain at its worst” item of 
the MDASI-MPM repeated over 2 assessment time points.
Time to improvement of symptoms characteristic of mesothelioma, as measured by the 
MDASI-MPM questionnaire total score of the subset of symptoms will be evaluated for 
patients who still have room for improvement in symptoms. Patients will be considered as 
“censored” at the date of their last MDASI-MPM questionnaire on or before the date of their 
last tumor evaluation, if the reason for stopping treatment is not related to PD. Patients 
dropping out due to progression-related reason or experiencing a PD event or death due to any 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  238 of 269
reason will be considered censored at the largest observation time (of events and censoring in 
all patients evaluated for improvement), plus 1 day.
Time to improvement of pain based on a 1 or 2 point decrease in the “pain at its worst” item 
of the MDASI-MPM repeated over 2 assessment time points.
Further sensitivity analyses for the MDASI-MPM and the LCSS-Meso will be described in 
the SAP (e.g. might involve different handling of the last response status for that patient or 
considering PD and death as censored).
Secondary efficacy analysis
The secondary efficacy OS analysis tests the following hypotheses:
[…]
At each analysis, OS will also be evaluated be summarized using Kaplan-Meier (33) 
estimates. Plots will be produced by treatment arm. Medians and Brookmeyer-Crowley (34) 
confidence intervals will be reported.
The final efficacy analysis for other secondary endpoints will be conducted at the time of the 
primary endpoint analysis.
Other secondary time-to-event variables (time to worsening of symptoms characteristic of 
mesothelioma, time to worsening of pain, time to improvement of symptoms characteristic of 
mesothelioma, time to improvement of pain, DOR) will be summarized using Kaplan-Meier 
(33) estimates. Plots will be produced by treatment arm. Medians and Brookmeyer-Crowley 
(34) confidence intervals will be reported.
Response rate variables (ORR, DCR) will be summarized by treatment arm including number 
of patients (N), response rates, and Clopper-Pearson (38) exact binomial confidence intervals. 
In addition, each response category will be summarized. Further details will be described in 
the SAP.
Sensitivity analyses will be performed, including analyses to assess the impact of missing data 
and the possibility of survivorship and selection biases. Further details will be described in the 
SAP.
[…]
New text:
[…]
Disease control rate (DCR): A patient has disease control if the patient has a confirmed 
tumor response of CR or PR or a tumor response of SD as determined by the central 
radiological reviewer per mRECIST criteria. The DCR in each arm is defined as the number 
of patients with disease control divided by the number of randomized patients.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  239 of 269
Duration of response (DOR) is defined in responders as the time from documentation of 
tumor response to disease progression or death without documented progression, as 
determined by the central radiological reviewer.
Durable response rate (DRR): A durable responder is defined as a responder with a duration 
of response (CR or PR per mRECIST criteria, as determined by the central radiological 
reviewer) of 180 days or more. The DRR in each arm is the number of durable responders 
divided by the number of randomized patients.
Patient-reported outcomes
Patient-reported outcomes (PROs) will be evaluated based on the MD Anderson Symptom 
Inventory-Malignant Pleural Mesothelioma (MDASI-MPM).
An independent PRO review committee of PRO, statistical, and psychometric experts, blinded 
to study treatment, will conduct analyses based on regulatory feedback, data from 
independent studies, and pooled study data from this study following database lock at primary 
analysis, to support validation of the MDASI-MPM instrument and determine key definitions 
and details as described below.
Time to worsening of symptoms characteristic of mesothelioma is defined in patients 
evaluable for assessing worsening of symptoms, as the time from randomization until the 
first worsening of symptoms characteristic of mesothelioma. Worsening must be confirmed 
by a second MDASI-MPM assessment. Patients who died, were lost to follow-up, or ended 
MDASI-MPM assessments without confirmed worsening of symptoms will be censored at the 
date of their last MDASI-MPM assessment with a non-missing total subset score.
Time to worsening of pain is defined in patients evaluable for assessing worsening of pain, 
as time from randomization until the first worsening of pain. Worsening must be confirmed 
by a second MDASI-MPM assessment. Patients who died, were lost to follow-up, or ended 
MDASI-MPM assessments without confirmed worsening of pain will be censored at the date 
of their last MDASI-MPM assessment with a non-missing pain score.
Improvement rate of symptoms characteristic of mesothelioma is defined in each 
randomized study arm as the number of patients with confirmed improvement of symptoms 
characteristic of mesothelioma, divided by the number of patients evaluable for 
improvement of symptoms characteristic of mesothelioma. Improvement in each patient 
must be confirmed by a second MDASI-MPM assessment.
Improvement rate of pain is defined in each randomized study arm as the number of patients 
with confirmed improvement of pain, divided by the number of patients evaluable for 
improvement of pain. Improvement in each patient must be confirmed by a second MDASI-
MPM assessment.
For analyses of the above PRO endpoints, the following terms will be defined by the 
independent blinded PRO review committee:

Worsening of symptoms characteristic of mesothelioma as measured by the 
MDASI-MPM questionnaire total score of the subset of symptoms. 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  240 of 269

Improvement of symptoms characteristic of mesothelioma as measured by the 
MDASI-MPM questionnaire total score of the subset of symptoms.

Worsening of pain as measured by the “pain at its worst” item of the MDASI-MPM.

Improvement of pain as measured by the “pain at its worst” item of the MDASI-
MPM.
For each term, the independent blinded PRO review committee will determine the specific 
change from baseline constituting improvement or worsening, and will define the minimum 
and/or maximum baseline score and other criteria constituting evaluability to determine 
improvement or worsening for the respective term.
For symptoms characteristic of mesothelioma, the independent blinded PRO review 
committee will also define the applicable subset of MDASI-MPM items, and the calculation 
algorithm to calculate the total subset score on that subset at each assessment, including 
handling of missing or partially missing data.
The independent blinded PRO review committee and its analyses will be further described in 
the Independent Blinded PRO Review Committee Charter and/or the Independent Blinded 
PRO Review Analysis Plan.
Secondary efficacy analysis
For regulatory label claim purposes, to preserve the overall Type I error rate, secondary 
endpoint hypothesis testing will be performed for the following key secondary efficacy 
variables in the event of primary endpoint superiority, according to the following hierarchy:

Overall survival

Time to worsening of symptoms characteristic of mesothelioma

Time to worsening of pain

Improvement rate of symptoms characteristic of mesothelioma

Improvement rate of pain
Secondary OS will be evaluated separately in a 2-stage group sequential procedure as further 
described below, with final analysis expected to occur after the primary endpoint analysis. 
Final analysis for duration of response and durable response rate will be performed at the time 
of the final OS analysis. An interim analysis of these variables will be performed at time of 
the final PFS analysis. Details will be described in the SAP. 
Final analysis for other secondary variables will occur at the same time as the primary 
endpoint analysis. To preserve the validity of the secondary endpoint hierarchy and control of 
overall study-wide secondary Type I error, superiority for secondary endpoint hypothesis tests 
ranking below OS in the hierarchy cannot be declared for regulatory label claim purposes 
until OS hypothesis testing succeeds. Accordingly, unless OS superiority is found at the 
interim OS analysis, the hypothesis testing outcome of endpoints ranking below it will not be 
fully effective, and any superiority for these endpoints cannot be declared for regulatory label 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  241 of 269
claim purposes, until the outcome of the OS hypothesis test is determined and OS superiority 
found at the final OS analysis. An updated analysis of these secondary variables will occur at 
time of the final OS analysis. 
The secondary efficacy OS analysis tests the following hypotheses:
[…]
At each analysis, OS will also be evaluated be summarized using Kaplan-Meier (33) 
estimates. Plots will be produced by treatment arm. Medians and Brookmeyer-Crowley (34) 
confidence intervals will be reported.
Other key secondary time-to-event variables (time to worsening of symptoms characteristic of 
mesothelioma, time to worsening of pain) will be tested using a 1-sided log-rank test stratified 
by geographic region (RoW versus Asia) and per TTP on 1st line treatment (≥6 months versus 
< 6 months), with a 1-sided significance level of 0.025. In addition, all other secondary time-
to-event variables (time to worsening of symptoms characteristic of mesothelioma, time to 
worsening of pain, DOR) will be summarized using Kaplan-Meier (33) estimates. Plots will 
be produced by treatment arm. Medians and Brookmeyer-Crowley (34) confidence intervals 
will be reported. Further details will be described in the SAP.
Select secondary response rate variables (improvement rate of symptoms characteristic of 
mesothelioma, improvement rate of pain) will be tested using a Cochran-Mantel-Haenszel test 
(40) stratified by geographic region (RoW versus Asia) and per TTP on 1st line treatment 
(≥6 months versus < 6 months), with a 1-sided significance level of 0.025. In addition, all 
secondary response rate variables (ORR, DCR, DRR, improvement rate of symptoms 
characteristic of mesothelioma, improvement rate of pain) will be summarized by treatment 
arm including number of patients (N), response rates, and Clopper-Pearson (41) exact 
binomial confidence intervals. In addition, each response category will be summarized. 
Further details will be described in the SAP.
Sensitivity analyses will be performed, including analyses to assess the impact of missing data 
and the possibility of survivorship and selection biases. Further details will be described in the 
SAP.
[…]
15.2.2.32
Section 10.3.3.3 Safety variables
Old text:
Safety variables will include AEs, laboratory changes (hematology, clinical chemistry and 
clinical urinalysis), abnormal findings in physical examination, changes in ECOG PS, 
changes in vital signs (weight, blood pressure, heart rate, respiratory rate, and body 
temperature), changes in ECG, changes in cardiac function test (EchoCG or MUGA scan) and 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  242 of 269
changes in ophthalmologic examinations (visual acuity and slit lamp examination, IOP and 
Schirmer test if repeated). 
[…]
New text:
Safety variables will include AEs, infusion-related reactions (IRRs), laboratory changes 
(hematology, clinical chemistry and clinical urinalysis), abnormal findings in physical 
examination, changes in ECOG PS, changes in vital signs (weight, blood pressure, heart rate, 
respiratory rate, and body temperature), changes in ECG, changes in cardiac function test 
(EchoCG or MUGA scan) and changes in ophthalmologic examinations (visual acuity and slit 
lamp examination, IOP and Schirmer test if repeated).
[…]
15.2.2.33
Section 10.3.4.2 Biomarker variables
Old text:
[…]
Biomarker variables and analyses will be further described in the SAP.
New text:
[…]
Biomarker variables and analyses will be further described in the SAP and/or in a separate 
document.
15.2.2.34
Section 10.4.1 Primary endpoint progression-free survival
Old text:
[…]
Assuming a maximum accrual rate of 12.5 patients/month (20.83 patients/ month screened 
with 40% overall screening failure rate) with 6-month linear accrual ramp-up, and a 
3.4%/month dropout (loss to follow-up and unevaluable for tumor assessment) rate, 
210 patients be will accrued in approximately 19.8 months and reach endpoint maturation of 
117 events in approximately 22.0 months. 
[…]
New text:
[…]
Assuming a maximum accrual rate of 12.5 patients/month (25 patients/ month prescreened 
with 50% overall pre-screening and screening failure rate) with 6-month linear accrual ramp-
up, and a 3.4%/month dropout (loss to follow-up and unevaluable for tumor assessment) rate, 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  243 of 269
210 patients be will accrued in approximately 19.8 months and reach endpoint maturation of 
117 events in approximately 22.0 months. 
[…]
15.2.2.35
Section 11.1 Data recording
Old text:
[…]
Data recorded from prescreening and full screening failures
At minimum, the following data should be recorded in the CRF:

Demographic information (patient number; year of birth / age; sex; if applicable race / 
ethnicity)

Date of all informed consent(s)that were signed
[…]
New text:
[…]
Data recorded from prescreening and full screening failures
At minimum, the following data should be recorded in the CRF:

Demographic information (patient number; year of birth / age; sex; if applicable race / 
ethnicity)

Disease characteristics 

Date of all informed consent(s)that were signed
[…]
15.2.2.36
Section 11.4 Missing data
Old text:
[…]
Strategies to reduce impact of missing data when present include:
[…]

Analyses will ensure conservative treatment of missing values. For tumor response 
endpoints, missing assessments will count as non-responders. For non-time-to-event 
QoL endpoints, time point analysis will include patients present both at baseline and at 
the time point, mitigating survivorship bias.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  244 of 269
New text:
[…]
Strategies to reduce impact of missing data when present include:
[…]

Analyses will ensure conservative treatment of missing values. For tumor response 
endpoints, missing assessments will count as non-responders. For non-time-to-event 
disease symptom and QoL endpoints, time point analysis will include patients present 
both at baseline and at the time point, mitigating survivorship bias.
15.2.2.37
Section 13.1 Investigator(s) and other study personnel
Old text:
Sponsor’s medical expert 
Name: 
Address: 
Telephone:
Mobile:
[…]
New text:
Sponsor’s medical expert 
Name: 
Address: 
Telephone:
Mobile:
[…]
15.2.2.38
Section 14 Reference list
Old text:
4.
Stahel RA, Weder W, Lievens Y, Felip E, Group EGW. Malignant pleural 
mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 
Ann Oncol. 2010;21 Suppl 5:v126-8.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  245 of 269
New text:
4.
Stahel RA, Weder W, Lievens Y, Felip E, ESMO Guidelines Working Group. 
Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment 
and follow-up. Ann Oncol. 2010;21 Suppl 5:v126-8.
New references added by amendment 4:
36.
EMA. Appendix 1 to the guideline on the evaluation of anticancer medicinal products 
in man, 2012. Available online: 
http://www.google.fi/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&uact=8&ved
=0ahUKEwi12K62sbbNAhUGbhQKHS-
BD5UQFggiMAA&url=http%3A%2F%2Fwww.ema.europa.eu%2Fema%2Fpages%2Finclud
es%2Fdocument%2Fopen_document.jsp%3FwebContentId%3DWC500137126&usg=AFQjC
NEOUdPPE1LoZOiaWFaz_8VfRiM1mA.
37.
FDA. Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer 
Drugs and Biologics Guidance for Industry, April 2015. Available online: 
www.fda.gov/downloads/Drugs/.../Guidances/UCM259421.pdf.
40.
Agresti A. Categorical Data Analysis. Third Edition. New Jersey: John Wiley & Sons. 
2013.
42.
Miller AC, Miettinen M, Schrump DS, Hassan R. Malignant mesothelioma and central 
nervous system metastases. Report of two cases, pooled analysis, and systematic review. 
Annals of the American Thoracic Society. 2014;11(7):1075-81.
43.
Yamagishi T, Fujimoto N, Miyamoto Y, Asano M, Fuchimoto Y, Wada S, et al. Brain 
metastases in malignant pleural mesothelioma. Clinical & experimental metastasis. 
2016;33(3):231-7.
49.
Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the 
context of other dry eye tests. Cornea. 2003;22(7):640-50.
15.2.2.39
Section 16.9 Grading staining: Oxford Schema (new addition)
Old text:
Not applicable.
New text:
Oxford Schema was added by amendment 4.
[Oxford Schema not repeated here, see the respective Appendix]
Reference: (49)


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  246 of 269
15.3
Amendment 5
Amendment 5 is a global amendment dated 18 APR 2017.
15.3.1
Overview of changes to the study
15.3.1.1
Modification 1: Addition of dextrose as alternative diluent for 
anetumab ravtansine
Dextrose was added as an alternative diluent for anetumab ravtansine. As anetumab 
ravtansine is in development, further testing has been performed following feedback on the 
preparation of the drug and this alternative diluent has been developed.
Sections affected by this modification: Section 7.2.1 Test drug - anetumab ravtansine
15.3.1.2
Modification 2: Clarification regarding the definition of mesothelin 
overexpression
The definition of mesothelin overexpression was clarified with the addition of moderate and 
stronger referring to “membrane staining” in at least 30% of “viable” tumor cells for 
consistency with the language used by Ventana in their protocol and in their communication 
to Authorities.
Sections affected by this modification: Section 5.1 Design overview, Section 5.3 Justification 
of the design, Section 6.1.1 Eligibility criteria for prescreening, Section 6.1.2 Eligibility 
criteria for full study, Section 6.3.1.1.1 Prescreening failure, Section 9.2.3 Treatment period, 
Section 9.7.1 Biomarkers
15.3.1.3
Modification 3: Clarification regarding continued treatment after 
centrally confirmed progression and tumor assessment requirements
Clarification was added to the Section of Radiological tumor assessments that patients who 
have centrally confirmed progression may continue on treatment provided that the patient 
derives clinical benefit as determined by the treating physician to ensure consistency with the 
witdrawal criteria for the study. Further details were added to confirm the requirements for 
tumor assessments for these patients.
Sections affected by this modification: Section 9.4.1 Radiological tumor assessments
15.3.1.4
Modification 4: Addition of parameter for pharmacokinetics samples
Addition of alpha-1 acid glycoprotein (AAG) as a test that may be performed on 
pharmacokinetic samples to estimate unbound DM4 and DM4-Me exposure. 
Sections affected by this modification: Section 9.5 Pharmacokinetics / pharmacodynamics
15.3.1.5
Modification 5: Clarification regarding criteria on continuation of 
treatment with anetumab ravtansine
In the Section of Continuation of treatment with anetumab ravtansine, a correction has been 
made to align with the withdrawal criteria and dose modifications to confirm that anetumab 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  247 of 269
ravtansine can be re-started if the TEAE requiring dose modification has resolved to 
“Grade ≤ 2” within 6 weeks after the last dose of anetumab ravtansine.
Sections affected by this modification: Section 7.4.2.1.4 Continuation of treatment with 
anetumab ravtansine
15.3.1.6
Modification 6: Clarification regarding anetumab ravtansine infusion 
duration
A clarification has been added to confirm that the anetumab ravtansine infusion can be longer 
than the stipulated 1 hour if following the dose modification guidelines outlined in the 
protocol. 
Sections affected by this modification: Section 7.4.1.1 Administration of anetumab ravtansine
15.3.1.7
Other modifications and corrections
In addition to the modifications specified above, there have been minor corrections for better 
clarity and consistency.

List of abbreviations has been updated. Sections affected by this modification: List of 
abbreviations

A duplication was removed regarding pathomechanism of the disease in the 
description of additional biomarkers that may be measured. Sections affected by this 
modification: Section 9.7.1 Biomarkers

The PRO review committee was added to the list of external data evaluation bodies 
since it was mistakenly not added to the list when added to other sections of the 
protocol by amendment 4. Sections affected by this modification: Section 13.1 
Investigator(s) and other study personnel
15.3.2
Changes to the protocol text
In the sections on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version. As applicable, changes to the protocol text are highlighted as 
follows:

Addition of a whole new portion: Brief identification of the new portion

Removal of a whole portion: Complete display of the removed portion, formatted as 
crossed out

Editing of an existing portion: Comparative presentation of “old text” versus “new 
text”, with “old text” referring to the most recent previous protocol version. Deletions 
are crossed out in the “old text”. Additions are underlined in the “new text”.

Tables / figures: The term “amended” is added to the caption.

Terminological changes: Brief specification of the terminological change
Correction of typos or omissions are not highlighted.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  248 of 269
15.3.2.1
List of abbreviations
Old text:
5-HT3
5-hydroxytryptamine (serotonin)
[…]
New text:
5-HT3
5-hydroxytryptamine (serotonin)
AAG
Alpha-1 acid glycoprotein
[…]
15.3.2.2
Section 5.1 Design overview
Old text:
[…]
At the time of the start of study treatment, the patients will have advanced or metastatic MPM 
recurrent/relapsing after a 1st line treatment with platinum in combination with pemetrexed 
with or without bevacizumab, and overexpressing mesothelin as determined by 
immunohistochemistry (IHC). Only patients who demonstrate mesothelin overexpression at 
the moderate and stronger level by IHC in at least 30% of tumor cells can be randomized into 
the study.
[…]
New text:
[…]
At the time of the start of study treatment, the patients will have advanced or metastatic MPM 
recurrent/relapsing after a 1st line treatment with platinum in combination with pemetrexed 
with or without bevacizumab, and overexpressing mesothelin as determined by 
immunohistochemistry (IHC). Only patients who demonstrate mesothelin overexpression at 
the moderate and stronger membrane staining level by IHC in at least 30% of viable tumor 
cells can be randomized into the study.
[…]
15.3.2.3
Section 5.3 Justification of the design
Old text:
[…]
Study population. Objective responses or prolonged SD cases in the 15051 study of 
anetumab ravtansine occurred in patients with moderate to stronger mesothelin expression. 
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  249 of 269
New text:
[…]
Study population. Objective responses or prolonged SD cases in the 15051 study of 
anetumab ravtansine occurred in patients who demonstrated mesothelin overexpression at the 
moderate and stronger membrane staining level by IHC in at least 30% of viable tumor cells. 
[…]
15.3.2.4
Section 6.1.1 Eligibility criteria for prescreening
Old text:
Overexpression of mesothelin at the moderate and stronger level in at least 30% of tumor cells 
is a prerequisite to be eligible for this study. […]
New text:
Overexpression of mesothelin at the moderate and stronger membrane staining level in at least 
30% of viable tumor cells is a prerequisite to be eligible for this study. […]
15.3.2.5
Section 6.1.2 Eligibility criteria for full study
Old text:
[…]
2.
Histological documentation of MPM overexpressing mesothelin at the moderate and 
stronger level in at least 30% of tumor cells as determined by centrally performed IHC.
[…]
New text:
[…]
2.
Histological documentation of MPM overexpressing mesothelin at the moderate and 
stronger membrane staining level in at least 30% of viable tumor cells as determined by 
centrally performed IHC.
[…]
15.3.2.6
Section 6.3.1.1.1 Prescreening failure
Old text:
A patient whose tumor tissue is centrally tested by IHC for mesothelin overexpression and 
whose result is not moderate and stronger mesothelin overexpression in at least 30% of the 
tumor cells, or who fails to meet any of the other eligibility criteria for prescreening, is 
regarded as a “prescreening failure”. These patients should not undergo any further screening 
procedures.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  250 of 269
New text:
A patient whose tumor tissue is centrally tested by IHC for mesothelin overexpression and 
whose result is not moderate and stronger membrane staining for mesothelin overexpression 
in at least 30% of viable tumor cells, or who fails to meet any of the other eligibility criteria 
for prescreening, is regarded as a “prescreening failure”. These patients should not undergo 
any further screening procedures.
15.3.2.7
Section 7.2.1 Test drug - anetumab ravtansine
Old text:
[…]
The drug product is available as a lyophilizate. Each vial contains 62.5 mg of anetumab 
ravtansine; the amount available for administration, based on retractable volume of 
reconstituted solution, is 60 mg of anetumab ravtansine. It should be reconstituted in water for 
injection and diluted in 0.9% sodium chloride solution (normal saline) prior to administration 
as IV infusion.
[…]
New text:
[…]
The drug product is available as a lyophilizate. Each vial contains 62.5 mg of anetumab 
ravtansine; the amount available for administration, based on retractable volume of 
reconstituted solution, is 60 mg of anetumab ravtansine. It should be reconstituted in water for 
injection and diluted in 0.9% sodium chloride solution (normal saline) or dextrose 5% 
solution prior to administration as IV infusion.
[…]
15.3.2.8
Section 7.4.1.1 Administration of anetumab ravtansine
Old text:
[…]
See Section 9.1 for details on scheduled administrations.
New text:
[…]
See Section 9.1 for details on scheduled administrations.
Anetumab ravtansine infusion longer than 1 hour is permitted if following the dose 
modification guidelines. See Section 7.4.2.1 for details on dose modifications of anetumab 
ravtansine.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  251 of 269
15.3.2.9
Section 7.4.2.1.4 Continuation of treatment with anetumab ravtansine
Old text:
Treatment with anetumab ravtansine could be re-started at the appropriate dose if the TEAE 
requiring dose modification has resolved to Grade < 2 within 6 weeks after the last dose of 
anetumab ravtansine.
New text:
Treatment with anetumab ravtansine could be re-started at the appropriate dose if the TEAE 
requiring dose modification has resolved to Grade ≤ 2 within 6 weeks after the last dose of 
anetumab ravtansine.
15.3.2.10 Section 9.2.3 Treatment period
Old text:
After all screening assessments have been completed and the patient’s eligibility has been 
confirmed and documented (confirmation of mesothelin overexpression moderate and 
stronger in at least 30% of tumor cells will be obtained from central lab and confirmation of 
radiological eligibility will be obtained from central radiological review), the patient may 
begin treatment. 
New text:
After all screening assessments have been completed and the patient’s eligibility has been 
confirmed and documented (confirmation of mesothelin overexpression moderate and 
stronger membrane staining in at least 30% of viable tumor cells will be obtained from central 
lab and confirmation of radiological eligibility will be obtained from central radiological 
review), the patient may begin treatment. 
15.3.2.11 Section 9.4.1 Radiological tumor assessments
Old text:
[…]
In the event of locally suspected progression, the site will inform the central review service 
and central review will start. Radiological real-time confirmation by central independent 
blinded evaluation is required before a final decision to stop the treatment is made. The site 
should also wait for the central review results before administering the next dose of treatment. 
In case of uncertain radiological disease progression, the patient may stay on treatment at the 
investigator’s discretion until progression is definitely confirmed by central review on the 
subsequent tumor assessment.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  252 of 269
When the central review assessment confirms progression, study treatment should be stopped 
permanently and patient will enter safety follow-up (safety follow-up visit to be scheduled 
30+7 days after the last administration of study treatment) and long-term follow-up period.
[…]
New text:
[…]
In the event of locally suspected progression, the site will inform the central review service 
and central review will start. Radiological real-time confirmation by central independent 
blinded evaluation is required before a final decision to stop the treatment is made. The site 
should also wait for the central review results before administering the next dose of treatment. 
In case of uncertain radiological disease progression, the patient may stay on treatment at the 
investigator’s discretion until progression is definitely confirmed by central review on the 
subsequent tumor assessment.
When the central review assessment confirms progression, treatment may be continued if the 
patient derives clinical benefit as determined by the treating physician per the withdrawal 
criteria (see Section 6.3.1.2). Otherwise, study treatment should be stopped permanently and 
patient will enter safety follow-up (safety follow-up visit to be scheduled 30+7 days after the 
last administration of study treatment) and long-term follow-up period.
Once centrally confirmed radiological progression is reported, protocol tumor assessment 
requirements end. Subsequent tumor imaging may be performed according to treating 
physician’s discretion if study treatment is continued. The investigator is not required to send 
imaging taken following centrally confirmed PD to central review, and the central reviewer is 
not required to review any such imaging sent.
[…]
15.3.2.12 Section 9.5 Pharmacokinetics / pharmacodynamics
Old text:
[…]
Unscheduled PK samples are requested at the next clinic visit after the initial onset of corneal 
epitheliopathy and after the radiological assessment of the first PR (the first local observation 
of at least a 30% reduction in the total tumor measurement according to mRECIST). The date 
and actual clock time of this unscheduled PK sample and of the last dose of anetumab 
ravtansine has to be recorded on the CRF as an Unscheduled Procedure.
[…]


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  253 of 269
New text:
[…]
Unscheduled PK samples are requested at the next clinic visit after the initial onset of corneal 
epitheliopathy and after the radiological assessment of the first PR (the first local observation 
of at least a 30% reduction in the total tumor measurement according to mRECIST). The date 
and actual clock time of this unscheduled PK sample and of the last dose of anetumab 
ravtansine has to be recorded on the CRF as an Unscheduled Procedure.
Measurement of alpha-1 acid glycoprotein (AAG) may be performed in select 
pharmacokinetic samples to estimate unbound DM4 and DM4-Me exposure.
[…]
15.3.2.13 Section 9.7.1 Biomarkers
Old text:
Preclinical and Phase I evidence suggests that mesothelin expression (or expression level 
above a certain threshold) in human tumors may be required for binding, internalization, and 
anti-tumor activity of anetumab ravtansine. All patients will have formalin-fixed, paraffin-
embedded (FFPE) tumor samples available for IHC determination of mesothelin expression at 
prescreening as a potential predictive biomarker (see also flow chart in Section 9.1). In the 
absence of archival tissue, fresh biopsies may be used if deemed safe by the investigator and 
there is no additional risk for the patient in the investigator’s judgement. Only patients whose 
tumors express mesothelin at staining intensity of moderate and stronger in at least 30% of 
tumor cells will participate further in this study. Mesothelin levels will be determined using a 
validated IHC assay (clone SP74).
[…]
In addition to the biomarkers listed above, other biomarkers deemed relevant to gain further 
knowledge about the pathomechanism of the disease or about the drug (i.e. mode of action-
related effect or safety of the drug) and/or the pathomechanism of the disease may be 
measured, based on newly emerging data from other ongoing studies and/or literature data.
[…]
New text:
Preclinical and Phase I evidence suggests that mesothelin expression (or expression level 
above a certain threshold) in human tumors may be required for binding, internalization, and 
anti-tumor activity of anetumab ravtansine. All patients will have formalin-fixed, paraffin-
embedded (FFPE) tumor samples available for IHC determination of mesothelin expression at 
prescreening as a potential predictive biomarker (see also flow chart in Section 9.1). In the 
absence of archival tissue, fresh biopsies may be used if deemed safe by the investigator and 
there is no additional risk for the patient in the investigator’s judgement. Only patients whose 
tumors express mesothelin at membrane staining intensity of moderate and stronger in at least 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  254 of 269
30% of viable tumor cells will participate further in this study. Mesothelin levels will be 
determined using a validated IHC assay (clone SP74).
[…]
In addition to the biomarkers listed above, other biomarkers deemed relevant to gain further 
knowledge about the pathomechanism of the disease or about the drug (i.e. mode of action-
related effect or safety of the drug) may be measured, based on newly emerging data from 
other ongoing studies and/or literature data.
[…]
15.3.2.14 Section 13.1 Investigator(s) and other study personnel
Old text:
[…]
Central laboratory
Biomarker, PK, immunogenicity, mesothelin expression, and CYP2D6 pharmacogenetic tests 
will be performed centrally. Further details will be provided in the Laboratory Manual.
New text:
[…]
Central laboratory
Biomarker, PK, immunogenicity, mesothelin expression, and CYP2D6 pharmacogenetic tests 
will be performed centrally. Further details will be provided in the Laboratory Manual.
Independent blinded PRO review committee
An independent PRO review committee of PRO, statistical, and psychometric experts, blinded 
to study treatment, will conduct analyses based on regulatory feedback, data from 
independent studies, and pooled study data from this study following database lock at primary 
analysis, to support validation of the MDASI-MPM instrument and determine key definitions 
and details regarding secondary PRO endpoints.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  255 of 269
15.4
Amendment 6
Amendment 6 is a global amendment dated 27 MAR 2018.
15.4.1
Overview of changes to the study
15.4.1.1
Modification 1: Evaluations and data collection reduced for patients 
ongoing on treatment post OS maturation
Following OS data maturation, patients remaining on study will continue to be followed with 
reduced mandated assessments and data collection. Active follow-up, efficacy, and some 
safety assessments will no longer be required. New study flow charts (Table 9–2 and Table 9–
3) were added for patients ongoing on treatment post OS maturation in anetumab ravtansine 
and vinorelbine arms, respectively.
The intent of this modification is to continue to treat patients who are benefitting from 
treatment with a more limited assessment schedule removing all non-essential procedures to 
reduce the burden on patients. 
Sections affected by this modification: Section 2 Synopsis, Section 5.1 Design overview, 
Section 6.3.1.2 Withdrawal criteria, Section 8.1 Prior and concomitant therapy, 
Section 9.1 Tabular schedule of evaluations, Section 9.2.3.2 Treatment – Cycle 2 and higher – 
prior to OS maturation, Section 9.2.3.3 Treatment post OS maturation – anetumab ravtansine 
arm – Day 1, Section 9.2.3.4 Treatment post OS maturation – vinorelbine arm – Days 1, 8 and 
15, Section 9.2.4 Efficacy assessments, Section 9.2.5.1 Safety follow-up prior to OS 
maturation, Section 9.2.5.2 Safety follow-up post OS maturation, Section 9.2.5.3 Active 
follow-up, Section 9.2.5.4 Long-term follow-up, Section 9.4.1 Radiological tumor 
assessments, Section 9.4.3 Patient-reported outcomes, Section 9.5 Pharmacokinetics / 
pharmacodynamics, Section 9.6.3.1 Laboratory evaluations, Section 9.6.3.3 ECOG 
Performance Status, Section 9.6.3.4 Vital signs, Section 9.6.3.5 12-lead ECG, Section 9.6.3.7 
Ophthalmologic examinations, Section 10.1 General considerations
15.4.1.2
Modification 2: Continuation of collection of survival data post OS 
maturation
The sponsor will continue to assess survival data on patients after OS data maturation until 
24 months after last patient’s last treatment. The rationale for this survival data collection is to 
better understand the total duration of potential clinical benefit and treatment experience of 
patients with anetumab ravtansine.
Sections affected by this modification: Section 2 Synopsis, Section 5.1 Design overview, 
Section 6.3.1.2 Withdrawal criteria, Section 9.2.5.4 Long-term follow-up, Section 9.4.2 
Survival
15.4.1.3
Modification 3: Clarification of end of study definition
Clarification that end of study is defined by last visit of the last patient within the 15743 study 
and addition of possibility that treatment or follow up of subjects could continue within a 
separate program were included. This caveat was added in the event that such a program 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  256 of 269
would be launched and approved to allow patients to continue treatment and/or be followed 
up. 
Sections affected by this modification: Section 5.4 End of study
15.4.1.4
Modification 4: Modification of withdrawal criteria
Removal of requirement for radiological progression to be centrally confirmed prior to 
withdrawal as central review will no longer be performed. 
Allow delay in administration of anetumab ravtansine for up to 12 weeks as the previous 
maximum allowed gap of 6 weeks was due to the efficacy endpoint and patients should be 
allowed to continue as per investigator’s discretion if they are benefitting from treatment. 
Sections affected by this modification: Section 6.3.1.2 Withdrawal criteria, Section 7.4.2.1.2 
Non-hematological toxicities
15.4.1.5
Modification 5: Addition of reference to the investigator’s brochure to 
Clinical experience section
Reference to investigator’s brochure for updated safety information and results from this 
study was added to indicate where this information is available.
Sections affected by this modification: Section 3.1.2 Clinical experience
15.4.2
Changes to the protocol text
The detailed description of changes compared to the previous integrated protocol v. 4.0 
(amendment 5) is replaced by a “tracked changes” version of the protocol, separate from this 
document. Changes to the protocol body are tracked in this separate document using 
strike-through for deleted text and underline for new text.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  257 of 269
16.
Appendices
16.1
ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all pre-diseases performance without 
restriction.
(Karnofsky 90-100)
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g. light housework, office work).
(Karnofsky 70-80)
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
(Karnofsky 50-60)
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
(Karnofsky 30-40)
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair.
(Karnofsky 10-20)
16.2
New York Heart Association (NYHA) functional classification
NYHA Class
Symptoms
I
No symptoms and no limitation in ordinary physical activity, e.g. shortness of 
breath when walking, climbing stairs etc.
II
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g. walking short distances (20–100 m).
Comfortable only at rest.
IV
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients.
Source (44) 


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  258 of 269
16.3
Response assessment
Tumor response will be evaluated in this study using the mRECIST criteria for MPM (21).
At baseline, the pleural disease to be measured should have a short-axis diameter of at least 
1 cm for at minimum one of the 6 measurements, as lesions < 1 cm are considered non-
measurable (modified by amendment 2, see section 15.1.1.25).
Unidimensional measurements of tumor thickness perpendicular to the chest wall or 
mediastinum should be performed, measured in 2 sites (or positions) at 3 separate levels on 
transverse cuts of contrast-enhanced CT scan (or MRI). The sum of the measurements which 
meet the definition of measurable disease defines a pleural unidimensional measure: sum of 
up to 6 pleural thickness measurements = 1 univariate diameter. Transverse cuts used for 
measurements must be at least 1 cm apart and related to anatomical landmarks in the thorax as 
determined by the reviewer during baseline assessment by means of appropriate markers these 
cuts are chosen to allow reproducible assessment at later time points. If measureable tumor is 
present, transverse cuts in the upper thorax, above the level of division of the main bronchi 
are preferred. At reassessment, pleural thickness must be measured at the same position at the 
same level and by the same observer, whenever possible. This is not necessarily the greatest 
tumor thickness at that level (paragraph modified by amendment 2, see section 15.1.1.25).
Nodal, subcutaneous and other bidimensionally non-pleural measurable lesions (e.g. lung) are 
measured unidimensionally as per the RECIST 1.1 criteria (modified by amendment 2, see 
section 15.1.1.25). Unidimensional measurements are added to obtain the total tumor 
measurement.
Due to the natural evolution of disease, an isolated new pleural or pericardial effusion should 
be only considered as a new lesion and thus calling for PD in case it is substantial, cytological 
malignancy is confirmed and the patient had not had any pleural or pericardial effusion 
history before treatment. However, any isolated new or significant increases in existing 
pleural or pericardial effusions in a stable or responding patient, without any other evidence of 
progression, is insufficient evidence to call progression.
Additional detailed instruction on the measurement process and on the assessment of tumor 
response will be provided in the Imaging Manual.
Response Criteria
Complete response (CR): Disappearance of all target lesions. Disappearance of all non-
target lesions and normalization of tumor marker level, if applicable. Any pathological lymph 
nodes (whether target or non-target) must have decreased in size to have a short axis of 
< 10 mm.
Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions 
taking as reference the baseline sum diameters. No appearance of new lesions. Non-target 
lesions must be stable or can be not evaluable.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  259 of 269
Progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study = nadir (this includes the baseline sum if that is 
the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. For non-target lesions, unequivocal 
progression of existing lesions represents PD.
Note: the appearance of one or more new lesions is also considered progression.
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Table below provides an overview how the overall response is assessed.
Overall Response Assessment
Target 
lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/Non-PD
CR
NE
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
NE
Non-PD
No
NE
PD
Any
Yes or No
Any
PD
Yes or No
Any
Any
Yes
PD
CR = Complete response; NE = Not evaluated; PD = Progressive disease; PR = Partial response; 
SD = Stable disease 
Adapted from (45)
16.4
National Cancer Institute’s Common Terminology Criteria for Adverse 
Events, version 4.03
This study will utilize the NCI-CTCAE v4.03 for toxicity and SAE reporting by sites. A copy 
of the CTCAE v4.03 can be downloaded from the website (46).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  260 of 269
16.5
Patient-reported outcomes
16.5.1
MDASI-MPM


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  261 of 269


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  262 of 269
16.5.2
LCSS-Meso


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  263 of 269


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  264 of 269
16.6
CYP3A4 inhibitors and inducers
Table below provides an overview of strong CYP3A4 inhibitors and inducers.
Strong CYP3A4 inhibitors
Strong CYP3A4 inducers
Boceprevir
Clarithromycin
Conivaptan
Grapefruit juice
Indinavir
Itraconazole
Ketoconazole
Lopinavir / Ritonavir
Mibefradil (withdrawn in the US)
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
Avasimibe
Carbamazepine
Phenytoin
Rifampin
St. John’s wort
CYP3A4 = Cytochrome P450, family 3, subfamily A, polypeptide 4
Source (47)
16.7
Calculation of glomerular filtration rate by the Modification of Diet in 
Renal Disease formula
In accordance with established nephrology practice and guidelines, renal function at baseline 
and throughout the study will be assessed by means of the estimated GFR, calculated using 
the abbreviated MDRD study formula.
This equation of 4 variables (serum creatinine level, age, sex, and ethnicity) is recommended 
by the National Kidney Foundation for use in individuals 18 years or older. The formula can 
be found at the following website (48).
Patients with a baseline GFR < 30 mL/min/1.73 m2 calculated by this method will not be 
allowed to participate in the study.
16.8
Mosteller Equation for calculation of body surface area (BSA)
BSA (m2) = SQR RT ([Height(cm) x Weight(kg) ]/ 3600 )
Where SQR RT is square root (√).


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  265 of 269
16.9
Grading staining: Oxford Schema
Oxford Schema was added by amendment 4.


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  266 of 269


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  267 of 269


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  268 of 269


 
Integrated Clinical Study Protocol
No. BAY 94-9343 / 15743
27 MAR 2018
Version 5.0
Page:  269 of 269
Reference: (49)

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan  
Official Title: 
A randomized, open-label, active-controlled, Phase II study of 
intravenous anetumab ravtansine (BAY 94-9343) or vinorelbine in 
patients with advanced or metastatic malignant pleural 
mesothelioma overexpressing mesothelin and progressed on first 
line platinum/pemetrexed-based chemotherapy 
NCT Number: 
NCT02610140 
Document Date: 
18-Apr-2018 
 


Supplemental Statistical Analysis Plan 
Protocol No.: BAY 94-9343 / 15743 
Page: 1 of 7:
 
Reference Number: RD-OI-0119 
Supplement Version: 8 
A randomized, open-label, active-controlled, Phase II study of intravenous 
anetumab ravtansine (BAY 94-9343) or vinorelbine in patients with advanced or 
metastatic malignant pleural mesothelioma overexpressing mesothelin and 
progressed on first line platinum/pemetrexed-based chemotherapy 
[Phase II anetumab ravtansine as 2nd line treatment for malignant pleural mesothelioma 
(MPM)] 
Bayer study drug 
BAY 94-9343/anetumab ravtansine  
[Study purpose:] 
Efficacy and safety   
Clinical study phase: II 
Date: 
 18 Apr 2018 
Study No.: 
 
15743 
Version: 
 1.0 
Author: 
   
 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document, whether in 
part or in full, to parties not associated with the clinical investigation or its use for any other 
purpose without the prior written consent of the sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
 
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures. 
The approval of the Statistical Analysis Plan is documented in a separate Signature Document. 
 
 
 
PPD


Supplemental Statistical Analysis Plan 
Protocol No.: BAY 94-9343 / 15743 
Page: 2 of 7:
 
Reference Number: RD-OI-0119 
Supplement Version: 8 
Table of Contents 
 
1. 
Introduction ........................................................................................................................ 2 
2. 
Study Objectives ................................................................................................................. 2 
3. 
Study Design ....................................................................................................................... 3 
4. 
General Statistical Considerations ................................................................................... 3 
5. 
Analysis Sets ....................................................................................................................... 3 
6. 
Statistical Methodology ..................................................................................................... 4 
6.1 
Population characteristics ................................................................................................. 4 
6.2 
Efficacy ............................................................................................................................. 4 
6.2.1 
Waterfall plot of greatest reduction in sum of lesion measurements ............................ 4 
6.2.2 
Summary of investigator vs. central review response ................................................... 4 
6.3 
Pharmacokinetics/pharmacodynamics .............................................................................. 5 
6.4 
Safety ................................................................................................................................ 5 
6.4.1 
Summary of serious adverse events with incidence ≥ 5% ............................................ 5 
6.4.2 
Time to first incidence of corneal epitheliopathy .......................................................... 5 
6.4.3 
Summary of Peripheral Neuropathy .............................................................................. 5 
6.4.4 
Time to first incidence of peripheral neuropathy .......................................................... 6 
6.4.5 
Time from first dose modification to resolution of corneal epitheliopathy .................. 6 
6.4.6 
Time from first dose modification to resolution of peripheral neuropathy ................... 7 
7. 
Document history and changes in the planned statistical analysis ................................ 7 
8. 
References ........................................................................................................................... 7 
 
 
Abbreviations 
 
PN 
Peripheral Neuropathy 
SDE CRF 
Study Drug Exposure Case Report Form 
SMQ 
Standardized MedDRA Query 
For additional abbreviations, refer to the main SAP v3.0 dated 9 May 2017. 
1. 
Introduction 
This Supplemental Statistical Analysis Plan (SAP) describes analyses that were not included in the 
main SAP but may be used for Clinical Study Report (CSR) and submission purposes.  
This Supplemental SAP version 1.0 supplements SAP version 3.0 dated 9 May 2017.   
2. 
Study Objectives 
The primary objective of this study is to: 


Supplemental Statistical Analysis Plan 
Protocol No.: BAY 94-9343 / 15743 
Page: 3 of 7:
 
Reference Number: RD-OI-0119 
Supplement Version: 8 
• Test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-
free survival (PFS) 
The secondary objectives of this study are to: 
• Test overall survival (OS) 
• Evaluate patient-reported outcomes (PROs) – symptom burden and health-related quality of 
life (QoL) 
• Evaluate other indicators of treatment efficacy (indicators of tumor response) 
• Evaluate safety 
The other objectives of this study are to evaluate the: 
• Pharmacokinetics (PKs) 
• Immunogenicity 
• Biomarkers 
• Further biomarkers to investigate the drug (i.e. mode-of-action-related effect and / or 
safety) and / or the pathomechanism of the disease (exploratory). 
 
3. 
Study Design 
Refer to the main SAP v3.0 dated 9 May 2017. 
 
4. 
General Statistical Considerations 
Refer to the main SAP v3.0 dated 9 May 2017. 
If there are fewer than 10 patients included in a supplemental summary table or figure, listings only 
may be produced.  
Except as otherwise provided in this supplemental SAP, all tables, listings, and figures described in 
this supplemental SAP will be produced at the time of the OS analysis.  
Unless otherwise specified in this supplemental SAP, all endpoints introduced and defined in this 
SAP will be designated as exploratory.  
 
5. 
Analysis Sets 
Refer to the main SAP v3.0 dated 9 May 2017. 
 


Supplemental Statistical Analysis Plan 
Protocol No.: BAY 94-9343 / 15743 
Page: 4 of 7:
 
Reference Number: RD-OI-0119 
Supplement Version: 8 
6. 
Statistical Methodology 
 
6.1 
Population characteristics 
 
6.2 
Efficacy 
Unless otherwise specified in this supplemental SAP, efficacy tables, listings, and figures (TLFs) 
will be provided for the ITT analysis set.  
 
6.2.1 
Waterfall plot of greatest reduction in sum of lesion measurements  
The reduction in sum of the lesion measurements is defined for each included patient at each 
post-baseline timepoint, as the difference between the reference baseline sum of the lesion 
measurements (pleural and non-pleural target lesion diameters) and the sum of the lesion 
measurements (pleural and non-pleural target lesions diameters) at the timepoint, based on the lesion 
measurements determined by the central reviewer.  
The greatest reduction in sum of the lesion measurements is defined for each included patient as 
the maximum reduction in the sum of the lesion measurements at any post-baseline timepoint.  
ITT patients with both a baseline and at least one post-baseline lesion measurement assessment will 
be included in this analysis.  
Confirmation of reduction is not required for this analysis. 
A waterfall plot of the greatest  reduction in sum of the lesion measurements will be produced in the 
form of a bar chart. Each bar will represent one subject. Bars will be ordered from maximum 
increase (left) to greatest reduction (right). Increases will be shown as bars upwards from the 
baseline, decreases as bars downwards, and 0 change as spaces on the baseline (gap between upward 
and downward bars). Each patient’s treatment group will be depicted as a pattern or grey scale color 
on the bar.  
This analysis will be produced for both the PFS lock data and the OS lock data. 
 
6.2.2 
Summary of investigator vs. central review response 
A frequency tabulation will be provided of best response on-study per investigator (CR, PR, SD, 
PD, UE) versus best response on-study per central review (CR, PR, SD, PD, UE).  
Best responses of UE (Unevaluable) may be reported as NE (Not Evaluable). 
This frequency tabulation will be provided both for the pooled population, and separately for each 
treatment arm. 
This analysis will be produced for both the PFS lock data and the OS lock data. 


Supplemental Statistical Analysis Plan 
Protocol No.: BAY 94-9343 / 15743 
Page: 5 of 7:
 
Reference Number: RD-OI-0119 
Supplement Version: 8 
6.3 
Pharmacokinetics/pharmacodynamics 
Not applicable.  
6.4 
Safety 
Unless otherwise specified in this supplemental SAP, safety tables, listings, and figures (TLFs) will 
be provided for the SAF analysis set. 
 
6.4.1 
Summary of serious adverse events with incidence ≥ 5% 
A summary of treatment-emergent SAEs with incidence (any grade) at least 5% in either treatment 
arm will be provided by treatment arm and overall, ordered by highest incidence, in a manner 
otherwise similar to the SAP summary of SAEs. 
 
6.4.2 
Time to first incidence of corneal epitheliopathy 
The time to first incidence of corneal epitheliopathy (CE) is defined in each anetumab ravtansine-
treated patient as the time (in weeks) from first anetumab ravtansine treatment to first incidence of 
treatment-emergent corneal epitheliopathy, i.e. start date of the first CE AE.  Patients not 
experiencing treatment-emergent CE will be censored at the date of their last slit lamp exam.  
Time to first incidence of corneal epitheliopathy will be summarized for the anetumab ravtansine 
treatment arm using Kaplan-Meier estimates. Plots will be produced. Medians and Brookmeyer-
Crowley confidence intervals with complementary log-log transformation will be reported. The 
number of patients at risk, number of events, and number of censored patients per month will also be 
reported. For analysis confidence intervals, 95% 2-sided intervals will be calculated.  A listing will 
be provided.  
 
6.4.3 
Summary of Peripheral Neuropathy 
Peripheral neuropathy (PN) adverse events will be defined and identified in accordance with the 
Standardized MedDRA Query (SMQ) for peripheral neuropathy as published by MedDRA for the 
applicable MedDRA version.  
The following summary tables of treatment-emergent peripheral neuropathy will be reported in a 
manner similar to the respective SAP summaries of adverse events: 
• any treatment-emergent PN AEs 
• any study treatment related PN TEAEs 
• any study procedure related PN TEAEs 
• any serious PN TEAEs 
• any serious study treatment related PN TEAEs 
• any serious study procedure related  PN TEAEs 


Supplemental Statistical Analysis Plan 
Protocol No.: BAY 94-9343 / 15743 
Page: 6 of 7:
 
Reference Number: RD-OI-0119 
Supplement Version: 8 
• any CTCAE Grade ≥ 3 PN TEAEs 
• any PN TEAEs leading to discontinuation 
• any PN TEAEs leading to dose interruption 
• any PN TEAEs leading to dose reduction 
 
6.4.4 
Time to first incidence of peripheral neuropathy 
The time to first incidence of peripheral neuropathy is defined retrospectively in patients 
experiencing peripheral neuropathy  as the time from first study treatment to first incidence of 
treatment-emergent peripheral neuropathy, i.e. the start date of the first AE identified as PN by the 
SMQ.   
Time to first incidence of PN will be summarized using summary statistics.  A listing will be 
provided. 
 
6.4.5 
Time from first dose modification to resolution of corneal epitheliopathy 
The time from first dose modification to resolution of corneal epithelipathy is defined in 
anetumab ravtansine-treated subjects who received a dose modification (reduction, interruption, or 
discontinuation)  due to a CE AE, as the time (in weeks) from the date of dose modification to the 
date to the date of resolution of the CE AE associated with the dose modification.  If the associated 
CE AE did not resolve, the subject will be censored at the date of the last slit lamp exam.  
A patient experienced a dose modification due to a CE AE if the patient: 
• Experienced a dose reduction, interruption, or discontinuation, as recorded on the Study 
Drug Exposure (SDE) CRF. 
• The reason for this dose modification per the SDE CRF was adverse event 
• At least one of the AEs associated with the dose modification on the SDE CRF was a CE 
AE. 
The date of dose modification is defined as the date of the last dosing visit prior to the visit on which 
the modification was recorded. If a subject received more than one dose modification due to a CE 
AE, the first-dated one is selected. 
The CE AE associated with a dose modification is defined as the AE on the AE CRF which: 
• Is treatment emergent 
• Has the same preferred term as the dose modification AE on the SDE CRF. 
• Has a start date (or date of grade change if the AE represents a grade change) on or before 
the date of dose modification. 
• Has an action taken with study drug corresponding to the modification (reduction, 
interruption, or discontinuation) on the SDE CRF. 


Supplemental Statistical Analysis Plan 
Protocol No.: BAY 94-9343 / 15743 
Page: 7 of 7:
 
Reference Number: RD-OI-0119 
Supplement Version: 8 
• If more than one CE TEAE meets the above criteria the latest one with start or grade change 
date on or before the date of dose modification is selected. 
Time from first dose modification to resolution of CE will be summarized using Kaplan-Meier 
estimates. Plots will be produced. Medians and Brookmeyer-Crowley confidence intervals with 
complementary log-log transformation will be reported. The number of patients at risk, number of 
events, and number of censored patients per month will also be reported. For analysis confidence 
intervals, 95% 2-sided intervals will be calculated.  A listing will be provided. 
6.4.6 
Time from first dose modification to resolution of peripheral neuropathy 
The time from first dose modification to resolution of peripheral neuropathy is defined 
retrospectively in subjects who received a dose modification (reduction, interruption, or 
discontinuation)  due to a PN AE and whose peripheral neuropathy resolved, as the time (in weeks) 
from the date of dose modification to the date to the date of resolution of the PN AE associated with 
the dose modification.   
See Section 6.4.5 for definitions of patient experiencing dose modification due to PN AE, date of 
dose modification, the PN AE associated with the dose modification, substituting PN for CE events. 
No censoring is performed.   
Time from first dose modification to resolution of PN will be summarized using summary statistics. 
A listing of all patients with dose modifications due to a PN AE will be provided. If the patient’s 
selected PN AE did not resolve, a time to resolution will not be calculated.  
 
7. 
Document history and changes in the planned statistical analysis 
 
• Supplemental SAP FINAL version 1.0 dated 01 April  2018  
 
8. 
References 
Refer to the main SAP v3.0 dated 9 May 2017. 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
1 of 54
 
 
A randomized, open-label, active-controlled, Phase II study of 
intravenous anetumab ravtansine (BAY 94-9343) or vinorelbine in 
patients with advanced or metastatic malignant pleural 
mesothelioma overexpressing mesothelin and progressed on first 
line platinum/pemetrexed-based chemotherapy 
[Phase II anetumab ravtansine as 2nd line treatment for malignant pleural 
mesothelioma (MPM)] 
Bayer study drug BAY 94-9343/anetumab ravtansine    
Clinical study 
phase: 
II 
Date: 
9 MAY 2017 
Study No.: 
 
15743 
Version: 
3.0 
Author: 
   
 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended 
solely for the guidance of the clinical investigation.  Reproduction or disclosure 
of this document, whether in part or in full, to parties not associated with the 
clinical investigation or its use for any other purpose without the prior written 
consent of the sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected. 
 
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures. 
The approval of the Statistical Analysis Plan is documented in a separate Signature Document. 
 
 
PPD


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
2 of 54
 
 
Table of Contents 
 
1. 
Introduction ........................................................................................................................ 6 
2. 
Study Objectives................................................................................................................. 7 
3. 
Study Design ....................................................................................................................... 8 
3.1 
Determination of Sample Size ........................................................................................ 10 
3.1.1 
Primary endpoint progression-free survival ................................................................ 10 
3.1.2 
Secondary endpoint overall survival ........................................................................... 11 
3.2 
Blinding .......................................................................................................................... 12 
4. 
General Statistical Considerations ................................................................................. 12 
4.1 
General Principles ........................................................................................................... 12 
4.2 
Handling of Dropouts ..................................................................................................... 13 
4.3 
Handling of Missing Data ............................................................................................... 13 
4.3.1 
Imputation rules ........................................................................................................... 14 
4.4 
Interim Analyses and Data Monitoring .......................................................................... 14 
4.5 
Data Rules....................................................................................................................... 15 
4.6 
Blinded Review, Validity Findings, and Protocol Deviations ........................................ 15 
4.6.1 
Blinded Review ........................................................................................................... 15 
4.6.2 
Validity Findings ......................................................................................................... 15 
4.6.3 
Protocol Deviations ..................................................................................................... 15 
5. 
Analysis Sets ..................................................................................................................... 16 
6. 
Statistical Methodology ................................................................................................... 17 
6.1 
Population characteristics ............................................................................................... 17 
6.1.1 
Disposition of patients ................................................................................................. 17 
6.1.2 
Demographic and Baseline Characteristics ................................................................. 17 
6.1.3 
Medical history ............................................................................................................ 18 
6.1.4 
Prior and Concomitant Medications ............................................................................ 18 
6.1.5 
Prior Therapy for Cancer ............................................................................................. 20 
6.1.6 
Systemic anti-cancer therapy ...................................................................................... 20 
6.1.7 
Additional radiotherapies and diagnostic and therapeutic procedures ........................ 20 
6.2 
Efficacy ........................................................................................................................... 20 
6.2.1 
Primary Efficacy Analysis .......................................................................................... 20 
6.2.2 
Secondary Efficacy Analysis ...................................................................................... 25 
6.2.2.1 
Hierarchy and timing of analyses ............................................................................ 25 
6.2.2.2 
Overall Survival (OS) .............................................................................................. 26 
6.2.2.3 
Objective Response Rate (ORR).............................................................................. 28 
6.2.2.4 
Disease Control Rate (DCR) .................................................................................... 29 
6.2.2.5 
Duration of Response (DOR) ................................................................................... 29 
6.2.2.6 
Durable Response Rate (DRR) ................................................................................ 30 
6.2.2.7 
Time to worsening of symptoms characteristic of mesothelioma ........................... 30 
6.2.2.8 
Time to worsening of pain ....................................................................................... 33 
6.2.2.9 
Improvement rate of symptoms characteristic of mesothelioma ............................. 36 
6.2.2.10 Improvement rate of pain ......................................................................................... 38 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
3 of 54
 
 
6.2.3 
Other efficacy endpoint analysis ................................................................................. 39 
6.2.3.1 
Time-Averaged AUC MDASI-MPM CSS and Pain Score ..................................... 39 
6.2.3.2 
MDASI-MPM symptom interference score and LCSS-MESO scores .................... 41 
6.3 
Pharmacokinetics/pharmacodynamics ............................................................................ 41 
6.4 
Safety .............................................................................................................................. 41 
6.4.1 
Extent of exposure ....................................................................................................... 42 
6.4.2 
Adverse events ............................................................................................................ 42 
6.4.3 
Deaths .......................................................................................................................... 44 
6.4.4 
Clinical laboratory data ............................................................................................... 44 
6.4.5 
Slit-Lamp examination findings .................................................................................. 45 
6.4.6 
Other ophthalmologic examination findings ............................................................... 45 
6.4.7 
ECOG performance score ........................................................................................... 46 
6.4.8 
12-Lead ECG ............................................................................................................... 46 
6.4.9 
Cardiac function .......................................................................................................... 47 
6.4.10 Vital signs .................................................................................................................... 47 
6.4.11 Physical examinations ................................................................................................. 47 
6.5 
Other endpoints............................................................................................................... 47 
6.5.1 
Tumor assessments ...................................................................................................... 47 
6.5.2 
Patient reported outcomes ........................................................................................... 48 
6.5.2.1 
Disease Symptoms ................................................................................................... 48 
6.5.2.2 
Health Related Quality of Life (HRQoL) ................................................................ 48 
6.5.3 
Biomarkers .................................................................................................................. 48 
6.5.4 
Immunogenicity .......................................................................................................... 48 
6.6 
Examination of subgroups .............................................................................................. 49 
7. 
Document history and changes in the planned statistical analysis .............................. 49 
8. 
References ......................................................................................................................... 50 
9. 
Appendices ........................................................................................................................ 51 
9.1 
Imputation rules .............................................................................................................. 51 
9.1.1 
Imputation rules for adverse event and non-study medication dates .......................... 51 
9.1.2 
Imputation rules for systemic anti-cancer medication during treatment and 
follow-up ..................................................................................................................... 51 
9.1.3 
Imputation rules for last known alive date .................................................................. 51 
9.1.4 
Imputation rules for death date .................................................................................... 53 
9.1.5 
Imputation rules for time-to-event endpoints .............................................................. 54 
List of Tables 
Table 6-1 Medication classification .......................................................................................... 19 
Table 6-2 Censoring rules for PFS ............................................................................................ 21 
Table 6-3 Censoring for 2 consecutive missed assessments ..................................................... 22 
Table 6-4 Censoring for time to progression ............................................................................ 24 
Table 6-5 Censoring for Overall Survival ................................................................................ 27 
Table 6-6 Censoring for duration of response .......................................................................... 30 
Table 6-7 Censoring for time to worsening of symptoms characteristic of 
mesothelioma ......................................................................................................... 32 
Table 6-8 Censoring for time to worsening of pain .................................................................. 36 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
4 of 54
 
 
Table 6-9 Time-averaged score parameters .............................................................................. 40 
Table 9-3 Imputation rules for systemic anti-cancer medications during follow-up ................ 51 
Table 9-4 Key Data ................................................................................................................... 53 
Table 9-5 Imputation rules for LKAD derivation ..................................................................... 53 
Table 9-6 Imputation rules for death date derivation ................................................................ 54 
Table 9-7 Imputation rules for time-to-event assessment date ................................................. 54 
 
List of Figures 
Figure 3–1 Overall study design ................................................................................................. 8 
 
 
 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
5 of 54
 
 
List of Abbreviations 
 
AD 
As-Diagnosed 
ADAs 
Anti-Drug Antibodies 
AE 
Adverse Event 
AMR 
Application Maintenance Request 
AUC 
Area Under the Curve 
CI 
Confidence Interval 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CSS 
Composite Symptom Score 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
DRR 
Durable Response Rate 
eCRF 
Electronic Case Report Form 
HRQoL 
Health Related Quality of Life 
IBPRC 
Independent Blinded PRO (patient reported outcomes) Review Committee 
ICF 
Informed Consent Form 
IHC 
Immunohistochemistry 
IMM 
Immunogenicity 
IRR 
Infusion Related Reaction 
ITT 
Intent-to-treat 
IxRS 
Interactive (voice or web) Response system 
LCSS-Meso 
Lung Cancer Symptom Scale-Mesothelioma 
LKAD 
Last Known Alive Date 
MDASI-MPM 
MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRECIST 
Modified Response Evaluation Criteria in Solid Tumors 
M&S 
Modelling and Simulation 
N/A 
Not Applicable 
NABs 
Neutralizing Antibodies 
NCI-CTCAE 
National Cancer Institute’s Common Terminology Criteria for Adverse Events 
OS 
Overall Survival 
PD 
Progression Disease 
PFS 
Progression Free Survival 
PIR 
Pain Improvement Rate 
PK 
Pharmacokinetics 
PR 
Partial Response 
PRO 
Patient Report Outcome 
QoL 
Quality of Life 
RoW 
Rest of the World 
SAE 
Serious Adverse Event 
SAF 
Safety 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SIR 
Symptom Improvement Rate 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent AE 
TTP 
Time To Progression 
TTWP 
Time to Worsening of Pain 
TTWS 
Time to Worsening of Symptoms 
UE 
Un-Evaluable 
WHO-DD 
World Health Organization Drug Dictionary 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
6 of 54
 
 
1. 
Introduction 
Study 15743 is a randomized, open-label, active-controlled Phase II registrational study to 
compare the efficacy and safety of intravenous anetumab ravtansine (BAY 94-9343) against 
vinorelbine in patients with advanced or unresectable locally metastatic malignant pleural 
mesothelioma overexpressing mesothelin who progressed on first line platinum/pemetrexed-
based chemotherapy. 
Two analyses are planned, the final analysis for primary endpoint progression-free survival 
(PFS), which will also serve as an interim analysis for secondary endpoint overall survival 
(OS), and the final OS analysis.  
This Statistical Analysis Plan (SAP) specifies the analyses and data presentations planned for 
both the final primary endpoint and the final OS analysis.   
This SAP was written based on the following documentation: 
 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
7 of 54
 
 
Document 
Date 
Version 
Protocol 
17 August 2015 
1.0 
Protocol Amendment no. 1, local amendment for 
UK only 
04 December 2015 
Integrated CSP 
version 1.0  
Protocol Amendment no. 2, global amendment 
9 February 2016 
Integrated CSP 
version 2.0 
Protocol Amendment no. 3, local amendment for 
Finland only   
23 May 2016  
Integrated CSP 
version 2.0 
Protocol Amendment no. 4, global amendment 
11 Aug 2016  
Integrated CSP 
version 3.0  
Protocol Amendment no. 5, global amendment 
18 April 2017 
Integrated CSP 
version 4.0 
eCRF - Subject Case Report Forms 
30 November 2015 
1.0 
eCRF – AMR1 
 26 Feb 2016 
2.0 
eCRF – AMR2  
15 Mar 2016 
3.0 
eCRF – AMR3 
18 Apr 2016  
4.0 
eCRF – AMR4 
30 Aug 2016 
5.0 
eCRF – AMR5 
19 Sep 2016 
6.0 
eCRF – AMR6 
7 Dec 2016 
7.0 
Bayer Therapeutic Area Oncology Standards 
(TAS) 
2 August 2016 
July 2016 
Bayer Oncology Standard Tables 
08 Dec 2016 
3.3 
Anetumab Ravtansine Standards  
11 August 2016 
August 2016 
Bayer Global Medical Standards (GMS) 
9 May 2016 
March-April 2016  
15743 Data Monitoring Committee (DMC) Charter  
2 Feb 2016  
1.0  
15743 Data Monitoring Committee (DMC) Charter 
24 May 2016  
2.0 
15743 Independent Radiological Review Imaging 
Charter 
16 December 2015  
1.0 
 
15743 Independent Radiological Review Imaging 
Charter 
21 March 2016  
2.0 
 
2. 
Study Objectives 
The primary objective of this study is to: 
 Test the superiority of anetumab ravtansine monotherapy over vinorelbine in 
progression-free survival (PFS) 
The secondary objectives of this study are to: 
 Test overall survival (OS) 
 Evaluate patient-reported outcomes (PROs) – symptom burden and health-related 
quality of life (QoL) 
 Evaluate other indicators of treatment efficacy (indicators of tumor response) 
 Evaluate safety 
The other objectives of this study are to evaluate the: 
 Pharmacokinetics (PKs) 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
8 of 54
 
 
 Immunogenicity 
 Biomarkers 
 Further biomarkers to investigate the drug (i.e. mode-of-action-related 
effect and / or safety) and / or the pathomechanism of the disease 
(exploratory). 
3. 
Study Design 
Figure 3–1 Overall study design 
Stratification 
 Geographic 
region (RoW 
vs. Asia) 
 TTP on 1st line 
treatment        
(≥ 6 months vs.    
< 6 months)
Randomization
2:1
(N=210)
Anetumab 
ravtansine 
6.5 mg/kg Q3W 
Day 1 
of each 21-day Cycle
Vinorelbine 
30 mg/m2 QW
 Days 1, 8 and 15      
of each 21-day Cycle
Disease 
progression
Blinded central 
radiology review
Long-term
 follow-up
Active 
follow-up
 
This is a randomized, open-label, active-controlled, 2-arm, multicenter, Phase II trial to 
evaluate the safety and efficacy of anetumab ravtansine as a single agent administered as an 
IV infusion Q3W in comparison to IV vinorelbine given according to the usual QW schedule. 
Approximately 210 patients will be randomized in this study. 
At the time of the start of study treatment, the patients will have unresectable locally 
advanced or metastatic MPM recurrent/relapsing after a 1st line treatment with platinum in 
combination with pemetrexed with or without bevacizumab, and overexpressing mesothelin 
as determined by immunohistochemistry (IHC). Only patients who demonstrate mesothelin 
overexpression at the moderate and stronger level by IHC in at least 30% of tumor cells can 
be randomized into the study. A prescreening step, including the mesothelin expression level 
testing, can be performed without evidence of disease progression after the initial treatment 
cycles with platinum/pemetrexed (with or without bevacizumab) at the investigator’s 
discretion. 
The start of the study is defined by signing of the informed consent form (ICF) for 
prescreening. After meeting the eligibility criteria for prescreening and signing the ICF for 
full study), approximately 210 patients who meet all of the inclusion and none of the 
exclusion criteria will be randomly assigned in a 2:1 ratio to receive anetumab ravtansine or 
vinorelbine, respectively. The anetumab ravtansine arm will consist of approximately 140 
patients and the vinorelbine comparator arm of approximately 70 patients. 
Patients will be stratified at randomization according to geographic region (Rest of the world 
[RoW] versus Asia) and per time to progression (TTP) on 1st line treatment (≥ 6 month 
versus < 6 months). An approximately 54% screen fail rate is anticipated (25% at 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
9 of 54
 
 
prescreening and a subsequent 33% among biomarker expressers. Approximately 420 
patients are estimated to be required for prescreening to yield approximately 263 biomarker-
positive patients, resulting in 210 randomized eligible patients). 
The start of the treatment period is defined for efficacy purposes by randomization to study 
drug (anetumab ravtansine or vinorelbine), and for safety purposes by first administration of 
study drug. Start of treatment has to be within 24 hours after the randomization call. Patients 
in the anetumab ravtansine arm will receive anetumab ravtansine IV infusion at a dose of 6.5 
mg/kg (recommended Phase II dose [RPIID]) on Day 1 of a 21-day cycle. Patients in the 
comparator arm will receive vinorelbine 30 mg/m2 IV on Days 1, 8 and 15 of a 21-day cycle. 
Treatment will be continued until death or occurrence of PD as defined by Modified 
Response Evaluation Criteria in Solid Tumors (mRECIST) for mesothelioma [1] and 
assessed by blinded central radiology review, or clinical progression, or until another 
criterion for withdrawal from the study is met. In case of radiological progression, however, 
treatment may be continued provided that the patient derives clinical benefit as determined by 
the treating physician. 
All patients who discontinue study treatment for any reason will enter the safety follow-up 
period. Safety follow-up visit will be performed 30 (+7) days after the last administration of 
study treatment. 
Patients who discontinue study treatment for any reason other than centrally confirmed 
radiological PD will be followed for progression during active follow-up (which includes the 
safety follow-up period) until centrally confirmed PD for this patient is observed. 
All patients who end study treatment for any reason will be followed for OS and any new 
anti-cancer treatment every 3 months during the long-term follow-up period until data 
maturation for the OS final analysis is reached, or until death, consent withdrawal or end of 
study, whichever occurs first. 
Primary efficacy will be assessed based on radiological tumor evaluation by contrast 
enhanced CT or contrast-enhanced magnetic resonance imaging (MRI) of 
chest/abdomen/pelvis. The first tumor images will be obtained during full screening and will 
be sent to blinded central review to confirm radiological eligibility prior to randomization. 
During treatment as well as active follow-up, tumor imaging will be performed with the same 
modality every 6 weeks during the first 6 months after the start of study treatment, every 9 
weeks until the end of year 2, and every 12 weeks thereafter until centrally confirmed 
radiological disease progression or end of study. Primary analysis results will be based on 
central review. 
Patients will be contacted to assess survival status every 3 months during long-term follow-
up. In addition, extra survival sweep contacts will be conducted at the time of PFS final 
analysis and prior to OS final analysis to ensure that long-term follow-up data is current. 
The effect of treatment on disease-specific symptoms and disease-specific health-related QoL 
will be assessed using the MD Anderson Symptom Inventory-Malignant Pleural 
Mesothelioma (MDASI-MPM) and the Lung Cancer Symptom Scale-Mesothelioma (LCSS-
 Meso), respectively, at full screening, at each cycle during treatment, at the safety follow-up 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
10 of 54
 
 
visit, and during active follow-up. An independent blinded PRO review committee of PRO, 
statistical, and psychometric experts, will conduct analyses to support validation of the 
MDASI-MPM and determine endpoint definitional details. 
Safety evaluations will be done at full screening, at each clinic visit during the treatment, and 
at the safety follow-up visit. The National Cancer Institute’s Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) version 4.03 will be used to grade severity of adverse 
events (AEs). In addition, a Bayer grading system (see Protocol Table 7–5 and Table 7–6) 
will be used to assess corneal epitheliopathy. 
Sparse plasma sampling for PK will be performed on all patients. 
Immunogenicity assessment will be performed for patients in the anetumab ravtansine arm 
only. 
Obligatory biomarker sampling will be performed on all patients to measure mesothelin 
expression levels in tumor material at prescreening. In addition, plasma levels of soluble 
mesothelin will be studied to evaluate whether plasma mesothelin levels may correlate with 
response rate and be of predictive value. Biomarker plasma will be collected to analyze 
circulating tumor DNA, too. Exploratory biomarker analysis may also be performed using 
additional fresh or archival tumor tissue to determine alterations in tumor-associated genes 
and to perform gene expression analysis. 
3.1 
Determination of Sample Size 
The sample size is primarily designed to support hypothesis test of the primary endpoint PFS, 
and to provide a limited formal evaluation of secondary endpoint OS.  
Power calculations were performed using East 6.3 software. 
3.1.1 
Primary endpoint progression-free survival 
The sample size is designed to test the following hypotheses for primary endpoint PFS: 
Null Hypothesis H0: In patients with advanced or metastatic MPM overexpressing mesothelin 
and progressed on 1st line platinum/pemetrexed-based chemotherapy, PFS under treatment 
with anetumab ravtansine at 6.5 mg/kg Q3W is not superior to PFS under treatment with 30 
mg/m2 QW vinorelbine. 
versus 
Alternative Hypothesis HA: In patients with advanced or metastatic MPM overexpressing 
mesothelin and progressed on 1st line platinum/pemetrexed-based chemotherapy, PFS under 
treatment with anetumab ravtansine at 6.5 mg/kg Q3W is superior to PFS under treatment 
with 30 mg/m2 QW vinorelbine. 
These hypotheses will be tested using a 1-sided log-rank test, stratified by geographic region 
(RoW versus Asia) and per TTP on 1st line treatment (≥ 6 months versus < 6 months) at a 
significance level of 0.0125. 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
11 of 54
 
 
Assuming median PFS of 3.6 months under vinorelbine treatment and constant hazards and a 
2:1 treatment: comparator randomization, a 100% prolongation of PFS (hazard ratio 0.5) in 
the anetumab ravtansine arm in comparison to the comparator arm can be detected at a 1-
sided significance level of 0.0125 with 90% power, with a single-stage trial with 
approximately 117 PFS events. Assuming a maximum accrual rate of 12.5 patients/month 
(20.83 patients/month screened with 40% overall screening failure rate) with 6-month linear 
accrual ramp-up, and a 3.4%/month dropout (loss to follow-up and unevaluable for tumor 
assessment) rate, 210 patients be will accrued in approximately 19.8 months and reach 
endpoint maturation of 117 events in approximately 22.0 months. The total number of 
unevaluable/dropout patients over the duration of the study through final PFS analysis is 
estimated at 33 (15.7%). 
3.1.2 
Secondary endpoint overall survival 
The sample size is also designed to test the following hypotheses in secondary endpoint OS: 
Null Hypothesis H0: In patients with advanced or metastatic MPM overexpressing mesothelin 
and progressed on 1st line platinum/pemetrexed-based chemotherapy, OS under treatment 
with anetumab ravtansine at 6.5 mg/kg Q3W is not superior to OS under treatment with 30 
mg/m2 QW vinorelbine. 
versus 
Alternative Hypothesis HA: In patients with advanced or metastatic MPM overexpressing 
mesothelin and progressed on 1st line platinum/pemetrexed-based chemotherapy, OS under 
treatment with anetumab ravtansine at 6.5 mg/kg Q3W is superior to OS under treatment with 
30 mg/m2 QW vinorelbine. 
These hypotheses will be tested using a 1-sided log-rank test, stratified by geographic region 
(RoW versus Asia)  and per TTP on 1st line treatment (≥ 6 months versus < 6 months), at a 
significance level of 0.025. 
Assuming true median OS of 9.6 months under vinorelbine treatment and constant hazards, a 
60% prolongation of true OS (median 15.4 months) in the anetumab ravtansine arm in 
comparison to the comparator arm (median 9.6 months) can be detected with an overall 80% 
power and an overall 1-sided significance level of 0.025 (hazard ratio 0.625), with a 2-stage 
group sequential test with a total of 159 events (modified by amendment 2). 
The OS analysis assumes the same accrual as for primary endpoint PFS, with 210 patients 
accrued in approximately 19.8 months. A 0.3% per month loss to OS follow-up rate is 
assumed. An interim OS analysis will be performed at the time of the final primary endpoint 
(PFS) analysis at an estimated 22 months from first patient randomized, when an estimated 
80 OS events will have been observed. If the study is not stopped for superiority at the OS 
interim analysis, the final OS analysis will occur after approximately159 OS events have 
been observed, at approximately 41.3 months from first patient randomized. A Lan-Demets 
alpha spending function [10] with O’Brien-Fleming boundaries [11] will be used, based on 
actual events at the time of the interim analysis. Under the null hypothesis of no anetumab 
ravtansine OS superiority, approximately 0.00158 alpha is estimated to be spent at the interim 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
12 of 54
 
 
analysis and 0.02342 at the final (0.025 alpha overall). Under the alternative hypothesis of 
60% OS improvement under anetumab ravtansine treatment, the chance of finding superiority 
is estimated at 16.9% at the interim analysis and 63.2% at the final analysis (80% power 
overall). The total number of patients lost to OS follow-up over the duration of the study 
through final OS analysis is estimated at 10 (4.8%). 
3.2 
Blinding 
This is an open-label study except for:  
 The independent and central radiological review for the assessment of disease 
progression and other radiological imaging based endpoints, which will be conducted 
in a blinded fashion. 
 The independent blinded PRO review committee which will conduct analyses to 
support validation of the MDASI-MPM instrument and determine endpoint 
definitional details. 
An independent data monitoring committee (DMC) will monitor safety in this study, its role 
is further described in the Data Monitoring Committee Charter. An interim OS analysis will 
be performed by the sponsor  at the time of final PFS analysis. The sponsor will not perform 
interim efficacy assessments. No further interim efficacy analyses are planned. 
4. 
General Statistical Considerations 
4.1 
General Principles 
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). Calculations of significance level adjustment for 
group sequential designs based on alpha spending functions will be performed using East 6.3 
or higher (Cytel Software Corporation, Cambridge, MA, USA). 
All variables will be analyzed by descriptive statistical methods.  
In general, continuous variables will be summarized using number of non-missing values (n), 
mean, standard deviation, median, maximum, minimum, and interquartile range. 
Ordinal variables will be summarized using n,  median, maximum, minimum, and 
interquartile range. 
Categorical variables will be summarized using n, number of missing values, and 
percentages. 
Time-to-event variables will be summarized using Kaplan-Meier estimates [5]. 
Frequency tables will be generated for categorical data.  
Unless otherwise specified, stratified analyses will be performed based on IxRS stratification 
factors.In the event that a per-IXRS stratification factor enrollment distribution results in 
sparse cells preventing convergence or numerically reliable estimates, the stratification factor 
will be dropped from the analysis. 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
13 of 54
 
 
4.2 
Handling of Dropouts 
A “dropout” is defined as a randomized patient who discontinues study treatment prior to 
start of study treatment (i.e. without having received any study treatment) for any reason. 
Dropouts are asked to continue in active follow-up and/or long-term follow-up. 
Once randomized, patients (e.g. dropouts and patients withdrawn from study treatment) will 
not be replaced. Refer to Section 6.3 in the study protocol for withdrawal of patients from 
study. 
In addition, the following terms identify patients who discontinue study participation at 
stages prior to randomization: 
A patient whose tumor tissue is centrally tested by IHC for mesothelin overexpression and 
whose result is not moderate and stronger mesothelin overexpression in at least 30% of the 
tumor cells, or who fails to meet any of the other eligibility criteria for prescreening, is 
regarded as a “prescreening failure”; 
A patient who passes the prescreening, including the mesothelin overexpression testing, 
enters full screening, but for any other reason (e.g. failure to satisfy the remaining selection 
criteria) terminates the study before randomization is regarded as a “full screening failure”. 
4.3 
Handling of Missing Data 
All missing or partial data will be presented in the patient data listing as they are recorded on 
the Case Report Form (CRF). 
Additional descriptive analyses in the presence of missing data 
The number of patients who prematurely discontinue the study and study treatment for any 
reason, as well as the reasons for premature discontinuation of study and study treatment, will 
be reported. Kaplan-Meier [5] plots for “Time to end of study” and “Time to end of study 
treatment” will be provided. 
Patients withdrawing from treatment, active follow-up, and long-term follow-up will be 
evaluated with respect to 
 baseline characteristics 
 potential differences between the treatment groups in the proportion of patient 
withdrawals or in the timing of withdrawals, and 
 the reasons for premature discontinuation of study and/or study treatment  
and potential withdrawal patterns will be described.  
The number, timing, pattern, and reasons for missing values of all relevant efficacy and 
safety variables will be displayed by means of descriptive statistics and visualized if 
applicable. Data exploration will include investigation of  
 potential missing data imbalances  
 baseline characteristics of patients with and without missing values 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
14 of 54
 
 
 the direction of any change over time with time courses of patients with and without 
missing data 
Treatment withdrawal criteria are specified in Figure 6-1 in the Integrated Clinical Study 
Protocol.  
Unless otherwise specified, where values are required to be “known” or “valid” as a criterion 
for inclusion in an analysis set., the values must be complete without imputation (e.g. no 
partial dates). 
 
4.3.1 
Imputation rules 
Imputation rules for specific types of data are described in Appendix 9.1. 
 
4.4 
Interim Analyses and Data Monitoring 
No formal interim analysis will be performed for primary endpoint PFS. 
A formal interim analysis for secondary endpoint OS will be performed by the sponsor at the 
same time as the primary endpoint analysis. A Lan-Demets [10] alpha spending function with 
O’Brien-Fleming [11] boundaries will be used, based on actual events at the time of the 
interim analysis. The actual alpha level will be based on the actual number of OS events 
included in the interim analysis, i.e. in the database as of the PFS primary endpoint lock. The 
information fraction for interim OS analysis used as input into the alpha spending function 
will be calculated as the number of OS events occurring as of PFS primary endpoint lock, 
divided by the total number of OS events (159) planned for the final OS analysis per 
protocol. 
In addition, an interim descriptive analysis will be performed for duration of response and 
durable response rate at the time of the final PFS analysis. 
Accordingly, two analyses of this study are planned: the PFS analysis; which will be reported 
in the Clinical Study Report and include interim analyses of OS, DOR, and DRR; and the 
final OS analysis, which will include the final analysis of DOR and DRR and an updated 
analysis of other endpoints. 
Secondary OS will be evaluated separately in a 2-stage group sequential procedure as further 
described below, with final analysis expected to occur after the primary endpoint analysis. 
Final analysis for other secondary variables,  except for DOR and DRR, will occur at the 
same time as the primary endpoint analysis. Final analysis of DOR and DRR will occur at the 
time of final OS analysis. To preserve the validity of the secondary endpoint hierarchy and 
control of overall study-wide secondary Type I error, superiority for secondary endpoint 
hypothesis tests ranking below OS in the hierarchy cannot be declared for regulatory label 
claim purposes until OS hypothesis testing succeeds. Accordingly, unless OS superiority is 
found at the interim OS analysis, the hypothesis testing outcome of endpoints ranking below 
it will not be fully effective, and any superiority for these endpoints cannot be declared for 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
15 of 54
 
 
regulatory label claim purposes, until the outcome of the OS hypothesis test is determined 
and OS superiority found at the final OS analysis. 
4.5 
Data Rules 
Generally, for each date stored in the database, a set of organizational variables will be 
derived in order to describe the temporal context of that date in the specific study: phase of 
treatment (pre, during or post study treatment), day relative to the start of study treatment, 
day relative to the end of study treatment. 
Additional contextual variables may be created in analysis datasets. 
Unless otherwise specified, the baseline assessment will be the last valid value prior to first 
treatment. Unless otherwise specified, assessments or procedures which are performed prior 
to first treatment per protocol will be assumed to occur prior to first treatment. Any 
unscheduled assessments will be included in the determination of the baseline value. 
4.6 
Blinded Review, Validity Findings, and Protocol Deviations 
Protocol deviations and validity review will be performed as described in the sponsor’s 
operational instruction on conducting blinded review meetings, cleaning and reviewing study 
data, in addition to detailed guidance on important deviations and validity findings.  
4.6.1 
Blinded Review 
Blinded review will be conducted prior to database lock for each analysis, as described in the 
sponsor’s operational instruction on conducting blinded review meetings. Reviewers will be 
tasked with evaluating the overall quality and reliability of the study data and its suitability 
for the planned statistical analysis. Blinded review will also assess protocol deviations and 
validity findings. 
4.6.2 
Validity Findings 
Criteria for validity, i.e. eligibility for each analysis set, are described in Section 5. Details 
may be further described in a separate document. Validity findings will be obtained as 
described in both the sponsor’s operational instruction on cleaning and reviewing study data, 
and the sponsor’s detailed guidance on important deviations and validity findings, and 
include major protocol deviations as described in Section 4.6.3 and the separate Protocol 
Deviations Document. The blinded review will review and finalize the validity findings prior 
to the database lock for each analysis. 
4.6.3 
Protocol Deviations 
Protocol deviations will be classified as major, important or other. Major protocol deviations 
are deviations affecting analysis set eligibility or treatment group assignment and constitute 
validity findings as described in Section 4.6.2. 
 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
16 of 54
 
 
Important protocol deviations will be identified based on the criteria described in the 
sponsor’s operational instruction on cleaning and viewing study data. Assessment criteria, 
deviation definitions, methods of evaluation, and further details will be described in a 
separate Protocol Deviations Document. 
5. 
Analysis Sets 
 Intent-to-treat set (ITT). All randomized patients will be included in the ITT set. 
Patients in this set will be reported by treatment arm as randomized. This set will be 
used for patient characteristics, demographic, and efficacy evaluations.  Patients will 
be included in ITT analyses according to the treatment to which they were 
randomized per IxRS. 
 Safety set (SAF). All treated patients, that is, all randomized patients receiving any 
amount of any study treatment, will be included in the SAF. Patients in this set will be 
reported by treatment arm as treated. The SAF will be used for safety evaluations. 
 Pharmacokinetic set (PK). All patients with valid at least one valid PK sample for 
anetumab ravtansine will be included in the analysis set for the anetumab ravtansine 
PK analysis. All patients with at least one valid PK sample for vinorelbine will be 
included in the analysis set for the PK analysis of vinorelbine. PK samples will be 
considered valid under the following conditions: known dose, known duration of 
treatment, known time of sample collection.  
 Immunogenicity set (IMM). All patients who have received at least one dose of 
anetumab ravtansine and have at least one valid post-baseline measurement of anti-
drug antibodies (ADAs) or neutralizing antibodies (NABs) will be included in the 
immunogenicity set. The IMM analysis set will be used for the immunogenicity 
analysis of anetumab ravtansine. 
 Quality of life set (QoL). All randomized patients with at least one non-missing 
LCSS-Meso evaluation at baseline will be included in the QoL dataset. Patients in this 
set will be reported by treatment arm as randomized. The QoL set will be used for 
QoL evaluations. 
 Biomarker set (BIO), also called the As-Diagosed set (AD). All patients evaluated 
for mesothelin expression at pre-screening with a valid mesothelin expression test 
result) will be included in the biomarker set. The biomarker set will be used for 
biomarker analyses, for patient disposition, and for comparability to Ventana’s 
biomarker analysis. 
 Enrolled set (ENR). All patients who signed the informed consent for any portion of 
the study including pre-screening. Enrolled patients will be used for patient 
disposition. 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
17 of 54
 
 
6. 
Statistical Methodology 
6.1 
Population characteristics 
6.1.1 
Disposition of patients 
The number and percentage of patients entering pre-screening, completing pre-screening, 
entering screening, randomized, treated, entering safety follow-up, active follow-up and long-
term follow-up will be presented by treatment group and overall.  The number of patients 
discontinuing from pre-screening, screening, treatment, safety follow-up, active follow-up, 
and long-term follow-up will also be summarized by treatment group. The reasons for 
patients discontinuing from pre-screening, screening, treatment, safety follow-up, active 
follow-up, and long-term follow-up, will be summarized by treatment group. In addition, the 
number of patients screened and included in each analysis set will be displayed overall. and, 
the number of patients in the ITT and SAF analysis sets will also be displayed by region and 
country . 
6.1.2 
Demographic and Baseline Characteristics 
Descriptive summaries of demographics and baseline characteristics will be presented by 
treatment group and overall for the ITT analysis set. Comparability of the treatment groups 
with respect to demographics and baseline characteristics will be assessed using descriptive 
summaries. 
The following demographic data will be summarized: 
 Age (years) 
 Age category (< 65,  ≥65 years) 
 Sex (Male, Female)  
 Race (White, Black, Asian Other, NA)  
 Ethnicity (Hispanic, not Hispanic. NA)  
 Height (cm) 
 Weight (kg)  
The following baseline characteristics will be summarized: 
 Mesothelin overexpression level (percent moderate or stronger cells) (distribution of 
frequencies by 10% levels counting A+5% as A; ordinal summary statistics) 
 ECOG PS (0, 1) 
 Stage of malignant pleural mesothelioma at diagnosis 
 Histology (epithelioid, biphasic, sarcomatoid)  
 Time since initial diagnosis (months), defined as time from initial diagnosis as 
recorded on the CRF to randomization date 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
18 of 54
 
 
 Time since first progression (months), defined as time from date of first progression 
as recorded on the CRF to randomization date. 
 Number of mRECIST pleural lesion measurements 
 Sum of mRECIST pleural lesion measurements 
 Number of non-pleural target lesions 
 Sum of diameters of non-pleural target lesions 
 Sum of pleural lesion measurements and non-pleural target lesion diameters 
 MDASI-MPM symptom Composite Symptom Score (CSS)  (summary statistics; 
categories0-<4, ≥4) 
 MDASI-MPM pain score (summary statistics; categories0--<4, ≥4) 
 LCSS-Meso total score (summary statistics) 
Ophthalmologic characteristics will be reported separately by ocular laterality (Left eye, right 
eye, highest visual acuity of both eyes): 
 Slit Lamp Exam Bayer Grade (0, 1) 
 Snellen Acuity Equivalent (summary statistics)  
 Intra-ocular pressure (mmHg) (summary statistics) 
 Schirmer test (mm/5 min) (categories normal/abnormal, abnormal: ≤ 10 mm/5 min)  
Note that the date of MPM diagnosis will be described in a listing. 
Categorical summaries of each randomization stratification factor per IXRS:  
 Region (Rest of World, Asia)  
 Time to progression on first line treatment (≥ 6 months, < 6 months) 
, Categorical summaries the randomization stratification factor per CRF (time to progression 
on first-line treatment) will also be performed. 
6.1.3 
Medical history 
Medical history will be summarized by Medical Dictionary for Regulatory Activities 
(MedDRA) body system organ class (SOC) and preferred term for the ITT population, by 
treatment group. 
6.1.4 
Prior and Concomitant Medications 
All investigator-reported non-study medications taken before and/or during the study will be 
coded using the World Health Organization Drug Dictionary (WHO-DD) 2005 Q3 and the 
Anatomical Therapeutic Chemical (ATC) classification system. Coding will include the drug 
class and generic drug name. 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
19 of 54
 
 
Non-study medications taken before and/or during the study will be categorized as prior 
medications, concomitant medications, and post treatment medications.  
Post treatment medications are defined as non-study medications taken after the treatment 
period (including treatment and safety follow-up). 
Prior medications are defined as all medication used before the treatment period.  
Concomitant medications are defined as all medications used during the treatment period. 
All non-study medications will be listed, including verbatim descriptions and coded terms, 
and flags for prior and post-treatment medications. Priorand concomitant medications will be 
summarized using frequencies of patients reporting each drug category and generic drug 
name. For each patient, multiple records of the same concomitant medication will be counted 
once within a drug class and generic drug name. 
For the analysis of medications, the treatment period begins on the date of first treatment and 
ends 30 days following the date of last study treatment. A medication may be classified in 
more than one category. Classification details are shown in Table 6-1. 
Table 6-1 Medication classification 
 
Prior to 
study 
drug 
Start of 
study 
drug 
Treatment 
with study 
drug 
Safety 
Follo
w-Up 
Post 
Safety 
Follow 
up 
Prior 
Medicatio
n? 
Concomita
nt 
Medication
? 
Post-
treatment 
Medicatio
n? 
C1 
 
 
 
 
 
Yes 
No 
No 
C2 
 
 
 
 
 
Yes 
Yes 
No 
C3 
 
 
 
 
 
No 
Yes 
Yes 
C4 
 
 
 
 
 
Yes 
Yes 
Yes 
C5 
 
 
 
 
 
No 
Yes 
No 
C6 
 
 
 
 
 
No 
No 
Yes 
C7 
 
 
 
 
 
No 
Yes 
No 
C1= medication started and ended before study drug 
C2= medication began before study drug and ended during study drug administration  
C3= medication started at or after study drug administration and ended after end of safety follow-up 
C4= medication started before study drug administration and ended after end of safety follow-up  
C5= medication started after safety follow-up started and ended before safety follow-up ended 
C6= medication started after safety follow-up ended 
C7= medication started at or after study drug administration and ended before safety follow-up ended   
 
 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
20 of 54
 
 
6.1.5 
Prior Therapy for Cancer 
Prior therapies for cancer (MPM) will be summarized for the ITT population, by treatment 
group. The following summaries will be reported: 
 Prior Bevacizumab therapy (yes, no)  
 Prior pleurodesis (yes, no)  
 Number of prior systemic therapy regimens (0, 1, >1)  
 Number of prior surgeries (0, 1, 2, 3, >3) 
 Number of prior radiotherapies (0, 1, 2, 3, >3) 
 Number of prior other diagnostic and therapeutic procedures (i.e. other than systemic 
therapy regimens, surgeries, and radiotherapies) (0, 1, 2, 3, >3)  
In addition, prior systemic anti-cancer therapies will be summarized using frequencies of 
patients reporting each drug category and generic drug name. For each patient, multiple 
records of the same therapy will be counted once within a drug class and generic drug name. 
Prior anti-cancer therapy for study cancer will also be reported through listings. Pleurodesis 
represents either pleurodesis surgery or pleurodesis or a pleurodectomy procedure. 
6.1.6 
Systemic anti-cancer therapy 
Subsequent and any concomitant systemic anti-cancer therapy reported on the CRF will be 
reported through listings, and summarized using frequencies of patients reporting each drug 
category and generic drug name. For each patient, multiple records of the same therapy will 
be counted once within a drug class and generic drug name. 
 
6.1.7 
Additional radiotherapies and diagnostic and therapeutic procedures 
 Numbner of concurrent radiotherapies (0, 1, 2, 3, >3) 
 Concurrent diagnostic procedures (yes, no) 
 Concurrent therapeutic procedures (yes, no) 
 Number of radiotherapies during follow-up (0, 1, 2, 3, >3) 
 
6.2 
Efficacy 
6.2.1 
Primary Efficacy Analysis 
The primary efficacy variable is progression-free survival (PFS), as determined by the central 
radiological reviewer. The primary efficacy analysis will be performed in the ITT analysis 
set. 
 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
21 of 54
 
 
Endpoint Definition 
Progression-free survival (PFS) is defined as time from randomization until disease 
progression according to modified RECIST criteria for malignant pleural mesothelioma 
(mRECIST) per blinded central radiology review, or death. Patients not experiencing death or 
progression will be censored at the last tumor assessment. 
Modified RECIST criteria for malignant pleural mesothelioma (mRECIST) ([1],[2]) are 
further described in Protocol Section 16.3 and in the Image Review Charter for Study 15743. 
Censoring Rules 
Censoring rules for primary endpoint PFS are described in Table 6-2.  
Table 6-2 Censoring rules for PFS 
Censoring for progression-
free survival for Situation 
End Date  
Censored 
Reason for 
Censoring 
No baseline radiological tumor 
assessment 
Date of Randomization Yes 
No baseline 
assessment  
No post-baseline radiological 
assessment or death 
Date of randomization Yes 
No post-baseline 
radiological 
assessment or death 
No post-baseline radiological 
assessment, death following 
window for 2 consecutive 
missed tumor assessments 
following randomization  
Date of randomization Yes 
No post-baseline 
radiological 
assessment  
No post-baseline radiological 
assessment, death within 
window for 2 missed tumor 
assessments following 
randomization 
Date of death 
No 
N/A 
Patient had a radiological 
assessment of PD following 
randomization (no 2 consecutive 
missing radiological 
assessments) 
Date of first 
radiological 
progression event 
No 
N/A 
Death or PD immediately 
following two or more 
consecutive  missed radiological  
assessments 
Date of last radiological 
assessment before 
missed assessments 
Yes  
Missed two or more 
consecutive tumor 
assessments 
Patient discontinued from study 
without radiological PD or death 
Last radiological 
assessment date  
Yes 
Patient discontinued 
from study without PD 
or death 
Death during the study (no 2 
consecutive missing radiological 
assessments) or before first 
radiological PD assessment 
Date of Death 
No 
N/A 
Patient still on study at the time 
of data cut-off without PD 
Last radiological 
assessment  before 
data cut-off 
Yes 
Patient is still alive 
without PD 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
22 of 54
 
 
Censoring rules based on 2 consecutive missing tumor assessments prior to an event will be 
implemented programmatically based on tumor assessment results provided by the central 
radiological reviewer.  These rules are further described in Table 6-3. 
 
Table 6-3 Censoring for 2 consecutive missed assessments 
Last Non-Missed Assessment 
Event Time from 
Randomization 
Interval Required to Censor* 
No post-baseline assessments  
Any 
15 weeks 
Prior to 25 Weeks 
Prior to 25 Weeks 
15 weeks 
Prior to 25 Weeks  
25 Weeks to 106 weeks 
19 weeks 
25 Weeks to 106 Weeks 
25 Weeks to 106 Weeks 
23 weeks 
25 Weeks to 106 Weeks  
More than 106 Weeks 
27 weeks 
More than 106 Weeks 
More than 106 Weeks 
30 weeks 
*Event is censored if occurring more than indicated interval beyond last non-missing assessment. Interval represents 2.5 
scheduled assessments (2 missing in between) appropriate to assessment period. 
 
Hypotheses Tested 
The analysis tests the following hypotheses in primary endpoint PFS.  
Null Hypothesis H0: In patients with advanced or metastatic MPM overexpressing 
mesothelin and progressed on 1st line platinum/pemetrexed-based chemotherapy, PFS under 
treatment with anetumab ravtansine at 6.5 mg/kg Q3W is not superior to PFS under treatment 
with 30 mg/m2 QW vinorelbine. 
Versus 
Alternative Hypothesis HA: In patients with advanced or metastatic MPM overexpressing 
mesothelin and progressed on 1st line platinum/pemetrexed-based chemotherapy, PFS under 
treatment with anetumab ravtansine at 6.5 mg/kg Q3W is superior to PFS under treatment 
with 30 mg/m2 QW vinorelbine. 
Primary Analysis 
These hypotheses will be tested using a 1-sided log-rank test, stratified by geographic region 
(RoW versus Asia) and per TTP on 1st line treatment (≥ 6 months versus < 6 months), with a 
1-sided significance level of 0.0125.  
The final primary endpoint analysis will be performed after approximately 117 PFS events 
have been observed.  
In addition to the stratified log-rank test described above, PFS will be summarized using 
Kaplan-Meier estimates [5]. Plots will be produced by treatment arm. Medians and 
Brookmeyer-Crowley confidence intervals [6] with complementary log-log transformation 
[7] will be reported. The number of patients at risk, number of events, and number of 
censored patients per month will also be reported. The hazard ratio (anetumab ravtansine 
regimen/vinorelbine) will be estimated using Cox proportional hazards models [8] with Wald 
confidence intervals [9] stratified by the same factors. For primary endpoint analysis 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
23 of 54
 
 
confidence intervals, both 95% 2-sided intervals and 97.5% 2-sided intervals (reflecting 
primary endpoint significance level) will be calculated. 
Components Analysis 
A frequency table will be provided by treatment arm identifying  the component events of 
first progression or death in each arm, as follows: 
 Censored,  
 Death,  
 Progression of pleural or non-pleural target lesions,  
 Progression of non-target lesions,  
 New lesion(s) 
For patients with multiple first progression component events on the same day, all such 
components will be reported. 
For censored patients, a frequency table will be provided for censoring in each arm, as 
described in Table 6-2. 
Checking of Assumptions 
To assess the assumption of consistent observation across the treatment arms, summary 
statistics on the difference between actual and target tumor assessment study day for each 
arm will be calculated for each target visit study day by treatment arm. Each target tumor 
assessment visit date per the PFS visit schedule (every 6 weeks during the first 6 months 
(24  weeks) after the start of study treatment, every 9 weeks until the end of year 2 
(105  weeks), and every 12 weeks thereafter) will be associated with its closest actual tumor 
assessment visit date. Ties will be resolved in favor of the earlier visit.   For each patient, this 
assessment will be performed through the last included assessment prior to an event; events 
and assessments excluded from the primary analysis (e.g. due to the missing assessment 
censoring rule) will be excluded from this analysis. Absolute differences will be reported 
similarly.  
To assess the assumption of non-informative censoring, Kaplan-Meier [5] survival curves, 
and corresponding exponential regression hazard estimates will be calculated for censoring 
times by 3-month intervals, characterizing PFS censorings as events (events as censorings) 
for purposes of this analysis. Similarity and proportionality of the censoring times will be 
evaluated.  All primary analysis censorings, including censorings due to the missing 
assessment and other rules, will be included in this analysis. 
Sensitivity Endpoints and Analyses 
To evaluate proportionality of the hazards, hazards by time will be estimated in each arm 
using exponential regression models by 3-month intervals.  Tables and plots of hazards and 
corresponding estimated survival functions, with interval model estimates overlaying Kaplan-
Meier [5] estimate for each arm, will be produced. 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
24 of 54
 
 
A non-stratified log-rank test and a test stratified by stratification factors per CRF will be 
performed. In addition, stratification factors per IXRS and per CRF will be included in 
subgroup analyses. (Note: region is per site identifier, only time to progression on first line-
treatment differs per CRF). 
Sensitivity endpoints for primary endpoint PFS will be calculated programmatically based on 
the tumor assessments performed by the central reviewer or investigator as applicable, and 
applicable additional CRF data.  
The following sensitivity endpoints will be defined: 
Time to Progression (TTP), a component of PFS, is defined as time from randomization 
until disease progression according to modified RECIST criteria for malignant pleural 
mesothelioma (mRECIST) per blinded central radiology review. Patients who died, were lost 
to follow-up, or were alive at data cut-off without radiological progression will be censored at 
the last tumor assessment. Censoring for TTP is described in Table 6-4. Windows for missed 
assessments are described in Table 6-3. 
Table 6-4 Censoring for time to progression 
Situation 
End Date  
Censored 
Reason for 
Censoring 
No baseline radiological tumor 
assessment 
Date of Randomization Yes 
No baseline 
assessment  
No post-baseline radiological 
assessment  
Date of randomization Yes 
No post-baseline 
radiological 
assessment  
Patient had a radiological 
assessment of PD following 
randomization (no 2 consecutive 
missing radiological 
assessments) 
Date of first 
radiological 
progression event 
No 
N/A 
PD immediately following two or 
more consecutive  missed 
radiological  assessments 
Date of last radiological 
assessment before 
missed assessments 
Yes  
Missed two or more 
consecutive tumor 
assessments 
Patient discontinued from study 
without radiological PD 
Last radiological 
assessment date  
Yes 
Patient discontinued 
from study without PD  
Death without prior progression  Last radiological 
assessment date 
 
Yes 
Patient died without PD 
Patient still on study at the time 
of data cut-off without PD 
Last radiological 
assessment  before 
data cut-off 
Yes 
Patient still alive 
without PD 
Progression-free survival censored for subsequent therapy (PFS1) is defined in the same 
manner as primary PFS, except that patients receiving non-protocol anti-cancer therapy prior 
to centrally confirmed radiological progression will be censored at the last tumor assessment 
prior to first non-protocol anti-cancer therapy.  
Progression-free survival not censoring for missed assessments (PFS2) is defined in the 
same manner as primary PFS, except that events following 2 or more missed assessments are 
included, i.e. rule censoring events following 2 or more missed assessments does not apply.   


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
25 of 54
 
 
Investigator progression-free survival (PFS3) is defined in the same manner as primary 
PFS, except based on investigator assessments.  
Clinical progression-free survival per investigator (PFS4) is defined in the same manner 
as PFS3, except that clinical progression documented on the CRF will also be counted as an 
event.  
Sensitivity endpoint analyses (excluding TTP) will be performed in the same manner as the 
primary endpoint analyses, using a 1-sided log-rank test, stratified by geographic region 
(RoW versus Asia) and per time to progression on 1st line treatment (≥ 6 months versus < 
6  months), with a 1-sided significance level of 0.0125. Sensitivity endpoints (including TTP) 
will be summarized using Kaplan-Meier estimates [5]. Plots will be produced by treatment 
arm. Medians and Brookmeyer-Crowley confidence intervals [6] with complementary log-log 
transformation [7] will be reported. will be reported. The hazard ratio (anetumab ravtansine 
regimen/vinorelbine) will be estimated using Cox proportional hazards models [8] with Wald 
confidence intervals [9] stratified by the same factors. For confidence intervals, both 95% 2-
sided intervals and 97.5% 2-sided intervals will be calculated. 
6.2.2 
Secondary Efficacy Analysis 
All secondary efficacy endpoints will be analyzed for the ITT analysis set. 
6.2.2.1 
Hierarchy and timing of analyses 
The following secondary endpoints will be evaluated: 
 Overall Survival (OS) 
 Objective Response Rate (ORR) 
 Disease Control Rate (DCR) 
 Duration of Response (DOR) 
 Durable Response Rate (DRR) 
 Time to Worsening of Symptoms Characteristic of Mesothelioma (TTWS) 
 Time to Worsening of Pain (TTWP) 
 Improvement Rate of Symptoms Characteristic of Mesothelioma (SIR) 
 Improvement Rate of Pain (PIR) 
For drug label claim purposes, to preserve the overall Type I error rate, secondary endpoint 
hypothesis testing will be performed for the following key secondary endpoints, only in the 
event of primary endpoint superiority, according to the following hierarchy: 
 Overall survival 
 Time to Worsening of Symptoms Characteristic of Mesothelioma 
 Time to Worsening of Pain 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
26 of 54
 
 
 Improvement Rate of Symptoms Characteristic of Mesothelioma 
 Improvement Rate of Pain 
A secondary endpoint may be claimed in the drug label only if the 1-sided p-values for this 
endpoint and all that are ranked before it are 0.025 or less. Secondary OS will be evaluated 
separately in a 2-stage group sequential procedure as further described in Section 6.2.2.2. 
Final analysis of DOR and DRR will occur at the same time as the final OS analysis. Final 
analysis for other secondary endpoints will occur at the same time as the primary endpoint 
analysis. However, to preserve the validity of the secondary endpoint hierarchy and control of 
overall study-wide secondary Type I error for regulatory label claim purposes, secondary 
endpoint hypothesis tests ranking below OS in the hierarchy tests will be applied after OS 
hypothesis testing. Accordingly, unless OS is found superior at the interim OS analysis, the 
hypothesis testing outcome of endpoints ranking below it will not be fully effective for 
regulatory label claim purposes, and any superiority for these endpoints cannot be declared 
for such purposes, until the outcome of the OS hypothesis test is determined and OS 
superiority found at the final OS analysis. 
6.2.2.2 
Overall Survival (OS) 
Endpoint Definition 
Overall survival (OS) is defined as time from randomization until death from any cause. 
Patients lost to follow-up or alive at the time of analysis will be censored at the last known 
alive date. 
Censoring Rules 
Censoring rules for overall survival are described in Table 6-5. 
Hypotheses Tested 
The secondary efficacy OS analysis tests the following hypotheses: 
Null Hypothesis H0: In patients with advanced or metastatic malignant pleural mesothelioma 
overexpressing mesothelin and progressed on 1st line platinum/pemetrexed-based 
chemotherapy, OS under treatment with anetumab ravtansine at 6.5 mg/kg Q3W is not 
superior to OS under treatment with 30 mg/m2 QW vinorelbine. 
versus 
Alternative Hypothesis HA: In patients with advanced or metastatic malignant pleural 
mesothelioma overexpressing mesothelin and progressed on 1st line platinum/pemetrexed-
based chemotherapy, OS under treatment with anetumab ravtansine at 6.5 mg/kg Q3W is 
superior to OS under treatment with 30 mg/m2 QW vinorelbine. 
These hypotheses will be tested using a 2-stage group sequential hypothesis test procedure, 
with an overall significance level preserved at 0.025 one-sided. Each stage will utilize a 1-
sided log-rank test, stratified by geographic region (RoW versus Asia) and per TTP on 1st 
line treatment (≥ 6 months versus < 6 months). 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
27 of 54
 
 
 
Table 6-5 Censoring for Overall Survival 
Situation 
End Date  
Censored 
Reason for 
Censoring 
Death between randomization date and 
the date of analysis / database cut-off 
date (i.e. there is a death date and this 
date is before or on the date of analysis 
/ database cut-off date)  
Date of Death 
No 
N/A 
Alive at the date of analysis / database 
cut-off date (i.e. there is a clear 
assessment that the patient was alive 
this day, e.g. from information collected 
on or after the date of analysis / 
database cut-off date)   
Last known alive date 
(LKAD) prior to 
database cut-off 
Yes 
No Death 
No information of survival status as of 
the data cut-off date used for an 
analysis database (e.g., lost to follow-
up) 
Last known alive date 
(LKAD) prior to 
database cut-off 
Yes 
No Death and no 
survival status 
Lost to follow-up with no contact 
information at all after the randomization 
date 
Date of randomization 
Yes 
Lost to follow-up  after 
randomization date 
If month and/or year are missing for 
death date 
The nearest prior time 
point: Last known alive 
date (LKAD) prior to 
database cut-off 
Yes 
Missing month and/or 
year for death date 
 
The interim OS analysis will be performed at the time of the final primary endpoint (PFS) 
analysis. If the study is not stopped for superiority at the interim analysis, the final OS 
analysis will occur after 159 OS events have been observed. A Lan-DeMets alpha spending 
function [10] with one-sided O’Brien-Fleming superiority boundary [11] will be used to 
determine the alpha level applicable to the interim and final analyses, based on the actual 
number of OS events at the time of the interim analysis, i.e. as of the database cut-off for the 
final PFS analysis.  For this calculation, the information fraction for the interim OS analysis 
will be calculated as the actual number of OS events included in the final PFS analysis, 
divided by the per-protocol total number of OS events (159).  
The alpha level for the final analysis will be determined by subtracting the interim analysis 
alpha level from the total overall significance level of 0.025. 
In addition to the stratified log-rank test described above, OS will be summarized at each 
analysis using Kaplan-Meier estimates [5]. Plots will be produced by treatment arm. Medians 
and Brookmeyer-Crowley confidence intervals [6] with complementary log-log 
transformation [7] will be reported. The number of patients at risk, number of events, and 
number of censored patients per month will also be reported. The hazard ratio (anetumab 
ravtansine regimen/vinorelbine) will be estimated using Cox proportional hazards models [8] 
with Wald confidence intervals [9] stratified by the same factors. For confidence intervals, 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
28 of 54
 
 
both 95% 2-sided CIs, and CIs adjusted for the group sequential design (2-sided confidence 
intervals at 100*(1-2*αi)%, where αi is the calculated 1-sided significance level for the 
applicable analysis) will be reported. 
Assumption Checking 
To assess the assumption of non-informative censoring, Kaplan-Meier [5] survival curves, 
and corresponding exponential regression hazard estimates by  3-month intervals will be 
calculated for censoring times, characterizing OS censorings as events (events as censorings) 
for purposes of this analysis. Similarity and proportionality of the censoring times will be 
evaluated.  All primary analysis censorings, including censorings due to the missing 
assessment and other rules, will be included in this analysis. 
Sensitivity Endpoints and Analyses 
To evaluate proportionality of the hazards, hazards by time will be estimated in each arm 
using exponential regression modelsby 3-month intervals.  Tables and plots of hazards and 
corresponding estimated survival functions, with interval model estimates overlaying Kaplan-
Meier estimate [5] for each arm, will be produced. 
A non-stratified log-rank test and a test stratified by stratification factor per CRF will be 
performed. In addition, stratification factors per IXRS and per CRF will be included in 
subgroup analyses. 
6.2.2.3 
Objective Response Rate (ORR) 
Each patient’s best tumor response on-study will be calculated based on central review 
tumor assessments and CRF data for non-protocol anti-cancer therapy. For this calculation 
assessments of CR, PR, and SD following PD, and/or following non-protocol anti-cancer 
therapy, will be excluded. A best response of CR requires confirmation by a 2nd subsequent 
CR assessment at least 4 weeks later with no assessments of PR, SD, or PD in between. A 
best response of PR requires confirmation by a 2nd subsequent CR or PR assessment at least 
4 weeks later with no assessments of PD in between. Responses of SD must be recorded at 
least 5 weeks (6 weeks less 1-week per protocol window) following randomization. 
Responses will be ordered as follows: (CR, PR, SD, PD, UE). 
Endpoint Definition 
A patient is a responder if the patient has a confirmed best tumor response on-study of CR or 
PR, as determined by the central radiological reviewer per mRECIST criteria.  
The objective response rate (ORR) in each arm is the number of responders divided by the 
number of randomized patients. 
Summary statistics for objective response rates will be reported in each treatment arm with 
95% 2-sided exact binomial confidence intervals.  Summary statistics for best tumor response 
on-study with 95% 2-sided exact binomial confidence intervals will also be calculated.  
As sensitivity analysis, the same statistics will be performed based on investigator 
assessments. 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
29 of 54
 
 
6.2.2.4 
Disease Control Rate (DCR) 
A patient has disease control if the patient has a best tumor response on-study (See 
Section  6.2.2.5) of CR, PR, or SD.  
The disease control rate (DCR), defined as proportion of patients achieving CR, PR, or SD 
per mRECIST criteria, as determined by the central radiological reviewer. DCR is calculated 
in each arm as the number of patients with disease control divided by the number of 
randomized patients. 
Summary statistics for disease control rates will be reported in each treatment arm with 95% 
2-sided exact binomial confidence intervals.  Summary statistics and 95% 2-sided exact 
binomial confidence intervals will also be reported for patients’ best response observed on-
study (confirmed CR, confirmed PR, SD, PD, UE). 
As sensitivity analysis, the same statistics will be performed based on investigator 
assessments. 
6.2.2.5 
Duration of Response (DOR) 
Duration of response (DOR) is defined in responders (See Section 6.2.2.3) as the time from 
central documentation of tumor response (date of first response in the confirmation sequence) 
to the earlier of disease progression as determined by the central radiological reviewer, or 
death without centrally documented progression. 
Censoring rules for DOR are described in Table 6-6. 
Duration of response will be summarized at both the interim and final analyses using Kaplan-
Meier estimates [5]. Plots will be produced by treatment arm. Medians and Brookmeyer-
Crowley confidence intervals [6] will be reported. The number of patients at risk, number of 
events, and number of censored patients per month will also be reported.  
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
30 of 54
 
 
Table 6-6 Censoring for duration of response 
Situation 
End Date  
Censored 
Reason for 
Censoring 
Patient had a radiological 
assessment of PD following 
response (no 2 consecutive 
missing radiological 
assessments) 
 
Date of first 
radiological 
progression event 
No 
N/A 
Death or PD immediately 
following two or more 
consecutive  missed radiological  
assessments 
 
Date of last radiological 
assessment before 
missed assessments 
Yes  
Missed two or more 
consecutive tumor 
assessments 
Patient discontinued from study 
without radiological PD or death 
Last radiological 
assessment date  
Yes 
Patient discontinued 
from study without PD 
or death 
Death during the study (no 2 
consecutive missing radiological 
assessments)  
 
Date of Death 
No 
N/A 
Patient still on study at the time 
of data cut-off without PD 
Last radiological 
assessment  before 
data cut-off 
Yes 
Patient is still alive 
without PD 
Sensitivity Endpoints and Analyses 
The above statistics for duration of response will also be performed based on investigator 
assessments. 
6.2.2.6 
Durable Response Rate (DRR) 
A durable responder is a responder (See Section 6.2.2.3 with duration of response of 180 
days or more.  
The durable response rate (DRR) in each arm is the number of durable responders divided 
by the number of randomized patients. 
Summary statistics for durable response rates will be reported in each treatment arm with 
95% 2-sided exact binomial confidence intervals.   
Sensitivity Endpoints and Analyses 
The above statistics for durable response rate will also be performed based on investigator 
assessments. 
6.2.2.7 
Time to worsening of symptoms characteristic of mesothelioma 
Time to worsening of symptoms characteristic of mesothelioma will be evaluated based on 
the MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma (MDASI-MPM), 
and is defined as follows: 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
31 of 54
 
 
Time to worsening of symptoms characteristic of mesothelioma is defined in patients 
evaluable for assessing worsening of symptoms, as the time from randomization until the 
first worsening of symptoms characteristic of mesothelioma. Worsening must be confirmed 
by a second MDASI-MPM assessment. Patients who died, were lost to follow-up, or ended 
MDASI-MPM assessments without confirmed worsening of symptoms will be censored at 
the date of their last MDASI-MPM assessment with a non-missing composite symptom 
score CSS). 
Confirmation of this endpoint requires two consecutive MDASI-MPM assessments with 
worsened symptoms, with no more than one missing CSS assessment in between.  
An independent PRO review committee of PRO, statistical, and psychometric experts, 
blinded to study treatment, will conduct analyses based on pooled study data following 
database lock at primary analysis to support validation of the MDASI-MPM instrument and 
determine the key definitions and details described below. The PRO review committee and its 
analyses will be further described in the PRO review committee charter and/or the 
independent PRO review analysis plan. 
For analyses of this endpoint, the following terms will be defined by the independent blinded 
PRO review committee: 
 Worsening of symptoms characteristic of mesothelioma as measured by the MDASI-
MPM questionnaire composite symptom score  (CSS).  
 Composite Symptom Score (CSS) applicable to worsening of symptoms 
 Subset of Symptoms applicable to CSS 
 Evaluability for assessing worsening of symptoms 
The blinded PRO review committee will determine the specific change from baseline 
constituting worsening of symptoms characteristic of mesothelioma, and define the minimum 
and/or maximum baseline score and other criteria constituting evaluability to determine 
worsening.  
The blinded PRO review committee will also define the applicable subset of MDASI-MPM 
items constituting the relevant subset of symptoms, and the calculation algorithm to calculate 
the CSS on that subset at each assessment, including handling of missing or partially missing 
data. 
Censoring rules are described in Table 6-7. 
 
 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
32 of 54
 
 
 
Hypotheses Tested 
The analysis tests the following hypotheses.  
Null Hypothesis H0: In patients with advanced or metastatic MPM overexpressing mesothelin 
and progressed on 1st line platinum/pemetrexed-based chemotherapy, time to worsening of 
symptoms characteristic of mesothelioma under treatment with anetumab ravtansine at 6.5 
mg/kg Q3W is not superior to time to worsening of symptoms characteristic of mesothelioma 
under treatment with 30 mg/m2 QW vinorelbine. 
Versus 
Alternative Hypothesis HA: In patients with advanced or metastatic MPM overexpressing 
mesothelin and progressed on 1st line platinum/pemetrexed-based chemotherapy, time to 
worsening of symptoms characteristic of mesothelioma under treatment with anetumab 
ravtansine at 6.5 mg/kg Q3W is superior to time to worsening of symptoms characteristic of 
mesothelioma under treatment with 30 mg/m2 QW vinorelbine.  
Table 6-7 Censoring for time to worsening of symptoms characteristic of 
mesothelioma 
Situation 
End Date  
Censored 
Reason for 
Censoring 
No baseline CSS 
Date of Randomization Yes 
No baseline 
assessment  
No post-baseline CSS  
Date of randomization Yes 
No post-baseline 
assessment  
Patient had confirmed* 
worsening of symptoms  (no 2 
consecutive missing MDASI-
MPM CSS assessments) 
Date of first worsening 
of symptoms in 
confirmation sequence 
No 
N/A 
Confirmed* worsening of 
symptoms immediately following 
two or more consecutive  
missed MDASI-MPM CSS  
assessments 
Date of last non-
missing MDASI-MPM 
CSS assessment 
following missing CSS 
assessments 
Yes  
Missed two or more 
consecutive 
assessment 
Patient discontinued MDASI-
MPM assessments without 
confirmed* worsening of 
symptoms 
Date of last non-
missing MDASI-MPM 
CSS assessment 
Yes 
Patient discontinued 
MDASI-MPM 
assessments without 
worsening  
Death without prior confirmed* 
worsening  
Date of last non-
missing MDASI-MPM 
CSS assessment 
Yes 
Patient died without 
worsening 
Patient still on study at the time 
of data cut-off without 
confirmed* worsening 
Date of last non-
missing MDASI-MPM 
CSS assessment 
Yes 
Patient still alive 
without worsening 
*Confirmed worsening of symptoms requires 2 consecutive non-missing MDASI-MPM worsened CSS assessments separated 
by no more than 1 missing MDASI-MPM CSS assessment. 
 
 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
33 of 54
 
 
Analysis 
These hypotheses will be tested using a 1-sided log-rank test, stratified by geographic region 
(RoW versus Asia) and per time to progression on 1st line treatment (≥ 6 months versus < 6 
months), with a 1-sided significance level of 0.025, at the same time as the primary endpoint 
analysis. 
In addition to the stratified log-rank test described above, time to worsening of symptoms 
characteristic of mesothelioma will be summarized using Kaplan-Meier estimates [5]. Plots 
will be produced by treatment arm. Medians and Brookmeyer-Crowley confidence intervals 
[6] with complementary log-log transformation [7] will be reported. The number of patients 
at risk, number of events, and number of censored patients per month will also be reported. 
The hazard ratio (anetumab ravtansine regimen/vinorelbine) will be estimated using Cox 
proportional hazards models [8] with Wald confidence intervals [9] stratified by the same 
factors. For analysis confidence intervals, 95% 2-sided intervals will be calculated. 
Symptoms characteristic of mesothelioma will also be analyzed descriptively. Plots of mean 
CSS over time will be produced based on dosing-independent assessment points including 
screening and following randomization (every 6 weeks during the first 6 months (24 weeks) 
after the start of study treatment, every 9 weeks until the end of year 2 (105 weeks), and 
every 12 weeks thereafter).. For these plots, patients will be included in the analysis for a 
time point if their applicable assessment was taken within 1 week of target on or before 24 
weeks, within 3 week through 105 weeks, and every 4 weeks thereafter. In addition, plots by 
scheduled visit per CRF will be provided. For both sets of plots, data will be plotted until the 
last time point where >6 patients/arm have a non-missing data in both arms.  Plots will show 
95% confidence intervals for the mean, and the number of patients each mean is based on. 
Summary statistics will be provided, associated with each plot, for all timepoints plotted for 
both sets, including timepoints where < 6 patients/arm have non-missing data. 
6.2.2.8 
Time to worsening of pain 
Time to worsening of pain will be evaluated based on the “pain at its worst” (worst pain 
score) item of MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma (MDASI-
MPM), and is defined as follows: 
Time to worsening of pain is defined in patients evaluable for assessing worsening of 
pain, as time from randomization until the first worsening of pain. Worsening must be 
confirmed by a second MDASI-MPM assessment. Patients who died, were lost to follow-up, 
or ended MDASI-MPM assessments without confirmed worsening of pain will be censored at 
the date of their last MDASI-MPM assessment with a non-missing pain score. 
Confirmation of this endpoint requires two consecutive MDASI-MPM assessments with 
worsened pain, with no more than one missing assessment in between.  
An independent PRO review committee of PRO, statistical, and psychometric experts, 
blinded to study treatment, will conduct analyses based on pooled study data following 
database lock at primary analysis to support validation of the MDASI-MPM instrument and 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
34 of 54
 
 
determine the key definitions and details described below. The PRO review committee and its 
analyses will be further described in the PRO review committee charter and/or the 
independent PRO review analysis plan. 
For analyses of this endpoint, the following terms will be defined by the independent blinded 
PRO review committee: 
 Worsening of pain as measured by the MDASI-MPM questionnaire “pain at its worst” 
item  
 Evaluability for assessing worsening of pain. 
The blinded PRO review committee will determine the specific change from baseline in the 
“pain at its worst” MDASI-MPM item constituting worsening of pain, and define the 
minimum and/or maximum baseline score and other criteria constituting evaluability to 
determine worsening. 
Censoring rules are described in Table 6-8. 
Hypotheses Tested 
The analysis tests the following hypotheses.  
Null Hypothesis H0: In patients with advanced or metastatic MPM overexpressing mesothelin 
and progressed on 1st line platinum/pemetrexed-based chemotherapy, time to worsening of 
pain under treatment with anetumab ravtansine at 6.5 mg/kg Q3W is not superior to time to 
worsening of pain under treatment with 30 mg/m2 QW vinorelbine. 
Versus 
Alternative Hypothesis HA: In patients with advanced or metastatic MPM overexpressing 
mesothelin and progressed on 1st line platinum/pemetrexed-based chemotherapy, time to 
worsening of pain under treatment with anetumab ravtansine at 6.5 mg/kg Q3W is superior to 
time to worsening of pain under treatment with 30 mg/m2 QW vinorelbine. 
Analysis 
These hypotheses will be tested using a 1-sided log-rank test, stratified by geographic region 
(RoW versus Asia) and per time to progression on 1st line treatment (≥ 6 months versus < 6 
months), with a 1-sided significance level of 0.025, at the same time as the primary endpoint 
analysis.  
In addition to the stratified log-rank test described above, time to worsening of pain will be 
summarized using Kaplan-Meier estimates [5]. Plots will be produced by treatment arm. 
Medians and Brookmeyer-Crowley confidence intervals [6] with complementary log-log 
transformation [7] will be reported. The number of patients at risk, number of events, and 
number of censored patients per month will also be reported. The hazard ratio (anetumab 
ravtansine regimen/vinorelbine) will be estimated using Cox proportional hazards models [8] 
with Wald confidence intervals [9] stratified by the same factors. For analysis confidence 
intervals, 95% 2-sided intervals will be calculated.  


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
35 of 54
 
 
Pain will also be analyzed descriptively. Plots of mean “pain at its worst” score will be 
produced based on dosing-independent assessment points including screening and following 
randomization (every 6 weeks during the first 6 months (24 weeks) after the start of study 
treatment, every 9 weeks until the end of year 2 (105 weeks), and every 12 weeks thereafter). 
For these plots, patients will be included in the analysis for a time point if their applicable 
assessment was taken within 1 weeks of target on or before 24 weeks, within 3 weeks 
through 105 weeks, and every 4 weeks thereafter. In addition, plots by visit per CRF will be 
provided. For both sets of plots, data will be plotted until the last time point where >6 
patients/arm have a non-missing data in both arms.  Plots will show 95% confidence intervals 
for the mean, and the number of patients each mean is based on. 
Summary statistics will be provided, associated with each plot, for all timepoints plotted for 
both sets, including timepoints where < 6 patients/arm have non-missing data. 
The MDASI-MPM worst pain score analysis will also be performed subgrouped by baseline 
worst pain score (<4 vs. ≥ 4). 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
36 of 54
 
 
Table 6-8 Censoring for time to worsening of pain 
Situation 
End Date  
Censored 
Reason for 
Censoring 
No baseline “pain at its worst” 
score 
Date of Randomization Yes 
No baseline 
assessment  
No post-baseline “pain at its 
worst” score  
Date of randomization Yes 
No post-baseline 
assessment  
Patient had confirmed* 
worsening of pain (no 2 
consecutive missing MDASI-
MPM “pain at its worst” 
assessments) 
Date of first worsening 
of pain in confirmation 
sequence 
No 
N/A 
Confirmed* worsening of pain 
immediately following two or 
more consecutive  missed 
MDASI-MPM “pain at its worst”  
assessments 
Date of last non-
missing MDASI-MPM 
“pain at its worst” 
assessment following 
missing pain 
assessments 
Yes  
Missed two or more 
consecutive 
assessments 
Patient discontinued MDASI-
MPM assessments without 
confirmed* worsening of pain 
Date of last non-
missing MDASI-MPM 
“pain at its worst” 
assessment 
Yes 
Patient discontinued 
MDASI-MPM 
assessments without 
worsening  
Death without prior confirmed* 
worsening of pain 
Date of last non-
missing MDASI-MPM 
“pain at its worst” 
assessment 
Yes 
Patient died without 
worsening 
Patient still on study at the time 
of data cut-off without 
confirmed* worsening of pain 
Date of last non-
missing MDASI-MPM 
“pain at its worst” 
assessment 
Yes 
Patient still alive 
without worsening 
*Confirmed worsening of pain requires 2 consecutive non-missing MDASI-MPM “pain at its worst assessments separated by no 
more than 1 missing MDASI-MPM “pain at its worst” assessment. 
6.2.2.9 
Improvement rate of symptoms characteristic of mesothelioma 
Improvement rate of symptoms characteristic of mesothelioma will be evaluated based on the 
MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma (MDASI-MPM), as 
follows: 
Improvement rate of symptoms characteristic of mesothelioma is defined in each 
randomized study arm as the number of patients with confirmed improvement of symptoms 
characteristic of mesothelioma, divided by the number of patients evaluable for 
improvement of symptoms characteristic of mesothelioma. Improvement in each patient 
must be confirmed by a second MDASI-MPM assessment. 
Confirmation of this endpoint requires two consecutive MDASI-MPM assessments with 
improved symptoms, with no more than one missing CSS assessment in between.  
An independent PRO review committee of PRO, statistical, and psychometric experts, 
blinded to study treatment, will conduct analyses based on pooled study data following 
database lock at primary analysis to support validation of the MDASI-MPM instrument and 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
37 of 54
 
 
determine the key definitions and details described below. The PRO review committee and its 
analyses will be further described in the PRO review committee charter and/or the 
independent PRO review analysis plan. 
For analyses of this endpoint, the following terms will be defined by the independent blinded 
PRO review committee: 
 Improvement of symptoms characteristic of mesothelioma as measured by the 
MDASI-MPM questionnaire composite symptom score (CSS).  
 Composite Symptom Score (CSS) applicable to improvement of symptoms (Same as 
in Section 6.2.2.7 above) 
 Subset of Symptoms applicable to  CSS (Same as in Section 6.2.2.7 above) 
 Evaluability for assessing improvement of symptoms. 
The blinded PRO review committee will determine the specific change from baseline 
constituting improvement of symptoms characteristic of mesothelioma, and define the 
minimum and/or maximum baseline score and other criteria constituting evaluability to 
determine improvement.  
The blinded PRO review committee will also define the applicable subset of MDASI-MPM 
items constituting the relevant subset of symptoms, and the calculation algorithm to calculate 
the CSS on that subset at each assessment, including handling of missing or partially missing 
data. 
Hypotheses Tested 
The analysis tests the following hypotheses.  
Null Hypothesis H0: In patients with advanced or metastatic MPM overexpressing mesothelin 
and progressed on 1st line platinum/pemetrexed-based chemotherapy, improvement rate of 
symptoms characteristic of mesothelioma under treatment with anetumab ravtansine at 6.5 
mg/kg Q3W is not superior to improvement rate of symptoms characteristic of mesothelioma 
under treatment with 30 mg/m2 QW vinorelbine. 
Versus 
Alternative Hypothesis HA: In patients with advanced or metastatic MPM overexpressing 
mesothelin and progressed on 1st line platinum/pemetrexed-based chemotherapy, 
improvement rate of symptoms characteristic of mesothelioma under treatment with 
anetumab ravtansine at 6.5 mg/kg Q3W is superior to improvement rate of symptoms 
characteristic of mesothelioma under treatment with 30 mg/m2 QW vinorelbine. 
Analysis 
These hypotheses will be tested using a 1-sided Cochran-Mantel-Haenszel test [12], stratified 
by geographic region (RoW versus Asia) and per time to progression on 1st line treatment 
(≥  6 months versus < 6 months), with a 1-sided significance level of 0.025, at the same time 
as the primary endpoint analysis.  


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
38 of 54
 
 
Summary statistics on improvement rate of symptoms characteristic of mesothelioma in each 
arm will be reported with 95% 2-sided exact binomial confidence intervals. 
6.2.2.10 
Improvement rate of pain 
Improvement rate of pain will be evaluated based on the “pain at its worst” item of MD 
Anderson Symptom Inventory-Malignant Pleural Mesothelioma (MDASI-MPM), and is 
defined as follows: 
Improvement rate of pain is defined in each randomized study arm as the number of 
patients with confirmed improvement of pain, divided by the number of patients evaluable 
for improvement of pain. Improvement in each patient must be confirmed by a second 
MDASI-MPM assessment. 
Confirmation of this endpoint requires two consecutive MDASI-MPM assessments with 
improved pain, with no more than one missing assessment in between. An independent PRO 
review committee of PRO, statistical, and psychometric experts, blinded to study treatment, 
will conduct analyses based on pooled study data following database lock at primary analysis 
to support validation of the MDASI-MPM instrument and determine the key definitions and 
details described below. The PRO review committee and its analyses will be further 
described in the PRO review committee charter and/or the independent PRO review analysis 
plan. 
For analyses of this endpoint, the following terms will be defined by the independent blinded 
PRO review committee: 
 Improvement of pain as measured by the MDASI-MPM questionnaire “pain at its 
worst” item  
 Evaluability for assessing improvement of pain. 
The blinded PRO review committee will determine the specific change from baseline in the 
“pain at its worst” MDASI-MPM item constituting improvement of pain, and define the 
minimum and/or maximum baseline score and other criteria constituting evaluability to 
determine improvement. 
Hypotheses Tested 
The analysis tests the following hypotheses.  
Null Hypothesis H0: In patients with advanced or metastatic MPM overexpressing mesothelin 
and progressed on 1st line platinum/pemetrexed-based chemotherapy, improvement rate of 
pain under treatment with anetumab ravtansine at 6.5 mg/kg Q3W is not superior to 
improvement rate of pain under treatment with 30 mg/m2 QW vinorelbine. 
Versus 
Alternative Hypothesis HA: In patients with advanced or metastatic MPM overexpressing 
mesothelin and progressed on 1st line platinum/pemetrexed-based chemotherapy, 
improvement rate of pain under treatment with anetumab ravtansine at 6.5 mg/kg Q3W is 
superior to improvement rate of pain under treatment with 30 mg/m2 QW vinorelbine. 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
39 of 54
 
 
Analysis 
These hypotheses will be tested using a 1-sided Cochran-Mantel-Haenszel test [12], stratified 
by geographic region (RoW versus Asia) and per time to progression on 1st line treatment 
(≥  6 months versus < 6 months), with a 1-sided significance level of 0.025, at the same time 
as the primary endpoint analysis.  
Summary statistics on improvement rate in each arm will be reported with 95% 2-sided exact 
binomial confidence intervals. 
6.2.3 
Other efficacy endpoint analysis 
Other efficacy variables include: 
 MDASI-MPM CSS 
 MDASI-MPM Worst Pain Score 
 Time-Averaged AUC MDASI-MPM  CSS 
 Time-Averaged AUC MDASI-MPM Pain Score 
 MDASI-MPM symptom interference score 
 LCSS-Meso total score 
 LCSS-Meso 3 summary item score 
 
6.2.3.1 
Time-Averaged AUC MDASI-MPM CSS and Pain Score 
Time-Averaged area under the curve (AUC) MDASI-MPM composite symptom score is 
defined in each subject with a baseline and at least 1 post-baseline MDASI-MPM Composite 
Symptom Score (CSS) (as defined in Section 6.2.2.7), as the time-averaged MDASI-MPM 
CSS over the period during which MDASI-MPM was assessed for that patient, after imputing 
intermediate missing assessments as described below. 
Time-Averaged area under the curve (AUC) MDASI-MPM ain Score is defined in each 
subject with a baseline and at least 1 post-baseline MDASI-MPM worst pain score (as 
defined in Section 6.2.2.8, as the time-averaged MDASI-MPM worst pain score over the 
period during which MDASI-MPM was assessed for that patient, after imputing intermediate 
missing assessments as described below. 
 
Calculation details for time-averaged AUC MDASI-MPM CSS and pain score 
Time-averaged scores are calculated as follows: 
∑
(𝑆𝑐𝑜𝑟𝑒𝑖+ 𝑆𝑐𝑜𝑟𝑒(𝑖−1)) × (𝐷𝑎𝑡𝑒𝑖−𝐷𝑎𝑡𝑒(𝑖−1))
𝑚
𝑖=1
2 × (𝐷𝑎𝑡𝑒𝑚− 𝐷𝑎𝑡𝑒0)
 
Parameters are described in Table 6-9. 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
40 of 54
 
 
 
Table 6-9 Time-averaged score parameters 
m 
is the total number of MDASI-MPM score assessments for the 
subject (CSS or pain as applicable) including actual non-
missing-value and interpolated intermediate missing-value 
protocol-scheduled assessments 
Note: In the event e.g. the subject’s last pain score is missing 
but last CSS score is non-missing, or vice versa, m for CSS and 
pain scores may be different.  
Scorei  
for 0 ≤i ≤ m 
is the subject ith-dated MDASI-MPM score (including 
interpolated intermediate missing-value scores) for CSS or pain 
as applicable, with baseline score as Score0 
Date0 
Is the subject’s randomization date 
Datei  
for 0 < i ≤ m 
Is the date of the ith MDAS-MPM CSS or worst pain score as 
applicable (including interpolated intermediate missing-value 
scores) with date of subject’s last applicable non-missing 
MDASI-MPM score as Datem 
 
For each subject, a protocol-scheduled MDASI-MPM assessment, whether or not missing, is 
intermediate if it is not the baseline assessment and not the subject’s last assessment with a 
non-missing applicable score. If an intermediate MDASI-MPM assessment has a missing 
total symptom score, it is imputed by linear interpolation (with respect to date) from the 
proceeding and following non-missing (non-imputed) scores.  
Hypotheses Tested 
The analysis tests the following hypotheses.  
Null Hypothesis H0: In patients with advanced or metastatic MPM overexpressing mesothelin 
and progressed on 1st line platinum/pemetrexed-based chemotherapy, the population mean 
time-averaged AUC CSS for symptoms characteristic of mesothelioma (respectively, time-
averaged AUC pain score) under treatment with anetumab ravtansine at 6.5 mg/kg Q3W is 
not superior to the mean time-averaged AUC CSS for symptoms characteristic of 
mesothelioma (respectively, time-averaged AUC pain score) under treatment with 30 mg/m2 
QW vinorelbine. 
Versus 
Alternative Hypothesis HA: In patients with advanced or metastatic MPM overexpressing 
mesothelin and progressed on 1st line platinum/pemetrexed-based chemotherapy, the 
population mean time-averaged AUC CSS for symptoms characteristic of mesothelioma 
(respectively, time-averaged AUC pain score) under treatment with anetumab ravtansine at 
6.5 mg/kg Q3W is superior to the mean ime-averaged AUC CSS for symptoms characteristic 
of mesothelioma (respectively, time-averaged AUC pain score) under treatment with 30 
mg/m2 QW vinorelbine. 
 
 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
41 of 54
 
 
Analysis 
These hypotheses will be tested using a 1-sided t-test with a 1-sided significance level of 
0.025, at the same time as the primary endpoint analysis. The normality assumption will be 
checked with the Shapiro-Wilk test [17] and homoskedasticiy will be tested with the Folded-
F test [18]. If the data are not approximately normal, a Mann-Whitney-Wilcoxin test [19] will 
be used. If the data are normal but heteroskedastic, the Satterthwaite method will be used 
[18].  
Summary statistics for time-averaged AUC CSS and pain score will be reported in each arm 
with 2-sided 95% (normal) confidence intervals. 
The MDASI-MPM pain score will also be evaluated subgrouped by baseline worst pain score 
(<4 vs. ≥ 4).  
 
6.2.3.2 
MDASI-MPM symptom interference score and LCSS-MESO scores 
Plots of mean MDASI-MPM symptom interference score, LCSS-Meso total score, and 
LCSS-Meso 3 summary item score will be produced over time, by treatment arm with 95% 
confidence intervals for the mean. 
For these endpoints, plots over time will be produced by visit (per CRF) at every scheduled 
assessment visit (CxD1, CxD8, and CxD15 visits for the first 3 treatment cycles and CxD1 
visit of each cycle thereafter). Plots will show 95% confidence intervals for the mean, and the 
number of patients each mean is based on. Data will be plotted until the last time point where 
≥ 6 patients/arm have non-missing data in both arms. 
Summary statistics will be provided, associated with each plot, for all timepoints plotted, 
including timepoints where < 6 patients/arm have non-missing data. 
6.3 
Pharmacokinetics/pharmacodynamics 
The details of the PK modeling analysis will be described in a separate Modelling and 
Simulation (M&S) Analysis Plan and the results will be reported in a separate M&S Report. 
Plasma concentration data for all analytes will be listed in the CSR. 
6.4 
Safety 
No formal statistical tests will be done for the safety endpoints.  
A safety analysis will be performed at the same time as the final primary endpoint analysis. 
This analysis will include treatment-emergent safety events as of database closure for primary 
endpoint completion, and will form the basis of the safety evaluation in the Clinical Study 
Report.  
An updated analysis of safety events will be performed as of the final OS analysis. Results of 
this analysis will be reported separately in an update or an addendum for the OS analysis.   


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
42 of 54
 
 
6.4.1 
Extent of exposure 
Extent of exposure will be summarized for the Safety set (SAF) by treatment group, using 
descriptive statistics.  
 Duration of study treatment for each patient will be calculated in days, depending 
upon study treatment received, as follows:  
o Anetumab ravtansine: the date of the last dose of study treatment – date of the 
first dose of study treatment + 21 
o Vinorelbine: the date of the last dose of study treatment – date of the first dose 
of study treatment + 7 
 Number of study treatment infusions received.  
 Cumulative dose of study treatment will be calculated for each patients as the sum of 
all doses received (mg/kg anetumab ravtansine and  mg/m2  vinorelbine) 
 Dose intensity of study treatment will be calculated for each patient as  
 (cumulative dose)/(duration of study treatment) (mg/kg/day anetumab ravtansine and  
mg/m2/day  vinorelbine) Patients with dose modifications will be summarized by dose 
modification category (dose omission, infusion interruption, change in infusion rate, 
dose delay, dose reduction, or permanent discontinuation of study drug). In addition, 
descriptive statistics on number of dose modifications will be reported in patients 
experiencing at least one modification. 
6.4.2 
Adverse events 
All adverse events will be coded according to the latest MedDRA Version as of database lock 
for the applicable analysis. The MedDRA version used will be documented in the CSR. The 
intensity of an AE will be documented using the NCI-CTCAE v4.03. Corneal epitheliopathy 
events will be graded according to the Bayer Grading System for corneal epitheliopathy, as 
described in Protocol Tables 7-5 and 7-6. Corneal epitheliopathy adverse events will be 
reported under the  MedDRA classification category corneal disorders, and will also be 
reported separately classified according to Bayer Grading System classification.  
Adverse Events of Special Interest 
Adverse events of special interest for anetumab ravtansine are: 
 Any grade corneal epitheliopathy  
Treatment Period  
The treatment period for this study, for purposes of safety analyses, extends from the 
initiation of study treatment until 30 days after the last administration of study treatment.   
 
 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
43 of 54
 
 
Pre-treatment AEs 
Pre-treatment AEs will be defined as AEs that started and either stopped before the first dose 
of study treatment or continued after and did not worsen in intensity (i.e. increase in CTCAE 
toxicity grade or became serious) during the treatment period.  
Treatment-emergent AEs (TEAEs) 
All AEs starting or worsening within the treatment period will be considered TEAEs, for 
example: 
 Events that started on or after the first dose and within the treatment period and are 
not a continuation of a pre-treatment event. 
 Events that started before the first dose, and worsened on or after the first dose and on 
or before the end of the treatment period.  
Post-treatment AEs 
Post-treatment follow-up AEs will be defined as AEs that started or worsened after the 
treatment period.  
An overall summary of AEs will be provided to present the number and percentage of 
patients with 
 any pre-treatment AEs 
 any TEAEs 
 any study treatment related TEAEs 
 any study procedure related TEAEs 
 any serious TEAEs  
 any serious study  treatment related TEAEs 
 any serious study procedure related TEAEs 
 any CTCAE or Bayer Grade ≥3 TEAEs 
 any TEAEs leading to discontinuation 
 any TEAEs leading to dose interruption 
 any TEAEs leading to dose reduction 
 any infusion related reactions (IRR)  
 any TEAEs leading to death 
 any TEAEs of special interest  
TEAEs will be summarized by MedDRA system organ class and preferred term.  For each 
patient, multiple occurrences of the same event will be counted once within a system organ 
class and preferred term. 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
44 of 54
 
 
The same summaries will be repeated for study treatment related TEAE, study procedure 
related TEAEs, serious TEAEs, serious study treatment related TEAEs, CTCAE or Bayer 
Grade ≥3 TEAEs, TEAEs leading to discontinuation,  and TEAEs leading to dose 
interruption, TEAEs leading to dose reduction, and TEAEs leading to death. 
The maximum severity of the TEAEs will be summarized according to the NCI-CTCAE 
toxicity criteria, except for corneal epitheliopathy, whose severity will be summarized 
according to the Bayer Grading system.  For each patient, multiple occurrences of the same 
event will be counted once at their maximum severity within a system organ class and 
preferred term.  TEAEs will also be summarized by NCI-CTCAE toxicity or Bayer Grading 
grade (as applicable) and relationship to study medication. Corneal epitheliopathy will be 
summarized classified both according to MedDRA (as corneal disorders) and according to the 
Bayer Grading System. In addition, corneal disorder  (per MedDRA) AEs other than corneal 
epitheliopathies (identified per Bayer Grading System) will be reported separately.  
The analysis of TEAEs will be reported for the Safety set (SAF), by treatment group as 
treated. 
IRR listings will include the IRR diagnosis and its associated symptoms. 
AE Listings 
Data listings will be produced for all AEs recorded in the study. Verbatim descriptions and 
coded terms will be listed for all AEs.  
Serious adverse events (SAEs), deaths, AEs leading to discontinuation and AEs of special 
safety interest will each have a separate listing.   
6.4.3 
Deaths 
Deaths reported during the study period will be tabulated by treatment group.  
6.4.4 
Clinical laboratory data 
The following laboratory parameters will be summarized: 
 Complete blood count : Hemoglobin, hematocrit, platelet count, white blood cell 
count (WBC) including differential: neutrophil, lymphocyte, monocyte, basophil, and 
eosinophil counts, red blood cell count (RBC) 
 Electrolyte and chemistry panel: sodium, potassium, chloride, calcium (total, 
corrected, or ionized), phosphorus, glucose (fasting or random/unspecified), AST, 
ALT, gamma-glutamyl transferase (GGT), bilirubin (total and direct), ALP, uric acid, 
total protein, albumin, lipase, amylase, lactic dehydrogenase (LDH), blood urea 
nitrogen (BUN) or urea, and creatinine 
 Coagulation panel: PTT or aPTT or PTT ratio, and PT or PT-INR or PT ratio. 
 eGFR  
Urinalysis and serum pregnancy test results will be reported through listings.  


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
45 of 54
 
 
Where possible, worst grades for hematological and biochemical toxicities will be calculated 
according to CTCAE, version 4.03 based on laboratory measurements. Where clinical data is 
required by CTCAE criteria to provide a valid grade (e.g.  fasting status for glucose),  this 
requirement will be noted on the report, and the worst grade will be imputed.  
Baseline laboratory grades will be determined based on the last non-missing (gradable) 
assessment taken between 28 days prior to first treatment and first treatment day (inclusive).   
For graded labs, worst grade on study and a shift table (worst grade on study by worst grade 
at baseline) will be reported. The number of grades imputed due to missing clinical data, if 
applicable, will be reported. For ungraded labs with normal ranges, low/normal/high status 
will be reported as applicable.  
Descriptive statistics (number of observations, mean, standard deviation, minimum, median 
and maximum values) will be presented, including mean change  changefrom baseline by 
treatment arm.  Box plots of mean and quartile values over time will be generated for 
laboratory parameters comprising adverse events of special interest (e.g. hematology, eGFR) 
to investigate trends over time and outliers in the data.  
If more than one assessment occurred at any visit (i.e. repeat samples taken), the last valid 
(non-missing) value will be used in the summaries. Where clinical data is required for 
grading, assessments with both laboratory and clinical data non-missing will be selected over 
assessments with non-missing laboratory and missing clinical data. Unscheduled laboratory 
data will be listed but will not be included in the summary tables. 
6.4.5 
Slit-Lamp examination findings 
Slit-lamp biomicroscopy findings will be classified and graded according to the Bayer 
Grading System, described in Protocol Tables 7-6 and 7-7. For each laterality, the number 
and percent of patients with each abnormality term and worst Bayer grade on-study will be 
reported by treatment arm. In addition, the number and percentage with the worst Bayer 
grade for any laterality will be reported. 
6.4.6 
Other ophthalmologic examination findings 
The following ophthalmologic safety endpoints will be reported: 
 Snellen acuity equivalent 
 Intraocular pressure (mmHg) 
 Schirmer test (mm/5 min) 
For these endpoints, the baseline value for each patient and laterality is the latest-dated non-
missing value taken between 28 days before first study treatment and first study treatment 
(inclusive). 
 
 
 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
46 of 54
 
 
Snellen acuity equivalent 
For each patient and laterality, the worst (lowest) on-study Snellen acuity equivalent will be 
calculated by applying the Snellen fraction (e.g. 20/50 = 0.4).  The percent worst change from 
baseline for any post-baseline assessment for that patient and laterality will be calculated. 
Snellen acuity equivalent will be evaluated by three lateralities: left eye, right eye, and the 
eye with the best Snellen acuity equivalent at baseline.  
Descriptive statistics on percent change from baseline will be reported for each laterality by 
arm (n, mean, std, median, interquartile range). For each arm and laterality, the number and 
percent of patients with a ≥50% and ≥75% decrease in Snellen acuity from baseline at any 
time on-study will be reported.  
Intraocular Pressure (IOP) 
For each patient and eye laterality, the highest and lowest intra-ocular pressure on-study will 
be determined. Summary statistics will be provided for worst change from baseline in 
intraocular pressure.  The percent worst changes from baseline (greatest increase and 
decrease) will be calculated and summarized respectively). The number and percentage of 
patients who develop IOP > 21 mmHg at any time on study, and the number and percentage 
of patients with an increase of 10 mmHg or more from baseline at time on study, will also be 
reported.  
Descriptive statistics on percent changes from baseline will be reported for each laterality by 
arm (n, mean, std, median, interquartile range). For each arm and laterality, the number and 
percent of patients with a ≥50% and ≥75% decrease (respectively increase) in intraocular 
pressure from baseline at any time on-study will be reported.  
Schirmer Test 
On-study Schirmer test findings will be reported through listings. 
6.4.7 
ECOG performance score 
The baseline ECOG PS value for each patient is the latest-dated non-missing value taken 
between 28 days before first study treatment and first study treatment (inclusive). 
A shift table will be reported with the number and percent of patients in each baseline and 
worst-on-study ECOG performance score category. 
6.4.8 
12-Lead ECG 
Each patient’s 12-lead ECG results will be classified by the investigator into one of the 
following categories: Normal or normal variant; abnormal, clinically insignificant findings; 
abnormal, clinically significant findings.  
For each patient, the worst on-study findings will be determined. The number and percentage 
of patients with worst on-study findings will be reported by category. A shift table of baseline 
findings by worst on-study findings will be reported.  
Other ECG parameters and findings will be reported through listings. 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
47 of 54
 
 
6.4.9 
Cardiac function 
Each patient’s EchoCG or MUGA scan results will be classified by the investigator into one 
of the following categories: Normal or normal variant; abnormal, clinically insignificant 
findings; abnormal, clinically significant findings.  
For each patient, the worst on-study findings will be determined. The number and percentage 
of patients with worst on-study findings will be reported by category. A shift table of baseline 
findings by worst on-study findings will be reported.  
Summary statistics will be reported for percent left ejection fraction, by treatment arm. 
6.4.10 
Vital signs 
Summary statistics on vital signs (weight, blood pressure, heart rate, respiratory rate, 
temperature) will be reported for each visit. Vitals signs collected at unscheduled visits will 
not be summarized but will be included in listings using both change from baseline and by 
visit. 
6.4.11 
Physical examinations 
Not applicable 
6.5 
Other endpoints 
6.5.1 
Tumor assessments 
Endpoints based on tumor assessments are described in Section 6.2 Efficacy. Tumor 
assessment data supporting such endpoints will be provided as listings. For each patient, 
assessment and lesion (where applicable), the listings will comprise for each time point: 
 Pleural target lesion measurements (Date of procedure, measurement number, cut 
number, method of assessment, thickness (mm), reason not measured, other/specify) 
 Non-pleural target lesions (Lesion number, anatomical description, assessment period, 
date of procedure, method of assessment, longest diameter or short axis, reason not 
measured, other/specify) 
 Non-target lesions (Lesion number, anatomical location, anatomical description, 
assessment period, date of procedure, method of assessment, status, short axis [if 
present and lymph node], contributed to unequivocal progression, reason not 
assessed) 
 New lesions (Lesion number, anatomical location, anatomical description, assessment 
period, date of procedure, method of assessment, status, short axis [if present and 
lymph node], reason not assessed) 
 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
48 of 54
 
 
6.5.2 
Patient reported outcomes 
6.5.2.1 
Disease Symptoms 
MDASI-MPM Data 
The MDASI-MPM (See Protocol Appendix 16.5.1) asks patients to rate a list of symptoms 
(at the worst) and activities (amount of interference from symptoms) on a 0 (symptom not 
present or no interference) to 10 (symptom as bad as can be imagined or complete 
interference) numeric scale in the last 24 hours. The MDASI-MPM contains the 13 symptom 
items (those found to have the highest frequency and/or severity in patients with various 
cancers and treatment types) and 6 interference items of the validated MDASI-Core and an 
additional 6 symptom items developed by qualitative interviews of 20 patients with pleural 
mesothelioma and 6 patients with different types of cancer receiving anetumab ravtansine. 
The MDASI-MPM will be used to assess the severity of multiple symptoms and the impact 
of symptoms on daily functioning and is based on the ITT population. 
6.5.2.2 
Health Related Quality of Life (HRQoL) 
LCSS-Meso 
The Lung Cancer Symptom Scale for Mesothelioma (LCSS-Meso) is designed as a site-
specific measure of QoL, particularly for use in clinical trials. (Protocol Appendix 16.5.2; 
[14]; [15]). It evaluates 5 major symptoms associated with mesothelioma and their effect on 
overall symptomatic distress, functional activities, and global QoL. It captures in detail those 
dimensions most likely to be influenced by therapeutic interventions and evaluates other 
dimensions globally. 
The patient questionnaire consists of visual analogue scales (VAS) (100 mm horizontal line). 
The patient is instructed to put a mark on the line to indicate intensity of response to the items 
in question (0 = lowest rating; 100 = highest rating).  Completion of the patient scale takes 
approximately 8 min initially, including demonstration of the VAS and 3-5 min for 
subsequent administrations 
HRQoL data from the LCSS-Meso, whether or not included in efficacy analysis endpoints, 
will be reported through listings. Data from the LCSS-Meso information sheet will also be 
listed. The analysis of HRQoL data will be based on QoL set. 
6.5.3 
Biomarkers 
A listing will be provided showing the individual percentages of patients whose tumor cells 
express mesothelin at staining intensity of moderate and stronger in at least 30% of tumor 
cells. Exploratory biomarker analyses will be described in a separate document. 
6.5.4 
Immunogenicity 
Summary statistics will be reported on number and percent of patients with ADAs and NABs.  
Titers will be reported through listings. 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
49 of 54
 
 
7. 
Document history and changes in the planned statistical analysis 
• 
Final Version 1.0 dated 30 September 2016 
• 
Final Version 2.0 dated 20 April 2017 
• 
Final Version 3.0 dated 9 May 2017 
7.1 
Examination of subgroups 
Subgroup analyses will be conducted for the primary efficacy endpoints PFS and secondary 
efficacy endpoint OS on the ITT population. Subgroup analyses will be provided by 
randomized treatment arm.  Descriptive statistics and hazard ratio estimates with 95% CI will 
be provided at least for the subgroups listed below, provided there is a sufficient number of 
events in total (at least 10) within the subgroup.  
The hazard ratio (anetumab ravtansine regimen/vinorelbine) will be estimated using Cox 
proportional hazards models with Wald confidence intervals stratified by the same factors, 
and will be reported in tables and using forest plots. 95% 2-sided CIs will be used. In 
addition, the following adjusted confidence intervals will also be reported in tables and forest 
plots: 
 For primary endpoint PFS, confidence intervals based on the 0.0125 primary PFS 
significance level, i.e. 97.5% confidence intervals. 
 For secondary endpoint OS, confidence intervals adjusted for the group sequential 
design, i.e. 2-sided confidence intervals at 100*(1-2*αi)%, where αi is the calculated 
1-sided significance level for the applicable analysis. 
Subgroup analyses will be performed based on the following baseline categories: 
 Age category (< 65,  ≥65 years) 
 Sex (Male, Female) 
 Race (White, Black, Asian and Other) 
 Ethnicity (Hispanic, not Hispanic) 
 Prior bevacizumab therapy (yes, no)  
 ECOG PS (0, 1) 
 MDASI-MPM symptom Composite Symptom Score  (CSS) (<4, ≥4) 
 MDASI-MPM pain score (<4, ≥4)  
 Slit Lamp Exam Bayer Grade  (0 both eyes, > 0 any eye) 
Randomization stratification factors:  
 Region (Rest of World, Asia)  
 Time to progression on first line treatment (≥ 6 months, < 6 months) 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
50 of 54
 
 
CRF stratification factor: 
 Time to progression on first line treatment (≥ 6 months, < 6 months) 
 
8. 
References 
1. Byrne, MJ and Nowak, AK. Modified RECIST criteria for assessment of response in 
malignant pleural mesothelioma. Annals of Oncology 15: 257–260. (2004) 
2. Labby, ZE et al. Optimization of response classification criteria for patients with 
malignant pleural mesothelioma. J Thorac Oncol. 7: 1728–1734 (2012) 
3. Fleming, TR, Rothmann, MD, and Lu, HL. Issues in using progression-free survival 
when evaluating oncology products. J Clin Oncol. 27:2874-2880 (2009).  
4. United States Department of Health and Human Services, Food and Drug 
Administration. Guidance for Industry: Clinical trial endpoints for the approval of 
cancer drugs and biologics. May 2007.  
5. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53:457-81 (1958) 
6. Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics. 38:29-41 (1982). 
7. Collett, D. Modelling Survival Data in Medical Research: Third Edition. CRC Press. 
(2015) p. 29. 
8. Cox DR, Oakes D. Analysis of Survival Data. New York: Chapman & Hall. (1984). 
9. SAS Institute, Inc. SAS/STAT 9.2 Users Guide. SAS Institute, Inc. p. 4593 (2008) 
10. Lan, KG and DeMets, KL. Discrete sequential boundaries for clinical trials. 
Biometrika 70:659-63 (1983) 
11. O’Brien, PC and Fleming, TR. A multiple testing procedure for clinical trials. 
Biometrics 35:549-556 (1979).  
12. Agresti, A. Categorical Data Analysis. Wiley, 227-30 (2012) 
13. Lung Cancer Symptom Scale (LCSS) http: //www.lcss-ql.com/index.htm. 
14. Hollen PJ, et al. Adapting the Lung Cancer Symptom Scale (LCSS) to mesothelioma: 
using the LCSS-Meso conceptual model for validation. Cancer. 2004;101:587-95 
(2004). 
15. Hollen PJ, et al. Measuring quality of life in patients with pleural mesothelioma using 
a modified version of the Lung Cancer Symptom Scale (LCSS): psychometric 
properties of the LCSS-Meso. Support Care Cancer. 14:11-21 (2006). 
16. Kalbfleisch, J. D. and Prentice, R. L. The Statistical Analysis of Failure Time Data. 
New York: John Wiley & Sons. (1980) 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
51 of 54
 
 
17. Shapiro, SS and Wilk, MB. An analysis of variance test for normality (complete 
samples). Biometrika 52:591-611 (1965). 
18. SAS Institute, Inc. SAS/STAT 9.2 Users Guide. SAS Institute, Inc. pp. 7408-7410 
(2008) 
19. Hettmansperger, TW and McKean, JW. Robust nonparametric statistical methods, 2nd 
Edition. Chapman & Hall/CRC Press. (2010).  
 
9. 
Appendices 
9.1 
Imputation rules 
9.1.1 
Imputation rules for adverse event and non-study medication dates 
Adverse event and non-study medication start and stop dates will not be imputed. 
9.1.2 
Imputation rules for systemic anti-cancer medication during treatment 
and follow-up 
Dates for prior systemic anti-cancer medications will not be imputed.   
Stop dates for systemic anti-cancer medications will not be imputed.  
For systemic anti-cancer therapy start and stop dates during active follow-up,  
 
Table 9-1 Imputation rules for systemic anti-cancer medications during follow-up 
  Imputation Rules for start and stop dates 
Start Date Scenario 
Imputation rule 
Partially Missing  
 
Imputation of start date 
 If partial date has day and month missing:  
Date will not be imputed.H. If partial date has missing day only: 
If the month and year are same as the year and month of last 
dose date, then the day of last dose will be assigned to the 
missing day. 
Otherwise, the first day of the month will be assigned to the 
missing day. 
  
Completely Missing 
 
 
Date is not imputed. 
9.1.3 
Imputation rules for last known alive date 
The last known alive date (LKAD) is derived from the key data listed in Table 9-2 below. 
The last available date across all key data listed below will be picked as the LKAD by 
patient.   
To determine the LKAD from the key data panels in Table 9-2 with partial missing dates:  


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
52 of 54
 
 
 Impute the partial missing dates in each key data item according to the imputation 
rules below in Table 9-3,  
 Pick the last available date, following imputations, as the LKAD for each patient. 
Note: The imputation method applies only to dates imputed only as part of the LKAD 
calculation. If partial dates are imputed as part of the LKAD calculation but not imputed or 
imputed differently in analyses of the underlying data, LKAD may not match the underlying 
reported data date(s).  


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
53 of 54
 
 
Table 9-2 Key Data 
Data Item 
Start Date of Treatment 
End Date of Treatment 
Demographics Patient End Date 
Demographics Reference Start Date 
Start Date of Patient Disposition Event* 
 Date/Time of Laboratory Specimen Collection 
 End Date/Time of Patient Visit  
 Start Date/Time of Patient Visit 
 Date/Time of Tumor Measurement 
PRO Questionnaire Entry Date  
Survival Assessment Contact (Alive) Date 
*Note: Disposition events not indicating a patient contact, (LOST TO FOLLOW-UP) should not be used. 
Table 9-3 Imputation rules for LKAD derivation 
Scenario: 
Partially 
Missing  
 If partial date has day and month missing, date will not be imputed.  
 If partial date has missing day only, then the first day of the month will be 
assigned to the missing day. 
C 
 If the first of the month is before the randomization date, then the date will be 
imputed as randomization date.  
Scenario: 
Completely 
Missing 
No imputation. 
9.1.4 
Imputation rules for death date 
Every effort should be made to resolve incomplete or missing dates during the course of the 
study (i.e. edit checks, data cleaning/monitoring etc.). However, in rare circumstances, 
missing parts of either date of last contact or the date of death may occur where an imputation 
algorithm has to be defined. In general the following rule should be followed: Missing month 
or year is not acceptable. Dates will be imputed as the day after LKAD if LKAD is in the 
same month as the death date, otherwise as first of the month. Details are described in Table 
9-4 below. 


 
Statistical Analysis Plan 
Protocol No.:  BAY 94-9343 / 15743 
Page: 
54 of 54
 
 
Table 9-4 Imputation rules for death date derivation 
Scenario: Partially 
Missing 
A. If partial death date has day missing, and year and month are the 
same as LKAD year and month, then impute the missing day as the day 
after LKAD.  
B. If partial death date has day missing, and year and month are after 
the LKAD year and month, then impute the missing day as the first pf the 
month.  
C. If month and/or year are missing, death will be classified as missing 
and the patient will be censored according to the censoring rules.  
Scenario: 
Completely Missing 
 No imputation.  
9.1.5 
Imputation rules for time-to-event endpoints 
Unless otherwise specified, imputation rules for partial PFS and OS assessment dates will be 
as described in Table 9-5. Unless otherwise specified, other partial time-to-event endpoint 
assessment dates will not be imputed (calculated as missing).  
Table 9-5 Imputation rules for time-to-event assessment date 
Scenario: 
Partially 
Missing  
If partial date in the specific time-to-event endpoint data has day and month 
missing, then the date will be classified as missing (not imputed) If partial date in 
the specific time-to-event endpoint data has missing day only, then the first day of 
the month will be assigned to the missing day. 
If first of the month is before the [randomization date then the date will be imputed 
as the randomization date..  
 
Scenario: 
Completely 
Missing 
No imputation.