Clinical trial NCT03926143
Conditions: Solid Tumors
Keywords: Solid tumors Mesothelin Mesothelioma
Sponsor: Bayer
Start date: 2019-06-03; Completion date: 2022-05-18
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to enable patients with solid tumors, who received anetumab ravtansine in a Bayer-sponsored clinical trial, to continue treatment after their respective study has been closed. The patients will be observed to collect information on how safe and efficient the drug is.

Detailed description:
The primary objective of the study is to collect long-term safety information on anetumab ravtansine and to enable patients, who received an anetumab ravtansine-containing treatment in any Bayer-sponsored anetumab ravtansine parent study, to continue the treatment. The secondary objective is to further investigate the efficacy of the drug.

Arms: arm 1: Adult patients with solid cancer who received anetumab-ravtansine treatment in a completed Bayer study
Interventions: intervention 1: BAY94-9343 (Anetumab ravtansine)
Intervention descriptions: intervention 1: BAY94-9343 (Anetumab ravtansine) will be administered as specified in the parent studies

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Clinical Study Protocol 
Official Title: 
An open-label, multicenter rollover study to provide continued 
treatment with anetumab ravtansine for participants with solid 
tumors who were enrolled in previous Bayer-sponsored studies 
NCT Number: 
NCT03926143 
Document Date: 
18 JUN 2019 
 


CONFIDENTIAL
Clinical Study Protocol
BAY 94-9343 / 20322
Amendment 2
Title Page
Protocol Title:
An open-label, multicenter rollover study to provide continued treatment with anetumab 
ravtansine for participants with solid tumors who were enrolled in previous Bayer-sponsored 
studies
Protocol Number: 20322
Amendment Number: 2
Compound Number: BAY 94-9343
Study Phase: Phase 2
Short Title: Anetumab ravtansine rollover study
Sponsor Name and Legal Registered Address:
Sponsor (Non-US):
Bayer AG, D-51368 Leverkusen, Germany
Sponsor (US territory):
Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, P.O. Box 915, Whippany, 
New Jersey 07981-0915, USA
Regulatory Agency Identifier Number(s)
IND: 109169
EudraCT: 2019-000061-20
Approval Date: 18 JUN 2019
The information provided in this document is strictly confidential and is intended solely for the performance 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.


C O N FI D E N TI A L 
S p o ns o r Si g n at o r y 
Cli ni c al St u d y Pr ot o c ol 
B A Y 9 4- 9 3 4 3 I 2 0 3 2 2 
A m e n d m e nt 2 
 
D at e 
M e di c al M o nit or N a m e a n d C o nt a ct I nf or m ati o n will be pr o vi d e d s e p ar at el y. 
P a g e 2 of 4 8 
P P D
P P D
P P D


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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 2
18 JUN 2019
Amendment 1
10 JAN 2019
Original Protocol
07 DEC 2018
Amendment 2 (18 JUN 2019)
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.
Overall Rationale for the Amendment:
Technical correction of hidden text format in figure and tables footnote styles.
Section # and Name
Description of Change
Brief Rationale
Figure 1-1: Study schema
Table 1-1: Schedule of 
activities
Table 6-1: Bayer classification 
and management of corneal 
epitheliopathy
Table 6-2: Bayer classification 
of visual acuity changes
Footnotes previously not visible 
due to technical error were 
made visible.
Technical correction to ensure 
all footnotes are visible.
Sponsor Signatory
Due to role title change, the 
Sponsor Signatory’s title was 
updated from Global Clinical 
Leader (GCL) to Sr. Clinical 
Development Leader (CDL).
Administrative change.
Throughout
Minor editorial and document 
formatting revisions.
Minor, therefore, have not been 
summarized.


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Clinical Study Protocol
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Table of Contents
Title Page................................................................................................................................... 1
Sponsor Signatory .................................................................................................................... 2
Protocol Amendment Summary of Changes Table............................................................... 3
Table of Tables ......................................................................................................................... 6
Table of Figures........................................................................................................................ 6
1.
Protocol Summary ............................................................................................................ 7
1.1
Synopsis........................................................................................................................... 7
1.2
Schema............................................................................................................................. 8
1.3
Schedule of Activities (SoA) ........................................................................................... 9
2.
Introduction..................................................................................................................... 12
2.1
Study Rationale.............................................................................................................. 12
2.2
Background.................................................................................................................... 12
2.3
Benefit/Risk Assessment ............................................................................................... 12
3.
Objectives and Endpoints............................................................................................... 13
4.
Study Design .................................................................................................................... 13
4.1
Overall Design ............................................................................................................... 13
4.2
Scientific Rationale for Study Design ........................................................................... 14
4.3
Justification for Dose..................................................................................................... 14
4.4
End of Study Definition................................................................................................. 14
5.
Study Population............................................................................................................. 14
5.1
Inclusion Criteria ........................................................................................................... 14
5.2
Exclusion Criteria .......................................................................................................... 15
5.3
Lifestyle Considerations ................................................................................................ 16
5.3.1
Meals and Dietary Restrictions .................................................................................. 16
5.4
Screen Failures............................................................................................................... 16
6.
Study Intervention .......................................................................................................... 16
6.1
Study Intervention(s) Administered............................................................................... 16
6.2
Preparation/Handling/Storage/Accountability............................................................... 17
6.3
Measures to Minimize Bias: Randomization and Blinding........................................... 18
6.4
Study Intervention Compliance ..................................................................................... 18
6.5
Concomitant Therapy .................................................................................................... 18
6.6
Dose Modification ......................................................................................................... 19
6.7
Intervention after the End of the Study.......................................................................... 21
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 21
7.1
Discontinuation of Study Intervention........................................................................... 21
7.1.1
Temporary Discontinuation........................................................................................ 22
7.1.2
Rechallenge ................................................................................................................ 22
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 22
7.3
Lost to Follow up........................................................................................................... 22
8.
Study Assessments and Procedures............................................................................... 22
8.1
Efficacy Assessments .................................................................................................... 23


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8.2
Safety Assessments........................................................................................................ 23
8.2.1
Physical Examinations................................................................................................ 23
8.2.2
Vital Signs .................................................................................................................. 23
8.2.3
Clinical Safety Laboratory Assessments .................................................................... 23
8.2.4
Ophthalmological examinations................................................................................. 24
8.3
Adverse Events and Serious Adverse Events ................................................................ 24
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 24
8.3.2
Method of Detecting AEs and SAEs.......................................................................... 25
8.3.3
Follow-up of AEs and SAEs ...................................................................................... 25
8.3.4
Regulatory Reporting Requirements for SAEs .......................................................... 25
8.3.5
Pregnancy ................................................................................................................... 25
8.4
Treatment of Overdose .................................................................................................. 26
8.5
Pharmacokinetics........................................................................................................... 26
8.6
Pharmacodynamics ........................................................................................................ 26
8.7
Genetics ......................................................................................................................... 26
8.8
Biomarkers..................................................................................................................... 26
8.9
Medical Resource Utilization and Health Economics ................................................... 26
9.
Statistical Considerations ............................................................................................... 27
9.1
Statistical Hypotheses.................................................................................................... 27
9.2
Sample Size Determination ........................................................................................... 27
9.3
Populations for Analyses ............................................................................................... 27
9.4
Statistical Analyses........................................................................................................ 27
9.4.1
Efficacy Analyses....................................................................................................... 27
9.4.2
Safety Analyses .......................................................................................................... 27
9.5
Interim Analyses............................................................................................................ 28
10. Supporting Documentation and Operational Considerations .................................... 28
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 28
10.1.1
Regulatory and Ethical Considerations ...................................................................... 28
10.1.2
Financial Disclosure ................................................................................................... 28
10.1.3
Informed Consent Process.......................................................................................... 29
10.1.4
Data Protection ........................................................................................................... 29
10.1.5
Dissemination of Clinical Study Data ........................................................................ 29
10.1.6
Data Quality Assurance.............................................................................................. 30
10.1.7
Source Documents...................................................................................................... 30
10.1.8
Study and Site Closure ............................................................................................... 31
10.1.9
Publication Policy....................................................................................................... 31
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 31
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.............................................................................................. 33
10.3.1
Definition of AE......................................................................................................... 33
10.3.2
Definition of SAE....................................................................................................... 34
10.3.3
Recording and Follow-Up of AE and/or SAE............................................................ 35
10.3.4
Reporting of SAEs...................................................................................................... 36
10.3.5
Adverse events of special interest .............................................................................. 37
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......... 37
10.5
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments and Study 
Intervention Rechallenge Guidelines............................................................................. 39
10.6
Appendix 6: Oxford Schema ......................................................................................... 40


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10.7
Appendix 7: Abbreviations............................................................................................ 45
10.8
Appendix 8: Protocol Amendment History ................................................................... 47
11. References ........................................................................................................................ 48
Table of Tables
Table 1–1: Schedule of activities ............................................................................................... 9
Table 6–1: Bayer classification and management of corneal epitheliopathy........................... 20
Table 6–2: Bayer classification of visual acuity changes ........................................................ 21
Table 10–1: Protocol-Required Safety Laboratory Assessments............................................. 32
Table of Figures
Figure 1–1: Study schema.......................................................................................................... 8


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1.
Protocol Summary
1.1
Synopsis
Protocol Title: An open-label, multicenter rollover study to provide continued treatment with 
anetumab ravtansine for participants with solid tumors who were enrolled in previous Bayer-
sponsored studies
Short Title: Anetumab ravtansine rollover study
Rationale: The purpose of this study is to collect long-term safety information on anetumab 
ravtansine and to enable patients who received an anetumab ravtansine-containing treatment 
in any Bayer-sponsored anetumab ravtansine parent study, to continue to receive study 
treatment and/or, if applicable, follow-up at the time of parent study closure.
Objectives and Endpoints
Objectives
Endpoints
Primary

Safety

Incidence of TEAEs

Incidence of TESAEs

Incidence of Drug-related TEAEs 
and TESAEs
Secondary

Survival

Overall survival (OS)
Tertiary/Exploratory

Tumor response

Investigator determined tumor 
assessment
Overall Design:
Disclosure Statement: 
This is an open-label rollover study to enable participants having received anetumab 
ravtansine in any applicable Bayer sponsored anetumab ravtansine parent study, to continue 
treatment or follow up (as per current epoch of parent study) at the time of parent study 
closure.
Number of Participants:
Participants who are currently receiving treatment or follow-up in ongoing anetumab 
ravtansine studies may be eligible to enroll in the study. There may be periods when there are 
no active participants in this study but it will remain open for enrollment.
Intervention Groups and Duration:
The start of the treatment period is defined by the first administration of study medication in 
the rollover study. Participants will be treated in 21-day cycles with Q3W IV administration 
of anetumab ravtansine. Participants will continue treatment with study treatment until any of 
the discontinuation criteria specified in Section 7.2 occur. 


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After permanent discontinuation from study medication, a safety follow up visit will take 
place 30-35 days after the last dose of study medication was administered and participants 
may enter long-term follow up for OS.
Data Monitoring Committee: No
1.2
Schema
The design of the study is represented in Figure 1–1.
Figure 1–1: Study schema
Abbreviations: FU = Follow-up; OS = Overall survival; ROS = Rollover study


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1.3
Schedule of Activities (SoA)
Table 1–1: Schedule of activities
Procedure
Screeninga,b
Cycle X 
Day 1 (on 
treatment)
Safety FU 
(30-35 days 
after last 
dose)
Long term 
FU (every 3 
months)
Notes
Informed consent
X
For applicable parent studies, effort should be made to 
obtain informed consent to continue to collect survival 
information in study 20322 for participants in active 
and/or long-term FU.
Inclusion and exclusion 
criteria
X
X
Information to assess if participant can receive 1st
administration of study treatment, which is obtained
within maximum 7 days prior to ICF for ROS signature 
can be used.
Only to be reviewed on C1D1.
Serum pregnancy test
X
X
X
For women of childbearing potential, performed 
maximum 7 days prior to study intervention 
administration.
For screening, on-study pregnancy test methods of parent 
protocols are acceptable.
Demography/Diagnosis
X
Cancer Classification
X


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Procedure
Screeninga,b
Cycle X 
Day 1 (on 
treatment)
Safety FU 
(30-35 days 
after last 
dose)
Long term 
FU (every 3 
months)
Notes
Medical history
X
For on-treatment participants: 
Prior clinical and surgical conditions and relevant events 
that occurred during the course of parent study. Relevant 
events are defined as (S)AE’s leading to dose reduction 
or dose interruption/delay
Study drug administration
X
Study drug (s) dosing and treatment schedule as per 
parent study protocol.
Vital signs
X
X
A 1-day window pre-administration is allowed.
Brief physical 
examination
X
X
A 1-day window pre-administration is allowed.
Complete blood count and 
differential
X
X
X
A 3-day window pre-administration is allowed.
AST/ALT/total 
bilirubin/creatinine
X
X
X
A 3-day window pre-administration is allowed.
Ophthalmological 
examination
X
X
X
Every other cycle during treatment, and at the discretion 
of the investigator in consultation with the 
ophthalmologist. Can be performed up to 7 days before 
the planned drug administration.
Examinations to be performed per the instructions of the 
parent study.
For screening, testing time schedule of parent study will 
be accepted – results >7 days would be acceptable 
provided no ocular symptoms have arisen since the latest 
test.


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Procedure
Screeninga,b
Cycle X 
Day 1 (on 
treatment)
Safety FU 
(30-35 days 
after last 
dose)
Long term 
FU (every 3 
months)
Notes
AE/SAE review
X
X
X
Any (S)AE in the parent study which is ongoing at the 
time of signing informed consent for the rollover study, 
must be reported as (S)AE in the rollover study and re-
graded to CTCAE V5.0. Further follow-up and 
documentation should occur in the rollover study.
Concomitant medication 
review
X
X
X
For on-treatment participants: documentation of 
concomitant medication ongoing at the time of parent
study closure, and any new concomitant medication 
started after signing of ICF
Survival status and new or 
ongoing anti-cancer 
treatment
X
Collect local tumor 
response information
X
Collect local imaging information (assessment date and 
outcome) obtained as per standard of care
IxRS
X
X
X
Inform IxRS of end of Treatment in ROS as soon as 
possible, at the latest at Safety FU visit
Abbreviations: AE = Adverse event; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; C1D1 = Cycle 1 Day 1; FU = Follow-up; ICF = 
Informed consent form; IxRS = Interactive voice/web response system; ROS = Rollover study; SAE = Serious adverse event
a.
The treating investigator should ensure a seamless transition without a change in the treatment schedule. Any treatment interruption for medical 
reasons between last administration in the parent study and first administration in this study should not exceed 42 consecutive days.
b.
During the last planned visit in the parent study, ROS eligibility criteria will be reviewed and the participants may sign informed consent for the 
rollover study. After signature of ROS ICF, any further procedures/events including C1D1 drug administration are part of the ROS and will be 
documented there.


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2.
Introduction
There are currently multiple ongoing anetumab ravtansine clinical studies and some of the 
participants in these studies will still be ongoing at the time when their clinical study is 
planned to be closed. The intention of this rollover study is to enable participants, who are
still benefiting from treatment, to continue to receive treatment in the rollover clinical study 
instead of parent study. For applicable studies, patients in active and/or long-term follow up 
will also be enrolled in this rollover study for continued follow up.
2.1
Study Rationale
The purpose of this study is to collect long-term safety information on anetumab ravtansine 
and to enable patients who received an anetumab ravtansine-containing treatment in any 
Bayer-sponsored anetumab ravtansine parent study, to continue to receive study treatment 
and/or, if applicable, follow-up at the time of parent study closure.
2.2
Background
Since a variety of malignancies show high expression of mesothelin (1), several agents are in
development to target cell surface mesothelin expression. Among these novel agents are the
ADCs, which combine the specific targeting of an antibody with the potency of cytotoxins (2).
Anetumab ravtansine (BAY 94-9343) is an antibody-drug conjugate (ADC) consisting of a 
fully human immunoglobulin G1 (IgG1) antibody (BAY 86-1903) directed at mesothelin 
antigen and conjugated to a synthetic cytotoxic anticancer agent, maytansine derivative 
(DM4, BAY 1006640) as toxophore through a reducible disulfide linker.
Anti-tumor activity of anetumab ravtansine as a single agent or in combination with standard 
of care agents in vivo has been demonstrated in human tumor models exogenously and 
endogenously expressing mesothelin as well as in patient-derived xenograft tumor models. 
For more information, see the most recent investigator’s brochure (IB) for BAY 94-9343 
anetumab ravtansine.
2.3
Benefit/Risk Assessment
Only participants, who have been receiving treatment in any applicable previous Bayer-
sponsored anetumab ravtansine parent study, will be enrolled in this study. The on-treatment 
participants will continue anetumab ravtansine monotherapy or combination therapy at the 
dose level(s) that have been established and were well-tolerated by the respective participant
in the parent study before. The study investigator of the anetumab ravtansine study, to which 
the participant is initially assigned, is expected to assess the overall benefit/risk for each 
participant. If the investigator deems there is a positive benefit/risk assessment, the participant 
can continue to receive treatment in this rollover study.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of anetumab ravtansine may be found in the Investigator’s Brochure.
For combination treatment drugs, please refer to their respective prescribing information.


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary

Safety

Incidence of TEAEs

Incidence of TESAEs

Incidence of Drug-related 
TEAEs and TESAEs
Secondary

Survival

Overall survival (OS)
Tertiary/Exploratory

Tumor response

Investigator determined tumor 
assessment
4.
Study Design
This is an open-label rollover study to enable participants having received anetumab 
ravtansine in any applicable Bayer sponsored anetumab ravtansine parent study, to continue 
treatment or follow up (as per current epoch of parent study) at the time of parent study 
closure. 
4.1
Overall Design
The on-treatment participants in this open-label study will continue receiving the prior study 
therapy at the dose level previously assigned and well tolerated, under the following 
conditions:
•
the participant is continuing to derive clinical benefit from the treatment as assessed by 
study investigator
•
until participant withdraws consent 
•
until participant is non-compliant to the protocol requirements
•
until participant is lost to follow-up 
•
until an unacceptable toxicity or death occurs 
During the last planned visit of the parent study, if the eligibility criteria for the rollover study 
are met, the participants may sign informed consent for the rollover study. After signature of 
ROS ICF, any further procedures/events including C1D1 drug administration are part of the 
ROS and will be documented in the ROS eCRF.
The treating investigator should ensure a seamless transition without change in the treatment 
schedule.  Any medically-indicated treatment interruption between last administration in the 
parent study and first administration in this study should not exceed 42 consecutive days.
For participants in active or long term follow-up in the applicable parent studies, efforts 
should be made to obtain signed informed consent for the rollover study. When the signature 
is obtained, the survival follow-up and evaluation of safety can continue in the rollover study
for up to 5 years.


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Details of medical history must be recorded in the participant’s source documents and entered 
in the eCRF as required.
The study investigator will continually assess the clinical benefit/risk of anetumab ravtansine 
treatment when the participants visit the clinical site for their continued treatment and will 
ensure that participants who meet any of the withdrawal criteria above discontinue treatment. 
Safety assessments should be performed according to the protocol, either at the study site or 
by the participants’ healthcare professional. Additional safety assessments may be performed 
at investigator’s discretion.
During screening, the following information will be recorded in the rollover study eCRF: 

Demography including study number and participant’s identification number of the parent
study 

Medical history

Inclusion/exclusion criteria 

Ongoing (S)AE’s (re-graded per CTCAE V5.0)

Any new (S)AE’s

Concomitant medications
4.2
Scientific Rationale for Study Design
Not applicable for this rollover study.
4.3
Justification for Dose
Not applicable for this rollover study.
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled activity shown in the Schedule of Activities.
The end of the study is defined as the date when the last participant has completed the study 
and the sponsor has decided to close the trial.
5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply:

Participants ongoing in an applicable Bayer-sponsored anetumab ravtansine parent study 
at the time of its planned study closure. 

For on-treatment participants: participant is eligible to receive the next dose of study 
intervention per the parent study protocol.


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
For on-treatment participants: any ongoing adverse events that require temporary 
treatment interruption must be resolved to baseline grade or assessed as stable and not 
requiring further treatment interruption. For applicable studies: should treatment be 
permanently interrupted in the parent study, participants may be enrolled in the follow-up 
portion of the rollover study.

Women of childbearing potential and men with reproductive potential must be willing to 
continue practicing acceptable methods of birth control during the study treatment and 
until 6 months after stopping study treatment. Genetic consultation is recommended if the 
participant wishes to have children after ending treatment. Contraceptive use by men or 
women should be consistent with local regulations regarding the methods of contraception 
for those participating in clinical studies. The investigator or a designated associate is
requested to advise the participant how to achieve highly effective birth control. Highly
effective (failure rate of less than 1% per year) contraception methods include:
o
Combined (estrogen and progesterone containing: oral, intravaginal,
transdermal) and progesterone-only (oral, injectable, implantable) hormonal 
contraception associated with inhibition of ovulation.
o
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).
o
Bilateral tubal occlusion or vasectomized partner (provided that partner is the 
sole sexual partner and has received medical assessment of the surgical 
success).
o
Sexual abstinence (reliability to be evaluated in relation to the duration of the
clinical trial and the preferred and usual lifestyle of the participant).
Male participants 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
6 months after last study drug administration.

Capable of giving signed informed consent as described in Appendix 1 (Section 10.1)
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. For on-treatment participants: a positive serum pregnancy test.
Prior/Concomitant Therapy
2. For on-treatment participants: use of one or more of the prohibited medications listed 
in the respective parent study protocol. 
Other Exclusions
3. Participant is unable to comply with the requirements of the study as described in the 
SoA. 
4. Participants who are receiving SOC agent(s) but not anetumab ravtansine in the parent 
study, and are able to receive SOC agent outside of the clinical study. 


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5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
For prohibited food and drink items, please refer to parent study protocols sections on 
prohibited concomitant therapies.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE).
In case there would be a medically-indicated treatment interruption between last drug 
administration in the parent study and first drug administration in this study of more than 42 
consecutive days, the participant will also be considered to be a screen failure.
6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Intervention(s) Administered
The following investigational products will be used in the study:

Anetumab ravtansine 

Any other medication as specified in the parent study protocol used in combination with 
anetumab ravtansine.
Participants will be treated with the anetumab ravtansine/study medication as per the dosing 
instructions from the parent study protocol in a Q3W schedule.
Anetumab ravtansine
Combination drug
Intervention 
Name
BAY 94-9343 / Anetumab 
ravtansine 
Medication as specified in the 
parent study protocol used in 
combination with anetumab 
ravtansine
Type 
Drug; experimental
Drug
Dose 
Formulation
Lyophilizate
As specified in the parent study 
protocol
Unit Dose 
Strength(s)
Each vial contains 
62.5 mg of anetumab 
ravtansine; the amount 
As specified in the parent study 
protocol


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Anetumab ravtansine
Combination drug
available for 
administration, based on 
retractable volume of 
reconstituted solution is 
60 mg of anetumab 
ravtansine
Dosage Level(s)
As per the dosing 
instructions from the 
parent study protocol in a 
Q3W schedule
As per the dosing instructions 
from the parent study protocol
Route of 
Administration
IV infusion
As specified in the parent study 
protocol
IMP and NIMP
IMP
As specified in the parent study 
protocol
Sourcing
Provided by the Sponsor 
Will be at the discretion of the 
sponsor and can potentially 
change from central to local 
supply by the sponsor, to supply 
per prescription or any other 
available option.
Packaging and 
Labeling
Provided in 30 mL 
injection vials. Each vial 
will be labeled as required 
per country requirement.
As specified in the parent study 
protocol
Current/Former 
Name(s) or 
Alias(es)
Not applicable
As specified in the parent study 
protocol
6.2
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.


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3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record
maintenance (ie, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the handling, preparation, administration  of 
study interventions, and the final disposition of unused study interventions are 
provided in the Storage and Handling Instructions and the respective prescribing 
information
6.3
Measures to Minimize Bias: Randomization and Blinding
This is an open label study and there will not be any randomization or blinding.
Attempts will be made to enroll all eligible participants from the applicable parent studies.
6.4
Study Intervention Compliance
The administration of all study treatments will follow the schedule of their respective parent
study. Each administration must be recorded in the source documentation and on the CRF.
Reasons for dose interruption / delay, reduction, re-escalation or omission will also be 
recorded in the source documents and on the CRF.
An adequate record of receipt, distribution, and return/destruction of all study treatment must 
be kept in the form of a Drug Accountability Form.
The preparation and administration of all study treatment will be performed by members of 
the investigator team during hospitalization and site visits. These persons will ascertain and 
document that the participant receives all treatments as planned.
6.5
Concomitant Therapy
For concomitant therapy in this ROS, the requirements of the respective parent study protocol 
should be followed. For more details on permitted and prohibited concomitant medication 
during study, refer to parent study protocol.
Participants should be closely monitored for side effects of all concomitant medications 
regardless of path of elimination.
All ongoing concomitant medications (including start/stop dates, total daily dose, and 
indication) must be recorded in the participant’s source documentation and in the eCRF.
Concomitant use of contrast media need not be recorded unless the participant experiences an
AE and there is a reasonable possibility that the event might have been caused by exposure to
contrast media.
Please refer also to the latest version of the Investigator’s Brochures for anetumab ravtansine 
and prescribing information of combination treatments for guidance when prescribing other 
medications.


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6.6
Dose Modification
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-
CTCAE) version 5.0 will be used to assess toxicities; in addition, a Bayer grading system (see 
Table 6–1 and Table 6–2) will be used to assess corneal epitheliopathy and visual acuity 
changes. 
Treatment-emergent (serious) adverse event (TE(S)AE) requiring dose modification (dose 
omission, infusion interruption, change in infusion rate, dose delay, dose reduction, or 
permanent discontinuation of study intervention[s]) will be defined as an adverse event that is 
possibly, probably, or definitely related to study intervention(s) and occur any time during the 
study.
For dose modification of the study intervention(s) following TE(S)AE’s, please refer back to 
the relevant parent protocol guidelines. These remain valid also under CTCAE V5.0 AE 
assessment.


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Table 6–1: 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
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
Intensive therapy 
with ointments; 
topical steroids;
therapeutic contact 
lens or occlusion 
recommended at 
the discretion of 
investigator in 
consultation with 
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 in 
consultation with
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 in 
consultation with
ophthalmologist d
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 21 
days) d
2) Re-start at the 
original dose level if 
the first Grade 3 
event resolves to 
Grade ≤2 within 21 
days and does not 
recur d
3) If not resolved 
within 21 days 
continue at reduced 
-1 dose level (or 
-2 dose level) d
Discontinue treatment
MTD = Maximum tolerated dose; SPK = Superficial punctate keratitis
a
Oxford Schema must be used for grading SPK from stage 0 to V (see Appendix 10.6).
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
d
If the MTD of anetumab ravtansine is set at 5.5 mg/kg for either cholangiocarcinoma and/or pancreatic 
adenocarcinoma, only one dose reduction to 4.5 mg/kg will be allowed. If the MTD of anetumab ravtansine 
is set at 4.5 mg/kg for either cholangiocarcinoma and/or pancreatic adenocarcinoma, no dose reductions 
will be allowed; toxicities requiring dose reductions in this instance will result in permanent discontinuation 
of anetumab ravtansine.


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Table 6–2: 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.
6.7
Intervention after the End of the Study
There is no planned intervention following the end of the study.
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
All participants who enter the study should complete all applicable study periods. Participants 
can be withdrawn from any study period at any time. Withdrawal from the intervention period 
alone does not constitute withdrawal from the study.
Participants who withdraw from the intervention period for any reason are to be encouraged 
to remain on the study for follow-up. Participants are expected to participate in follow-up 
unless they explicitly object. Withdrawal of consent to the intervention period should be 
documented in the participant's medical record. If the participant does not wish to be followed 
up further, this additional consent withdrawal for follow-up must also be documented.
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. If study 
intervention is permanently discontinued, the participant will remain in the study to be 
evaluated for OS and new anti-cancer treatment. See the SoA for data to be collected at the 
time of discontinuation of study intervention.
Discontinuation of study intervention for abnormal liver function should be considered by the 
investigator when a participant meets one of the conditions outlined in Section 6.6 or if the 
investigator believes that it is in best interest of the participant.
If a clinically significant finding is identified (including, but not limited to changes from 
baseline in QT interval corrected using Bazett’s formula [QTcB] or Fridericia’s formula 
[QTcF]) after enrollment, the investigator or qualified designee will determine if the 
participant can continue in the study and if any change in participant management is needed. 
This review of the ECG printed at the time of collection must be documented. Any new 
clinically relevant finding should be reported as an AE.
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
Study intervention may need to be discontinued for other reasons as specified in the parent 
study protocols – refer to respective parent study protocol for full set of discontinuation rules. 


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7.1.1
Temporary Discontinuation
For temporary interruption of study intervention please refer to Section 6.6. The duration of 
study intervention interruption for medical reasons should not exceed 42 days. 
7.1.2
Rechallenge
Rechallenge should be done according to criteria specified in Section 6.6. The duration of 
study intervention interruption for medical reasons should not exceed 42 days. 
7.2
Participant Discontinuation/Withdrawal from the Study

A participant must be withdrawn from the study at any time at his/her own request.

A participant may be withdrawn from the study at any time at the discretion of the 
investigator for safety, behavioral, compliance, or administrative reasons. This is 
expected to be uncommon.

If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, and additionally requests destruction of 
her/his samples taken but not yet tested, the investigator must document this (either 
destruction by site or request to central lab, as applicable) in the site study records.
7.3
Lost to Follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered lost to 
follow-up.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1).
8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.


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
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
8.1
Efficacy Assessments
There will be no formal assessment of tumor response during the rollover study. Outcome of 
local tumor evaluation per local standard of care will be documented by the site.
Data on survival will be collected by the site.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Physical Examinations
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.
8.2.2
Vital Signs
Temperature, pulse rate, respiratory rate, weight and blood pressure will be assessed.

Blood pressure has to be measured in a consistent manner throughout the study.

Body weight to be assessed without shoes.
8.2.3
Clinical Safety Laboratory Assessments

See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed 
and to the SoA for the timing and frequency.

The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.


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o
All protocol-required laboratory assessments, as defined in Appendix 2 
(Section 10.2), must be conducted in accordance with the SoA.
o
If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.
8.2.4
Ophthalmological examinations
Ophthalmological examinations to be performed as per the parent study. However, the 
frequency and timing of the examinations should be as per this rollover study protocol.
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3).
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative or health care professional not involved in the 
study).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. They remain responsible for 
following up SAEs, or AEs, considered related to the study intervention or study procedures, 
or those that caused the participant to discontinue the study intervention (see Section 7). 
Events of Special Interest have to be followed up regardless of causality or relationship to 
study intervention.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
All (S)AEs will be collected from the signing of the informed consent form (ICF) until the 
follow-up visit at the time points specified in the SoA (Section 1.3).
For on-treatment participants, the following must be documented in the medical history 
section of the eCRF: prior clinical and surgical conditions and also relevant events that 
occurred during the course of parent study. Relevant events are defined as AE’s leading to 
dose reduction, interruption/delay.
Any AE/SAE in the parent study which is ongoing at the time of signing informed consent for 
the rollover study must be reported in a new CRF page on the rollover study, per CTCAE 
V5.0, or Bayer Grading system for corneal epitheliopathy events. Further follow-up of these 
events will occur in the rollover study.
Medical occurrences that begin before the start of study intervention in this study but after 
obtaining informed consent will be recorded on the AE section of the case report form (CRF).
Medical occurrences that started before but deteriorated after obtaining informed consent will 
be recorded as adverse events. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AE or SAE after the safety follow-up visit. 
However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be 


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reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.2
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as 
defined in Section 10.3.5), will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is given in Appendix 3 (Section 10.3).
8.3.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
8.3.5
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study intervention and until 6 
months past the last administration of study drug.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4).

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.


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8.4
Treatment of Overdose
In this study, any dose of anetumab ravtansine greater than 6.5 mg/kg, with an absolute 
maximum of 650 mg for a participant weighing 100 kg or more within a 21 day period, will 
be considered an overdose. For participants with dose reduction to 5.5 mg/kg or 4.5 mg/kg or 
3.5 mg/kg, corresponding absolute maximum dose will be 550 mg, 450 mg and 350 mg 
respectively for a participant weighing 100 kg or more.
The sponsor does not recommend specific treatment for an overdose.
There is no specific antidote for anetumab ravtansine overdose. Overdosage following the 
administration of anetumab ravtansine should be treated as clinically indicated with 
symptomatic support. 
In the event of an overdose, the treating physician should:
1. Closely monitor the participant for any AE/SAE and laboratory abnormalities.
2. Obtain a plasma sample for PK analysis within 14 days from the date of the last 
dose of study intervention if requested by the Medical Monitor (determined on a 
case-by-case basis).
3. Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).
4. Adverse events associated with an overdose or incorrect administration of study 
drug should be recorded on the Adverse Event eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
For detailed guidance on overdosing please refer to the most current version of the IB.
8.5
Pharmacokinetics
PK parameters are not evaluated in this study.
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7
Genetics
Genetics are not evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.


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9.
Statistical Considerations
Data from participants who are transferred to a rollover study may be pooled and analyzed 
together with the data from the study in which the participant was initially included.
Data will be presented in data listings or analyzed using summary or frequency statistics.
Time-to-event variables may be analyzed using Kaplan-Meier or other descriptive methods.
9.1
Statistical Hypotheses
No confirmatory statistical hypothesis testing is planned. All safety/efficacy analyses will be 
done in a descriptive manner.
9.2
Sample Size Determination
No formal sample size estimation will be done.
Participants of on-going or future parent studies will be enrolled in the study; therefore the 
number of participants is not predictable. 
9.3
Populations for Analyses
For purposes of statistical analysis, the following analysis sets are defined:
Analysis set
Description
Enrolled 
All participants who signed the ICF
Safety
All participants who take at least 1 dose of study intervention
within this rollover study. 
9.4
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will 
describe the participant populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints.
Any endpoint not designated as primary or secondary is considered to be exploratory.
9.4.1
Efficacy Analyses
The secondary endpoint overall survival will be analyzed for applicable participants using 
Kaplan-Meier or other descriptive methods as specified in the SAP. Data from subjects in this 
rollover study may be combined with data from the parent study to explore long-term 
survival.
Investigator-determined tumor response will be collected as an exploratory endpoint and 
presented in data listings. Other descriptive analyses may be detailed in the SAP.
9.4.2
Safety Analyses
All safety analyses will be performed on the Safety Population.
The incidence of TEAEs, treatment-emergent serious adverse events (TESAEs), and drug-
related TEAEs and TESAEs are primary endpoints and will be summarized overall and by 


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MedDRA term and maximum CTCAE grade or Bayer Severity Grading system. Additional 
presentations of corneal toxicity and other types of adverse events may be described in the
SAP.
Laboratory assessments, vital signs, and ophthalmologic examinations will be presented in 
data listings. Summary statistics may be presented, as specified in the SAP. The incidence of 
lab toxicities may be summarized in frequency tables.
9.5
Interim Analyses 
No formal interim analysis is planned.
10.
Supporting Documentation and Operational Considerations
The focus of this rollover study is to provide anetumab ravtansine to participants and to 
collect safety and efficacy information as specified in the SoA.
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
10.1.2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 


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are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study.

Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
10.1.4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred.

The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
10.1.5
Dissemination of Clinical Study Data
Result Summaries of Bayer’s sponsored clinical trials in drug development phases 2, 3 and 4
and phase 1 trials in patients are provided in the Bayer Trial Finder application after
marketing authorization approval in line with the position of the global pharmaceutical
industry associations laid down in the “Joint Position on the Disclosure of Clinical Trial
Information via Clinical Trial Registries and Databases”. In addition results of clinical drug
trials will be provided on the publicly funded website www.ClinicalTrials.gov and EU
Clinical Trials Register in line with the applicable regulations.
Bayer commits to sharing upon request from qualified scientific and medical researchers
patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials
in patients for medicines and indications approved in the United States (US) and European
Union (EU) on or after January 01, 2014 as necessary for conducting legitimate research.


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All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative.
10.1.6
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification 
to the sponsor.
10.1.7
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.


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10.1.8
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
10.1.9
Publication Policy
Not applicable. It is not planned to publish data from this study, it might be that rollover study 
data will contribute to publications on parent study data.
10.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in 

Table 10–1 will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Serum Pregnancy Testing


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Table 10–1: Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
White blood cell (WBC) count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC) 
count
Hemoglobin
Hematocrit
Clinical 
Chemistry
Aspartate Aminotransferase
(AST)/ Serum Glutamic-
Oxaloacetic Transaminase (SGOT)
Total bilirubin
Creatinine
Alanine Aminotransferase
(ALT)/ Serum Glutamic-Pyruvic 
Transaminase (SGPT)
Other 
Screening 
Tests

Highly sensitive Serum human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential)
The results of each test must be entered into the case report form (CRF).
Investigators must document their review of each laboratory safety report.


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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE 
or SAE.


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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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
In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.


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e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Bayer’s pharmacovigilance department in lieu of completion of 
the AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Bayer’s pharmacovigilance department. In this case, all participant 
identifiers, with the exception of the participant number, will be redacted on the 
copies of the medical records before submission to Bayer’s pharmacovigilance 
department.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it as per CTCAE V5.0. For corneal epitheliopathy events and visual 
acuity changes, Bayer grades should be applied as per Table 6–1 and Table 6–2.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 


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Assessment of Causality
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to Bayer’s pharmacovigilance 
department. However, it is very important that the investigator always make an 
assessment of causality for every event before the initial transmission of the 
SAE data to Bayer’s pharmacovigilance department.

The investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Bayer’s 
pharmacovigilance department to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the Bayer’s 
pharmacovigilance department within 24 hours of receipt of the information.
10.3.4
Reporting of SAEs
SAE Reporting to Bayer’s pharmacovigilance department via an Electronic Data 
Collection Tool

The primary mechanism for reporting an SAE to Bayer’s pharmacovigilance 
department will be the electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 


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SAE Reporting to Bayer’s pharmacovigilance department via an Electronic Data 
Collection Tool
collection tool in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form.

Contacts for paper SAE reporting can be found in the SAE paper template.
10.3.5
Adverse events of special 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 the parent study protocols. An alternative severity grading system for 
corneal epitheliopathy will be used in addition to the CTCAE criteria, since the CTCAE may 
not adequately capture the severity of these novel adverse reactions, also specific dose 
modifications are in place (see Table 6–1 and Table 6–2). The relationship to treatment and 
the intensity of corneal epitheliopathy will be determined by the investigator, in consultation 
with the ophthalmologist.
Infusion-related reactions (IRR) are considered as AE of special interest. These adverse drug 
reactions are often associated with the administration of monoclonal antibodies and other 
therapeutic agents. Generally they are defined as ‘any signs or symptoms experienced by 
patients during the infusion of pharmacologic or biologic agents or any event occurring on the 
first day of drug administration’ (3). All adverse events that are diagnosed as IRRs by 
investigators and all associated signs and symptoms will be reported on a separate case report 
form with individual severity grading and timing for each sign/symptom. Only the IRR 
diagnosis will be reported on the AE case report form. Severity grading for the IRR itself will 
also be recorded in accordance with CTCAE V5.0. Dose modification guidance will be based 
on the reported severity of the IRR and not the signs and symptoms. Only drug-related 
reactions should be classified as IRRs.
There is no need for expedited reporting or use of complementary pages to report AESI, 
unless it meets the criteria for an SAE.
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential (WOCBP)


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A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

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 (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required. 

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
Collection of Pregnancy Information
Male participants with partners who become pregnant

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female Participants who become pregnant


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
The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant's pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, after 
obtaining the signed informed consent from both parents of the neonate, unless local 
law or specific circumstances of the respective case allow otherwise, and the 
information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy related SAE considered reasonably related to the 
study intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting.

Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
10.5
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments 
and Study Intervention Rechallenge Guidelines
See Section 6.6.


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10.6
Appendix 6: Oxford Schema


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Source: See Reference (4).


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10.7
Appendix 7: Abbreviations
List of abbreviations
ADC
Antibody-drug conjugate
AE
Adverse event
AESI
Adverse event of special safety interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
C1D1
Cycle 1 day 1
CDL
Clinical Development Leader
CIOMS
Council for International Organizations of Medical Sciences
CFR
Code of federal regulations
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case report form
CTCAE
Common terminology criteria for adverse events
ECG
Electrocardiogram
eCRF
Electronic case report form
e.g.
For example
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
FSH
Follicle stimulating hormone
FU
Follow-up
GCL
Global Clinical Leader
GCP
Good clinical practice
hCG
Human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HRT
Hormonal replacement therapy
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonization
IEC
Independent Ethics Committee
IgG1
Immunoglobulin G subclass 1
IMP
Investigational medicinal product
IRB
Institutional Review Board
IRR
Infusion-related reactions
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IxRS
Interactive voice/web response system
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum tolerated dose
NA
Not applicable
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NIMP
Non-investigational medicinal product
OS
Overall survival
PK
Pharmacokinetics
Q3W
Every 3 weeks
QT
Q wave T wave


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QTcB
Corrected QT using Bazett’s formula
QTcF
Corrected QT using Fridericia’s formula
RBC
Red blood cell
ROS
Rollover study
SAE
Serious adverse event
SAP
Statistical analysis plan
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SoA
Schedule of Activities
SOC
Standard of care
SPK
Superficial punctate keratitis
SUSAR
Suspected unexpected serious adverse reactions
TEAE
Treatment-emergent adverse event
TESAE
Treatment-emergent serious adverse event
TOC
Table of contents
US/ USA
United States/ United States of America
WBC
White blood cell
WOCBP
Women of childbearing potential


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10.8
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment 1 (10 JAN 2019)
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.
Overall Rationale for the Amendment
Section # and Name
Description of Change
Brief Rationale
Title Page
EudraCT number was updated.
A change in sponsorship 
requires a new EudraCT number 
for this study.
10.2 Appendix 2: 
Clinical Laboratory 
Tests
Direct bilirubin was removed.
Correction of an inconsistency 
between Schedule of Activities 
and Appendix 2 Clinical 
Laboratory Tests.
Throughout
Minor editorial and document 
formatting revisions.
Minor, therefore, have not been 
summarized.


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11.
References
1. Morello A, Sadelain M, Adusumilli PS. Mesothelin-Targeted CARs: Driving T Cells to 
Solid Tumors. Cancer Discov. 2016;6(2):133-46.
2. Tang Z, Qian M, Ho M. The role of mesothelin in tumor progression and targeted therapy. 
Anticancer Agents Med Chem 2013;13(2):276-80.
3. Doessegger L, Banholzer ML. Clinical development methodology for infusion-related 
reactions with monoclonal antibodies. Clinical & translational immunology. 
2015;4(7):e39.
4. 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.

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
An open-label, multicenter rollover study to provide continued 
treatment with anetumab ravtansine for participants with solid 
tumors who were enrolled in previous Bayer-sponsored studies 
NCT Number: 
NCT03926143 
Document Date: 
07 JUN 2022 
 


Statistical Analysis Plan
BAY 94-9343/20322
Page: 1 of 10
Title page
An open-label, multicenter rollover study to provide continued 
treatment with anetumab ravtansine for participants with solid 
tumors who were enrolled in previous Bayer-sponsored studies
Anetumab ravtansine rollover study
Bayer study drug
BAY 94-9343/Anetumab ravtansine
Study purpose:
Safety, enable participants still benefiting to continue treatment
Clinical study 
phase:
2
Date:
07 JUN 2022
Study No.:
20322
Version:
2
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
BAY 94-9343/20322
Page: 2 of 10
Table of Contents
Title page....................................................................................................................................1
Abbreviations ............................................................................................................................3
1.
Introduction........................................................................................................................3
2.
Study Objectives ................................................................................................................4
3.
Study Design.......................................................................................................................4
4.
General Statistical Considerations...................................................................................4
4.1
General Principles ............................................................................................................4
4.2
Handling of Dropouts.......................................................................................................5
4.3
Handling of Missing Data ................................................................................................5
4.4
Interim Analyses and Data Monitoring ............................................................................5
4.5
Data Rules ........................................................................................................................5
4.6
Validity Review Meeting .................................................................................................5
5.
Analysis Sets.......................................................................................................................5
6.
Statistical Methodology .....................................................................................................5
6.1
Population characteristics.................................................................................................5
6.1.1
Disposition ....................................................................................................................6
6.1.2
Demographic and Baseline Characteristics...................................................................6
6.1.3
Concomitant Medication...............................................................................................6
6.2
Efficacy.............................................................................................................................6
6.2.1
Overall Survival ............................................................................................................6
6.2.2
Disease Progression ......................................................................................................7
6.3
Safety................................................................................................................................7
6.3.1
Primary Safety Outcomes .............................................................................................7
6.3.2
Study Drug Exposure ....................................................................................................8
6.3.3
Adverse Events..............................................................................................................8
6.3.4
Laboratory assessments.................................................................................................9
6.3.5
Other Safety Measures ..................................................................................................9
7.
Document history and changes in the planned statistical analysis................................9
8.
References...........................................................................................................................9
Table of Tables
Table 6-1 Censoring for Overall Survival ..................................................................................7


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Abbreviations
ADC
Antibody-drug conjugate
AE
Adverse event
AESI
Adverse Events of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
BAY 94-9343
Anetumab ravtansine
CI
Confidence interval
CRF
Case Report Form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
ENR
Enrolled analysis set
ICF
Informed consent form
IRR
Infusion-related reaction
KM
Kaplan-Meier
LKAD
Last Known Alive Date
MedDRA
Medical Dictionary for Regulatory Activities
MSLN
Mesothelin
N/A
Not Applicable
NCI
National Cancer Institute
OS
Overall Survival 
PT
Preferred Term
RBC
Red Blood Cell
ROS
Rollover study
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
TEAE
Treatment-emergent adverse event
TESAE
Treatment-emergent serious adverse event
WBC
White Blood Cell
WHO-DD
World Health Organization Drug Dictionary
1.
Introduction
Anetumab ravtansine (BAY 94-9343) is an antibody-drug conjugate (ADC) directed at 
mesothelin (MSLN) antigens that are expressed in a variety of malignancies and conjugated to 
a synthetic cytotoxic anticancer agent, maytansine derivative (DM4, BAY 1006640). The 
purpose of this study is to collect long-term safety information on anetumab ravtansine and to 
enable participants who received an anetumab ravtansine-containing treatment in any Bayer-
sponsored anetumab ravtansine parent study to continue to receive study treatment and/or 
follow-up at the time of parent study closure.
This statistical analysis plan (SAP) is based on procedures and objectives as described in the 
clinical study protocol amendment 2, dated 18 JUN 2019.


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2.
Study Objectives
The primary purpose of this study is to assess the long-term safety of continued anetumab 
ravtansine treatment in patients who were treated with anetumab ravtansine in a parent study. 
Objectives
Endpoints
Primary

Safety

Incidence of TEAEs

Incidence of TESAEs

Incidence of drug-related TEAEs 
and TESAEs
Secondary

Survival

Overall survival (OS)
Tertiary/Exploratory

Tumor response

Investigator-determined tumor 
assessment
3.
Study Design
This is an open-label rollover study (ROS) to enable participants who received anetumab 
ravtansine in any applicable Bayer-sponsored anetumab ravtansine parent study to continue 
treatment or follow-up (per current epoch of parent study) at the time of parent study closure. 
Participants who discontinue treatment in this study will continue to receive survival follow-up 
in a long-term follow-up phase. All tumor assessments are at the investigator’s discretion and per 
investigator criteria. Clinic visits occur only during treatment and at the end of treatment safety 
follow-up visit 30 (+5) days after last treatment. This study has no active follow-up phase other 
than the safety follow-up visit.
4.
General Statistical Considerations
4.1
General Principles
Summary tables will be generated by overall and participant data listings will be generated 
separately for each parent study. Parent studies include Phase 1 studies 15051, 15834, 17631, 
18327, and 18329, and Phase 2 study 15743. 
The statistical evaluation will be performed using the SAS software package release 9.4 or 
higher (SAS Institute Inc., Cary, NC, USA). Data will be analyzed using descriptive statistical 
methods: 
Unless otherwise specified, the following statistics will be presented: For continuous and ordinal 
data, the number of participants with data available and missing data, mean, standard deviation, 


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minimum, interquartile range, median, and maximum. For categorical variables, the number of 
participants and percentage in each category will be generated.
If a subgroup has fewer than 8 participants, summary statistics will not be produced, and the 
results for the subgroup may be reported entirely with listings. 
4.2
Handling of Dropouts
Patients enrolled but not treated in this study will not be included in safety or efficacy 
summaries. All data available will be reported in safety listings.
4.3
Handling of Missing Data
All missing or partial data will be presented in the participant data listing as they are recorded on 
the Case Report Form (CRF). Missing data will not be imputed for analyses.
4.4
Interim Analyses and Data Monitoring
No interim analyses are planned. Safety will be monitored on an ongoing basis using clinical 
data only.
4.5
Data Rules
Duration in months will be calculated as (end date – start date + 1) / 30.4375.
4.6
Validity Review Meeting
At the Validity Review Meeting, participants will be assigned to the relevant analysis sets based 
on the rules described in Section 5.
5.
Analysis Sets
For purposes of statistical analysis, the following analysis sets were defined in the protocol:
Analysis set
Description
Enrolled (ENR)
All participants who signed the informed consent form (ICF)
Safety (SAF)
All participants who take at least 1 dose of study intervention
within this rollover study 
The enrolled analysis set will be used for study disposition and enrollment, and for listings of 
safety events. The safety analysis set (SAF) will be used for efficacy and safety summaries.
6.
Statistical Methodology
6.1
Population characteristics
Where summarized, population characteristics will be summarized by overall on the SAF. 


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6.1.1
Disposition
The number of participants in each analysis set will be presented on the enrolled analysis set.
The number and percentage of SAF participants who enroll, initiate treatment, discontinue 
treatment, receive safety follow-up, receive long-term follow-up, and discontinue long-term 
follow-up will be tabulated, along with reasons for discontinuation. Listings of all discontinued 
subjects including reasons for discontinuation will be provided by parent study.
6.1.2
Demographic and Baseline Characteristics
Data listings for all enrolled participants will contain the minimal information collected in this 
study, including parent study, age at entry into the study, weight, age group, sex, and race. 
Summary statistics will be reported for the SAF. Summary statistics and a listing of cancer type 
will be produced. 
6.1.3
Concomitant Medication
Concomitant medications are non-study medications used between the first date of treatment and 
30 days following the last study treatment in this study.
Concomitant medications will be coded using the most recent World Health Organization Drug 
Dictionary (WHO-DD) version at the time the study ends and the Anatomical Therapeutic 
Chemical (ATC) classification system. 
Concomitant medication will be reported in the safety analysis set. Listings will be provided by 
parent study. 
6.2
Efficacy
6.2.1
Overall Survival
Overall survival is defined in the SAF as the time from first treatment in this study until death 
from any cause. Participants without reported death as of the cut-off date for this study will be 
censored at their last known alive date. Overall survival data will be listed by overall. Last 
known alive date will be based on dates of actual participant contact including date of last visit 
or telephone contact of any kind, last assessment, and last laboratory sample collection date. 
Censoring rules are described in Table 6-1. Details on last known alive date will be described in 
programming specifications. 


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Table 6-1 Censoring for Overall Survival
Situation
End Date 
Censored
Reason for 
Censoring
Death between first treatment 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 participant 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 first treatment
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
OS will be summarized using Kaplan-Meier estimates [1]. Medians and 95% Brookmeyer-
Crowley confidence intervals [2] with complementary log-log transformation [3] will be 
reported. The number of participants at risk, number of events, and number of censored 
participants per month will also be reported.
6.2.2
Disease Progression
Investigator-determined disease progression will be collected as an exploratory endpoint at the 
end of treatment and presented in data listings for the enrolled analysis set. Clinical assessment 
and radiologically confirmed outcomes recorded on the CRF per the standard of care at the site.
Progression (clinical or radiological) and date of procedure (date on which radiological 
procedures were performed or date of clinical assessment) will be listed. 
6.3
Safety
Unless otherwise specified, safety analyses will be performed on the SAF. Data will be presented 
by overall and listings by parent study.
6.3.1
Primary Safety Outcomes
The primary safety outcomes include incidence of TEAEs and TESAE, as well as drug-related 
TEAEs and TESAEs. Their analysis is described in Section 6.3.3 below.


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6.3.2
Study Drug Exposure
Exposure to anetumab ravtansine will be summarized in the SAF, including number of cycles 
and duration of treatment during the rollover study. Exposure to combination therapies that 
continue from the parent study will be presented in data listings only.
Duration of treatment is defined as (last dose date-first dose date) +1.
6.3.3
Adverse Events
Treatment-emergent AEs (TEAEs) 
In this study, treatment-emergent adverse events are defined as adverse events starting or 
worsening during the treatment period. The treatment period extends from the first date of 
treatment in this study until the safety follow-up (30 days after the last administration of study 
treatment). 
Coding and grading of TEAEs 
TEAEs will be coded using the latest MedDRA version, and toxicity will be graded using NCI-
CTCAE v5.0. Corneal epitheliopathy events (classified as corneal disorders) will be graded 
according to the Bayer Grading System.
Study drug-related AEs
AEs will be reported as study drug-related if they are documented by the investigator as related 
to any study drug.
AEs of Special Interest (AESIs)
Adverse events of special interest include any corneal epitheliopathy and infusion-related 
reactions (IRRs). 
Reporting of TEAEs 
The incidence of TEAEs and TESAEs, as well as drug-related TEAEs and TESAEs will be 
summarized in descriptive summary tables (number  and percentage of participants) by latest 
MedDRA version SOC and prefered term (PT) and by worst grade for the following:

Overview of TEAEs

TEAEs 

TEAEs in descending order of frequency by Preferred Term (PT)

Study drug-related TEAEs

Study drug-related TEAEs in descending order of frequency by PT

TESAEs 

TESAEs in descending order of frequency by PT

Study drug-related TESAEs 

Study drug-related TESAEs in descending order of frequency by PT

TE(S)AEs leading to permanent discontinuation 

TE(S)AEs leading to dose interruption 


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
TE(S)AEs leading to dose reduction 

Overview AEs of special interest 
All AEs, TEAEs, TESAEs, and TEAEs leading to discontinuation of study drug will be 
presented in separate listings. Listings will be provided in all enrolled participants. AEs of 
special interest will be included in summary tables of AEs and will be presented in data listings. 
A summary of deaths during the treatment period and following 30 days after treatment end in 
this study will be reported for the safety set. A listing of all deaths at any time during the study 
will be provided in all enrolled participants. 
6.3.4
Laboratory assessments
The following laboratory parameters will be summarized in all treated participants:

Hematology: platelet count, red blood cell count (RBC), hemoglobin, hematocrit, white 
blood cell count (WBC) with differential

Clinical chemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
total bilirubin, creatinine

Serum pregnancy test results will be reported through listings
The clinically relevant laboratory parameter changes occurring during the study were to be 
reported as adverse events (Section 8.2.3 of the clinical study protocol). 
For purposes of the safety analysis, only numerical laboratory values (no clinical assessments) 
will be used for providing severity ranges for the laboratory data. Ranges are described in Bayer 
internal documentation [4]. Laboratory toxicities assigned by the investigator or reported as AEs 
will be documented in the AE CRFs and reported in AE tables and listings; these toxicities may 
include clinical assessments. The incidence of laboratory toxicities will be summarized in 
frequency tables.
For laboratory assessments with normal ranges, low/normal/high status will be reported in 
listings as applicable.
6.3.5
Other Safety Measures
In addition, all laboratory assessments, vital signs, and ophthalmologic examination results will 
be presented in data listings. Listings will be reported in all enrolled participants. 
7.
Document history and changes in the planned statistical analysis
SAP version 1.0, dated 23 MAY 2019. 
8.
References
1. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat 
Assoc. 53:457-81 (1958)
2. Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics. 38:29-41 (1982).


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3. Collett, D. Modelling Survival Data in Medical Research: Third Edition. CRC Press. 
(2015) p. 29.
4. Handling Laboratory Findings in Bayer Oncology Clinical Trials (Internal) 15 FEB 2019