Clinical trial NCT02369484
Conditions: NSCLC
Keywords: Stage IIIb/ IV NSCLC harbouring HER2 exon 20 mutations
Sponsor: ETOP IBCSG Partners Foundation
Start date: 2015-09-16; Completion date: 2017-09-15
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to investigate the control of disease in pretreated patients with advanced non small cell lung cancer (NSCLC) harbouring HER2 exon 20 mutations as well as the safety and tolerability (how severe the side effects are) of the treatment with afatinib.

Detailed description:
Previous clinical studies of NSCLC have shown that patients with tumors harboring specific gene mutations (changes) in the epithelial growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) showed better results after treatment with tyrosine kinase inhibitors (TKI), like afatinib (tradename Giotrif®) , compared with classical treatment with chemotherapy. The treatment with TKI has become a new standard-of-care for patient with advanced lung cancer and EGFR or ALK changes. Several novel mutations, which are candidates as targets for specific medication have been discovered. Human epidermal growth factor 2 (HER2, erbB-2/neu) is a protein of the so called ErbB family (including HER2 \[ErbB2\], ErbB3 and ErbB4). These proteins are involved in the growth and spread of cancer cells. Mutations in HER2 are found in about 2% of the NSCLC.

Afatinib works by blocking the activity of the ErbB family proteins and can inhibit growth and spread of cancer cells. Afatinib is approved by the European and the Swiss Medicines Agencies for the treatment of adult patients with a specific type of cancer of the lung (non-small cell lung cancer) that is identified by a change (mutation) in the gene for EGFR as first treatment or if prior chemotherapy treatment has been insufficient.

A total of 22 patients from centers around Europe are expected to be enrolled in this study over a period of 24 months.

All patients will be treated in the same way. The study will take approximately 40 months to be completed.

This clinical trial is conducted according to the applicable national laws and international guidelines.

Arms: arm 1: Afatinib 40 mg p.o./day until tumour progression or lack of tolerability
Interventions: intervention 1: Afatinib
Intervention descriptions: intervention 1: 40mg p.o./ day until documented progression or unacceptable toxicity

Protocol documents:
ICF_002.pdf: 
ETOP 7-14 NICHE Appendix 1: Patient Information (English)
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ETOP 7-14 NICHE
Afatinib in pretreated patients with advanced NSCLC harbouring
HER2 exon 20 mutations
1) This template Patient Information Sheet and Informed Consent has been written according
to ICH guidelines which state the Informed Consent should adhere to GCP and to the ethical
principles that have origin in the Declaration of Helsinki.
2) This template can be edited to incorporate information specific to your institution. Please
forward the edited version to the ETOP Coordinating Office for approval. Submit to the Ethics
Committee/IRB only after approval by the ETOP Coordinating Office. The final version must
have received the IRB/Local Ethics Committee approval in advance of use.
3) Following the ICH-GCP guidelines, the Informed Consent should contain information
about the following items:
a) The trial involves research
b) Purpose of the trial
c) Trial treatment(s) and the probability of random assignment
d) The subject’s responsibilities
e) The aspects of the trial that are experimental
f) Risks
g) Benefits
h) Alternative treatments available
i) Compensation/expenses
j) Subject’s participation is voluntary/right to withdraw
k) Confidentiality
l) Information about course of the trial
m) Circumstance under which trial may be terminated
n) Contact persons for further information or in case of injury
o) The approximate number of subjects involved in the trial
p) Duration of subject’s participation in the trial
q) Version number and date
4) This template has been designed to cover the above items. If the IRB/Local Ethics
Committee requires modifications, none of the above items should be completely excluded,
nor should the meaning of the highlighted areas be modified. Such modifications must be
submitted to ETOP for approval.
5) In order to assist in the preparation of your customized version, an electronic file in MS
Word will be distributed via e-mail to all Principal Investigators or ETOP members may
download it from the ETOP web site (www.etop-eu.org).


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PATIENT INFORMATION SHEET AND INFORMED CONSENT APPENDIX 1
ETOP PATIENT INFORMATION SHEET FOR CLINICAL RESEARCH
Dear patient,
You are being asked to participate in a clinical research study. The doctors at
different centers of the European Thoracic Oncology Platform (ETOP) and in other
cooperative groups or centers throughout the world study the nature of lung cancer
and attempt to develop improved methods of diagnosis and treatment. This is called
clinical research. In order to decide whether or not you should agree to be part of this
research study you should understand enough about its risks and benefits to make
an informed judgment. Your participation in this research study is entirely voluntary
and you will be given sufficient time to decide whether you wish to participate. This
process is known as Informed Consent.
This Patient Information Sheet gives detailed information about the research study,
which your doctor will discuss with you. Once you understand the study, if you wish
to participate, you will be asked to sign the Patient Informed Consent. You will have a
copy of this document and of the Patient Informed Consent to keep as a record.
The clinical research study being proposed to you is:
ETOP 7-14 NICHE
Afatinib in pretreated patients with advanced NSCLC harbouring
HER2 exon 20 mutations
PURPOSE OF THE RESEARCH STUDY
You have been diagnosed with a type of lung cancer that is called “non small cell
lung cancer (NSCLC)”. Your lung cancer has recently relapsed despite previous
treatment with chemotherapy. Relapsed means that, despite treatment, the cancer is
growing. Your doctor has decided that further treatment of your cancer is necessary.
Previous clinical studies of NSCLC have shown that patients with tumors harboring
specific gene mutations (changes) in the epithelial growth factor receptor (EGFR) or
anaplastic lymphoma kinase
(ALK) showed better results after treatment with
tyrosine kinase inhibitors (TKI), like afatinib
(tradename Giotrif®) , compared with
classical treatment with chemotherapy. The treatment with TKI has become a new
standard-of-care for patient with advanced lung cancer and EGFR or ALK changes.
Several novel mutations, which are candidates as targets for specific medication
have been discovered. Human epidermal growth factor 2 (HER2, erbB-2/neu) is a
protein of the so called ErbB family (including HER2 [ErbB2], ErbB3 and ErbB4).
These proteins are involved in the growth and spread of cancer cells. Mutations in
HER2 are found in about 2% of the NSCLC.
Afatinib works by blocking the activity of the ErbB family proteins and can inhibit
growth and spread of cancer cells.


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The aim of the current study is to investigate the control of disease in pretreated
patients with advanced NSCLC harbouring HER2 exon 20 mutations as well as the
safety and tolerability (how severe the side effects are) of the treatment with afatinib.
Afatinib is approved by the European and the Swiss Medicines Agencies for the
treatment of adult patients with a specific type of cancer of the lung (non-small cell
lung cancer) that is identified by a change (mutation) in the gene for EGFR as first
treatment or if prior chemotherapy treatment has been insufficient.
A total of 22 patients from centers around Europe are expected to be enrolled in this
study over a period of 24 months. In country it is planned that xx patients will take
part. All patients will be treated in the same way. The study will take approximately 40
months to be completed.
This clinical trial is conducted according to the applicable national laws and
international guidelines. The trial has been approved by the independent Ethics
Committee concerned insert name of the Ethics Committee.
DESCRIPTION OF THE CLINICAL RESEARCH STUDY
If you decide to participate in the study and meet the criteria to take part in the study,
you will receive the following treatment:
Afatinib 40 mg orally, daily. You will take afatinib tablets every day. Tablets should be
taken at a fixed time each day and at least 1 hour before or 3 hours after the
ingestion of food.
Inpatient admission into a hospital is not envisaged, but can potentially become
necessary.
In order to determine if you can participate in this trial a piece of your tumor, that has
been removed at the time of diagnosis, must be available for later central review of
HER2 mutation
You will have a full medical history taken, physical examination, radiological and lab
workout performed at the time you enter the study. If you are a female of child-
bearing potential, a pregnancy test will be done.
During the study treatment, you must visit your treating physician every 3 weeks for
the first 12 weeks, then every 4 weeks for a physical examination. Please take with
you all empty, full and partly used boxes of afatinib tablets. Routine blood and urine
analyses including liver and kidney function will be carried out every 3 or 4 weeks
respectively, as part of standard medical routine. If you develop side effects, more
frequent examinations may be necessary.
Your physician will document your general condition and all hospital stays during the
clinical trial. He/she will similarly ask you about all side effects, which you
experienced and about all medications or treatments, which you received since your
last visit.
To determine the status of your lung cancer and effects from the treatment,
radiological examinations (computer tomography (CT) of the chest) will be conducted
every 6 weeks (week 6 and 12) and later every 8 weeks until your tumour grows


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again. These examinations are carried out as part of medical routine and can be
performed more frequently, if your treating physician considers this appropriate.
Your doctor may suggest other tests, such as CT of the brain. The regular doctor’s
visits are part of your standard medical care and are handled the same way as if you
did not take part in the study.
If you participate in the study, you should follow the instructions of your treating
physician, follow the schedule of treatment visits, record on the patient diary the
afatinib tablets taken, inform your physician of any new signs and symptoms, and any
non-study medication you take.
VOLUNTARY PARTICIPATION/RIGHT TO REFUSE OR WITHDRAW
Your participation in this research study is entirely voluntary. If you decide not to
participate in the study, this will not affect your medical care in any way. If you begin
the study, you will have the right to withdraw at any time without giving any reason.
This will not affect your future medical assistance. You will be asked to have a final
examination before you withdraw and you will be advised for other available care
which suits your needs and medical condition. If you should withdraw, data already
collected until then will be used for analysis.
RISKS AND DISCOMFORTS
While you receive protocol treatment, you are at risk of side effects. Your physician
will be checking you closely to see if any of the side effects are occurring. You should
report any side effect or symptom that you experience to your physician. Other drugs
may be given to make some of these side effects less serious and uncomfortable.
Afatinib side effects:
Very common (≥10%):
• Diarrhoea
• Skin rash
• Mouth sores and inflammation
• Nail infection
• Decreased appetite
• Bleeding from the nose
Common (1 – 10%):
• Pain, redness, swelling or peeling of the skin of your hands and feet
• Increased levels of the liver enzymes in blood tests.
• Inflammation of the lining of the bladder
• Abnormal taste sensations (dysgeusia)
• Stomach pain, indigestion, heartburn
• Lip inflammation
• Decreased weight
• Runny nose
• Muscle spasms
• Fever
Rare (< 1%)
• Inflammation of the lungs called “interstitial lung disease”
• Eye irritation or inflammation


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Your physician will be checking you closely to see if any of these side effects are
occurring. Your doctor may prescribe medication to keep these side effects under
control.
You should tell your doctor:

If you have diarrhoea lasting more than 2 days. Diarrhoea may lead to fluid
loss (common, may affect up to 1 in 10 people), low blood potassium
(common) and worsening kidney function (common). Diarrhoea can be
treated. At the first signs of diarrhoea drink plenty of fluids. You should have
antidiarrhoeal medicine available prior to taking afatinib.

If a rash starts. If treatment for rash is not working and the rash is getting more
severe (for example, you have peeling or blistering of the skin) you should
notify your doctor immediately, since your doctor may decide to stop your
treatment with afatinib. Rash may occur or worsen in areas exposed to sun.
Sun protection with protective clothing and sunscreen is recommended.

If you develop new or sudden worsening of shortness of breath, possibly with
a cough or fever.

If you have sudden onset or worsening of eye symptoms such as pain or
redness or dry eye.
Pregnancy/Birth Control:
All women who participate in the trial and are able to become pregnant must use
effective contraception while they receive study medication.
You will not be allowed to enter this study if you are pregnant, plan to become
pregnant, or if you are breastfeeding. This is because the effects of the study drug on
an unborn baby or nursing infant are uncertain. While you are taking afatinib tablets
and for at least 28 days after the last dose you will also be asked to use one of the
required contraceptive methods (a way to prevent you from becoming pregnant).
Your doctor will discuss with you which methods constitute effective contraception.
If you become pregnant, you must tell your study doctor immediately so that he/she
may discuss with you the possibility of stopping study treatment.
Your doctor will
need to report this information and the outcome of your pregnancy to the ETOP
safety office.
If you are a man whose partner can get pregnant, you and your partner will need to
use birth control during afatinib treatment and for at least 1 month after the last dose.
If your partner becomes pregnant while you are receiving study medication, tell your
study doctor immediately as they will need to report the outcome of the pregnancy to
the ETOP safety office.
BENEFITS
The ultimate goal of conducting clinical research studies in lung cancer patients is to
better understand the behaviour of cancer and to find better ways of treatment. We
hope that the treatment under this clinical research study will be of benefit to you
and/or that it will help others, although we cannot guarantee this.


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ALTERNATIVE TREATMENTS
Instead of being in this study, your doctor may recommend that you receive other
form of treatment or chemotherapy not given as part of this study.
EXPENSES / REMUNERATION
Afatinib will be provided free of charge by Boehringer Ingelheim
All other expenses, for example, routine standard examinations, will be handled as if
you were receiving standard treatment and not participating in the clinical study.
You will receive no payment for taking part in this study.
INSURANCE
ETOP has concluded the appropriate liability insurance for this study (insert policy
number if required according to local guidelines). Patients, who may suffer injuries
due to the study, should report it immediately to their doctor, who will take the
necessary steps.
CONFIDENTIALITY
The researchers will need to collect personal information from you such as your age,
gender and relevant health information. All information collected is coded in a way
that without a key it will not be possible to link the information to your person.
Any personal or health information that is collected will be kept private and
confidential. It will be stored securely. Only authorised persons, who understand that
it must be kept confidential, will be able to get access to it. In any report of the
research made available to the public you will not be referred to by name.
Representatives of the project sponsor, ethics committees or drug regulatory
agencies may require access to personal or health information contained in your
medical records to verify clinical trial procedures and/or data. Your personal data will
be stored in a database and evaluated at ETOP Coordinating Office. ETOP
guarantees that the national and international data protection guidelines are
respected.
COLLECTION OF BIOLOGICAL MATERIAL
About Using Tissue for Research
In order for you to participate in this study, we need to be sure of the type of lung
cancer that you have. Your doctor will be required to send a sample of tumour that
was collected either when you were first diagnosed or when you had the relapse to a
central laboratory at the Medical University of Gdansk, Poland. The central laboratory
performs a pathology review and tests the sample of your tumour for the HER2
mutation.
In addition, we would like to keep this tissue for future research. If you allow the use
of this tissue, it will be kept at the central laboratory at the Medical University of


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Gdansk, Poland and used under the responsibility of the Foundation Council of the
ETOP.
Your tissue will be very helpful for future research. The research that may be done
with your tissue is not designed specifically to benefit you. It may have an impact on
the choice of a specific treatment for this type of lung cancer for others. By
broadening the knowledge about lung cancer, it might help other patients.
The research will not have an effect on your medical care. We will not examine if
cancer is hereditary in your family. In the unlikely case that information relevant to
you comes up in the future, we will contact your doctor.
The choice to let us keep the left over tissue for future research is up to you. No
matter what you decide to do, your choice will in no way affect the quality of
your care.
If you decide now to allow ETOP to use your tissue for research, you can change
your mind at any time. Just contact your doctor and let him/her know that you do not
want ETOP to use your tissue any longer. Then, any tissue that remains will be sent
back to the pathologist at your hospital.
The ultimate goals of research using tissue include learning more about what causes
lung cancer or other diseases, how to prevent it, and how to treat it.
There are no risks related to research with your tissue. We will make sure that your
personal information will be kept private.
TERMINATION OF THE STUDY
You might stop receiving study treatment without your consent for the following
reasons:
a) If your lung cancer worsens or a new tumour develops.
b) If the doctors treating you detect side effects that they consider dangerous.
c) If you refuse to have the treatments or follow-up examinations and tests
needed to determine whether the treatment is safe and effective.
d) If the early analyses of study data show insufficient benefit or a significant
potential harm of the treatment.
e) If the sponsor ETOP decided to stop the study.
NEW INFORMATION ARISING FROM THIS AND OTHER STUDIES
You have the right to be informed of the progress of the research study and of its final
results. You have also the right to be informed of all additional results of other
studies, which might be important for your treatment or might affect your willingness
to continue.
CONTACT PERSONS
The physician in charge of this study is (give name, telephone number of PI). If you need
more information about this study before you decide to join, or at any other time, you
may wish to contact him/her. In the event that you do decide to participate, he/she
should also be called if there are severe side effects from the treatment.


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PATIENT INFORMED CONSENT FOR CLINICAL RESEARCH
TITLE: ETOP 7-14 NICHE
Afatinib in pretreated patients with advanced NSCLC harbouring HER2 exon 20
mutations
STATEMENT OF PHYSICIAN OBTAINING INFORMED CONSENT
I have fully explained this clinical research study to the patient
____________________.
In my judgment, and that of the patient, there was sufficient access to information,
including risks and benefits, to make an informed decision.
DATE: _____________________
PHYSICIAN’S SIGNATURE:
______________________________________________
PHYSICIAN’S NAME:
____________________________________________________
PATIENT’S STATEMENT
I confirm that I have read and understood this Patient Information Sheet dated dd-
mmm-yyyy for the ETOP 7-14 NICHE study. I had the opportunity to discuss the
clinical study with the undersigning physician, ask questions and I am satisfied with
the answers that I have received.
I understand the purposes, procedures and risks of this research project as described
in the Information Sheet.
I was informed about alternative treatment options.
I had sufficient time to take the decision.
I take note that a sample of my tumour tissue will be collected, sent to the central
laboratory at the Medical University of Gdansk, Poland, and used for the purpose of
quality assurance (central pathology review) and review of HER2 mutation status.
I take note that future cancer research with my biological material will only be done
after approval by the relevant ethics committee.
Please choose one:
□
I allow the use of my tissue sample for future cancer research.
□
I do not allow the use of my tissue sample for future cancer research.
I take note that any research will be such that my privacy will be fully protected
I am informed that an injury as a result of participating in this research project is
covered by an insurance.
I agree that my General Practitioner will be informed of my participation in this study
I freely agree to participate in this project according to the conditions in the Patient
Information Sheet. I understand that I withdraw my consent any time without giving
any reasons and that this will not affect my future medical care.


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I understand that my personal data leaves the hospital only in anonymised form and
that the researchers will not reveal my identity and personal details if information
about clinical study is published. For quality control and inspections I give permission
to individuals from ETOP, to staff from the health authorities and ethics committees
for to have access to my medical records. In such cases personal information will
always remain confidential.
I am aware that the procedures and restrictions described in the Patient Information
Sheet have to be followed.
In the interest of my personal health the researcher can take me off the study.
I have received a copy of the Patient Information Sheet and Consent.
DATE: ______________________ [Date must be written by the patient]
PATIENT’S SIGNATURE:_______________________________________________
PATIENT’S NAME: ____________________________________________________
PATIENT’S DATE OF BIRTH:____________________________________________
Patient ID number assigned at randomization:_______________________________
PLEASE KEEP A COPY OF THE SIGNED INFORMED CONSENT. DO NOT SEND
THE SIGNED INFORMED CONSENT FORM TO ETOP.

Prot_001.pdf: 
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ETOP 7-14 NICHE
Afatinib in pretreated patients with advanced NSCLC harbouring HER2
exon 20 mutations
NICHE = afatinib in NSCLC with HER2 mutation
Sponsor: European Thoracic Oncology Platform (ETOP)
EudraCT number: 2014-005098-35
Boehringer number: 1200.230
ETOP c/o IBCSG Coordinating Center, Effingerstrasse 40, CH- 3008 Bern
Phone: +41 31 389 93 91
Fax: +41 31 389 93 92
Version 1.0


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Contacts
Trial Chair
Solange Peters, MD-
PhD
Address
Tel:
Fax:
Email:
Département d'Oncologie
Centre Hospitalier Universitaire Vaudois
1011 Lausanne, Switzerland
+41 79 556 01 92
+41 21 314 67 89 (assistant)
+41 21 314 07 37
solange.peters@etop-eu.org
Trial Chair
Rafal Dziadziuszko,
MD
Address
Tel:
Fax:
Email:
Dept. of Oncology and Radiotherapy
Medical University of Gdansk
7, Debinki Str.
80-211 Gdansk, Poland
+48 58 349 29 79
rafald@gumed.edu.pl
ETOP Chairman
Rolf Stahel, MD
Address
Tel:
Fax:
Email:
Laboratory of Molecular Oncology
Clinic of Oncology
University Hospital Zuerich
Häldeliweg 4
CH-8044 Zürich, Switzerland
+41 44 634 28 71
+41 44 634 28 72
rolf.stahel@usz.ch
Statistics
Urania Dafni, ScD
Zoi Tsourti, PhD
Address
Tel:
Fax:
Email:
Frontier Science Foundation - Hellas
118-120 Papadiamantopoulou Str.
15773, Zografou, Athens, Greece
+302107710902
+302107710903
udafni@frontier-science.gr
ztsourti@frontier-science.gr
Trial Manager
Data Management
Viktor Zsuffa
Anne-Christine
Piguet, PhD
Address
Tel:
Fax:
Email:
ETOP Coordinating Office
c/o IBCSG Coordinating Centre
Effingerstrasse 40
3008 Bern, Switzerland
+41 31 389 9221/+41 31 389 9187
+41 31 389 92 29
NICHE@etop-eu.org
Drug supply
Barbara Ruepp,
PharmD
Address
Tel:
Fax:
Email:
ETOP Drug Supply Office
c/o IBCSG Coordinating Centre
Effingerstrasse 40
3008 Bern, Switzerland
+41 31 389 93 91
+41 31 389 92 29
drugsupply@etop-eu.org
Safety and Regulatory
Affairs
Barbara Ruepp,
PharmD
Address
Tel:
Fax:
Email:
ETOP Safety and Regulatory Office
c/o IBCSG Coordinating Centre
Effingerstrasse 40
3008 Bern, Switzerland
+41 31 389 93 91
+41 31 389 92 29
regulatoryoffice@etop-eu.org


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ETOP Coordinating
Office
Anita Hiltbrunner
Rudolf Maibach,
PhD
Susanne Roux
Address
Tel:
Fax:
Email:
c/o IBCSG Coordinating Centre
Effingerstrasse 40
3008 Bern, Switzerland
+41 31 389 93 91
+41 31 389 92 29
anita.hiltbrunner@etop-eu.org
rudolf.maibach@etop-eu.org
susanne.roux@etop-eu.org
NICHE@etop-eu.org
Remote Data Entry
system
tbd
Technical assistance
NICHE@etop-eu.org
richard.king@etop-eu.org
Reference Lab for
Her2 mutation testing
Bartosz Wasag, PhD
Address
Tel:
Fax:
Email:
Dept. of Biology and Genetics
Medical University of Gdansk
1 Debinki Str., 80-210 Gdansk, Poland
+48 58 349 15 32
+48 58 349 15 35
bwasag@gumed.edu.pl
In collaboration with Boehringer Ingelheim Pharma GmbH & Co. KG


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Protocol Signature Page
Afatinib in pretreated patients with advanced NSCLC harbouring HER2
exon 20 mutations
ETOP 7-14 NICHE
Approved by:
Solange Peters
Trial Co-Chair
___________________________________________________
__________
Date
Rafal Dziadziuszko
Trial Co-Chair
___________________________________________________
__________
Date
Rolf Stahel
ETOP Chairman
___________________________________________________
__________
Date
Urania Dafni
Biostatistician
___________________________________________________
__________
Date


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Principal Investigator Protocol Signature Page
Afatinib in pretreated patients with advanced NSCLC harbouring HER2
exon 20 mutations
ETOP 7-14 NICHE
I have read the protocol and agree that it contains all necessary details for conducting this
trial. I will conduct the trial as outlined in the following protocol and in compliance with
GCP, and will apply due diligence to avoid protocol deviations. I will provide copies of the
protocol and all drug information relating to pre-clinical and prior clinical experience
furnished to me by ETOP, to all physicians responsible to me who participate in this trial. I
will discuss this material with them to assure that they are fully informed regarding the drug
and the conduct of the trial. I agree to keep accurate records on all patient information
including patient's informed consent statement, drug shipment and return forms, and all
other information collected during the trial for a minimum period of 15 years.
Name of Principal Investigator:___________________________________________
Institution’s name and place:___________________________________________
_____________________________________________________ ______________
Signature
Date


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TABLE OF CONTENTS
Section
Page
1.
Protocol Summary .....................................................................................................9
2.
Trial schedule...........................................................................................................13
3.
List of abbreviations ................................................................................................14
4.
Background and Rationale.......................................................................................16
4.1.
Disease background.............................................................................................16
4.2.
Targeted agents in non-small cell lung cancer ....................................................16
4.3.
HER2 ...................................................................................................................17
4.4.
Afatinib................................................................................................................18
4.5.
Rationale for trial design .....................................................................................19
4.6.
Overall Risk/Benefit Assessment ........................................................................19
5.
Objectives and endpoints.........................................................................................20
5.1.
Primary objective.................................................................................................20
5.2.
Secondary objectives ...........................................................................................20
5.3.
Primary endpoint .................................................................................................20
5.4.
Secondary endpoints............................................................................................20
6.
Trial design, duration and termination.....................................................................20
7.
Patient selection.......................................................................................................21
7.1.
Inclusion criteria for enrolment...........................................................................21
7.2.
Exclusion criteria for enrolment..........................................................................23
8.
Patient screening and enrolment..............................................................................24
8.1.
Screening .............................................................................................................24
8.2.
HER2 mutation testing.........................................................................................25
8.3.
Enrolment ............................................................................................................25
8.4.
Start of afatinib....................................................................................................25
9.
Investigational product ............................................................................................25
9.1.
Summary of the safety profile .............................................................................25
9.2.
Adverse Events of Special Interest......................................................................28
10.
Trial treatment .........................................................................................................28
10.1.
Administration.....................................................................................................28
10.2.
Delay and dose modification for toxicity ............................................................29
11.
Management of adverse events, concomitant therapy, restrictions and rescue
treatment ..................................................................................................................30
11.1.
Rescue medication, emergency procedures, and additional treatment(s)............30
11.2.
Management of expected adverse events ............................................................31
11.3.
Management of diarrhoea and dehydration.........................................................31
11.4.
Management recommendations for dermatological AEs ....................................32
11.5.
Management of mucositis/stomatitis...................................................................35
11.6.
Restrictions..........................................................................................................36
11.7.
Women of Child-Bearing Potential and Pregnancy Prevention..........................37
11.8.
Treatment compliance .........................................................................................38
11.9.
Treatment duration ..............................................................................................38
12.
Adverse events and reporting ..................................................................................39
12.1.
Adverse event reporting.......................................................................................39
12.2.
Definition of Serious Adverse Event (SAE)........................................................40
12.3.
Definition of Serious Adverse Reaction (SAR) ..................................................41


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12.4.
Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR)........41
12.5.
Reporting SAEs and Adverse Events of Special Interest....................................41
12.6.
Pregnancy ............................................................................................................42
13.
Response evaluation ................................................................................................43
13.1.
RECIST 1.1 criteria.............................................................................................43
13.2.
Determination of time point response .................................................................43
13.3.
Determination of best overall response ...............................................................43
14.
Endpoints definition.................................................................................................44
14.1.
Disease control ....................................................................................................44
14.2.
Progression-free survival.....................................................................................44
14.3.
Objective response...............................................................................................44
14.4.
Overall survival ...................................................................................................44
14.5.
Toxicity................................................................................................................44
15.
Trial procedures.......................................................................................................44
15.1.
Baseline evaluations (within 28 days prior to enrolment)...................................44
15.2.
At trial treatment start visit..................................................................................45
15.3.
During first 3 weeks of afatinib treatment...........................................................45
15.4.
Every visit during afatinib treatment...................................................................45
15.5.
Imaging................................................................................................................46
15.6.
End of treatment visit ..........................................................................................46
15.7.
Follow up after treatment stop, before progression.............................................46
15.8.
Follow up after progression.................................................................................47
16.
Case report forms and documentation.....................................................................47
16.1.
Case report forms schedule..................................................................................47
17.
Statistical considerations .........................................................................................48
17.1.
Primary objective.................................................................................................48
17.2.
Sample size determination...................................................................................48
17.3.
Evaluation of primary and secondary objectives.................................................49
17.4.
Early stopping rules.............................................................................................49
18.
Criteria for termination of the trial ..........................................................................50
18.1.
General criteria for termination of the trial .........................................................50
18.2.
Discontinuation of protocol treatment for individual patients.............................50
18.3.
Withdrawal of consent.........................................................................................50
19.
Ethics aspects, regulatory approval, and Patient Informed Consent........................51
19.1.
Ethical Review Board/Ethics Committee............................................................51
19.2.
Regulatory approval procedures..........................................................................51
19.3.
Informed consent .................................................................................................51
20.
Governance and administrative issues.....................................................................52
20.1.
Final report ..........................................................................................................52
20.2.
Steering Committee.............................................................................................52
20.3.
Independent Data Monitoring Committee...........................................................52
20.4.
Publication...........................................................................................................52
20.5.
Clinical trial insurance.........................................................................................53
20.6.
Quality Assurance................................................................................................53
20.7.
Protocol adherence ..............................................................................................53
20.8.
Data protection ....................................................................................................53
20.9.
Record Retention.................................................................................................54
21.
References................................................................................................................55


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Appendices:
1. Template for patient information and informed consent form
2. RECIST criteria V1.1
Index of tables:
Table 1.
ECOG Performance Status..................................................................................23
Table 2.
NYHA functional classification..........................................................................24
Table 3.
Summary of ADRs per frequency category........................................................26
Table 4.
Very common ADRs in trial LUX-Lung 3.........................................................27
Table 5.
Dose reduction scheme for afatinib ....................................................................29
Table 6.
Grade specific treatment recommendations for afatinib related diarrhoea.........32
Table 7.
General recommendations for prophylaxis while receiving afatinib..................33
Table 8.
Grade specific treatment recommendations of skin reactions to afatinib ...........33
Table 9.
Grade specific treatment recommendations of trial-drug related
mucositis/stomatitis.............................................................................................36
Table 10.
List of potent inhibitors and inducers of P-glycoprotein (MDR1)......................37
Table 11.
Determination of time point response.................................................................43
Table 12.
Case report forms................................................................................................47


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1.
Protocol Summary
ETOP 7-14 NICHE – Afatinib in pretreated patients with advanced
NSCLC harbouring HER2 exon 20 mutations
Sponsor: European Thoracic Oncology Platform (ETOP)
Pharma Partner: Boehringer Ingelheim Pharma GmbH & Co. KG
Population: Advanced stage NSCLC, harbouring HER2 exon 20 mutations.
Design: Phase II single-arm multicenter trial
Sample size: 22 patients
Rationale:
Human cancers usually evolve through multistep processes. These processes are driven by
the accumulation of abundant genetic and epigenetic abnormalities. However, some lung
cancers depend on a single activated oncogene by somatic mutation, termed “driver
oncogenic mutations”, for their proliferation and survival. EGFR mutations and ALK
rearrangement are typical examples of such driver oncogenic mutations found in lung
adenocarcinomas. EGFR-tyrosine kinase inhibitors (TKIs) like erlotinib, gefitinib or afatinib
or ALK-TKIs, like crizotinib, ceritinib or alectinib, significantly improved treatment
outcomes compared with conventional cytotoxic chemotherapy in patients with lung cancers
harboring EGFR mutations or ALK-rearrangement, respectively.
Human epidermal growth factor 2 receptor (HER2, erbB-2/neu) is a member of the erbB
receptor tyrosine kinase family. The ERBB2 gene which encodes for HER2 is a major
proliferative driver that activates downstream signaling through PI3K-AKT and MEK-ERK
pathways. No ligand has been described for this receptor, which is activated by homo-
dimerization or hetero-dimerization with other members of the erbB family.
HER2 mutations consist of in-frame insertions in exon 20, leading to constitutive activation
of the receptor and downstream AKT and MEK pathways. HER2 mutations respond to the
genetic « driver » and preclinical models have proved the concept of transforming property
Stage
IIIB / IV
NSCLC,
pretreated
HER2
mutation
confirmed
locally
CT T&A
CT or MRI brain
Trial treatment
Screening, eligibility
and enrolment
Afatinib 40mg daily p.o.
until PD or unacceptable toxicity
CT week 20, then every 8 weeks until PD
For 6 months
after enroll-
ment of last
patient
Progression
Follow up
…….
…….
CT
week 6
CT
week 12


ETOP 7-14 NICHE V 1.0 01Dec2014
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of such a genetic alteration. Inducible expression of a HER2 mutant (HER2YVMA) in lung
epithelium of mice results in the emergence of invasive adenosquamous carcinomas, with
tumour maintenance requiring the continuous expression of the driver, as observed with
EGFR-driven cancer.
HER2 protein overexpression and gene amplification are present in 6–35% and in 10-20%,
respectively, of NSCLC. HER2 mutations were identified in about 2-4% of NSCLC. In the
selected population of EGFR/KRAS/ALK negative patients, HER2 mutations can reach up
to
6%.
This
mutation
is
predominantly
observed
in
females,
non-smokers
and
adenocarcinoma subtype, similar to EGFR mutated NSCLC. HER2 mutations have never
been observed concomitantly with EGFR mutations or ALK rearrangement.
Among reported lung cancer biomarkers, HER2 as a target remains poorly described. HER2
overexpression or gene amplification is widely known to be associated with sensitivity to
HER2-targeting drugs (trastuzumab, lapatinib, pertuzumab and T-DM1) in breast cancer.
Involvement of HER2 in lung carcinogenesis has been known for many years, but clinical
research was slowed down when the first clinical trials with trastuzumab were negative.
Indeed, the addition of trastuzumab to gemcitabine-cisplatin or to docetaxel failed to show
any survival benefit in HER2 Immuno-Histo-Chemistry-positive (IHC) lung cancer patients.
However, HER2 mutations may be more relevant in lung carcinogenesis than HER2
amplification or overexpression.
Afatinib (BIBW2992) is a small molecule, selective and irreversible erbB family blocker. In
preclinical models it effectively inhibits EGFR, HER2 and HER4 phosphorylation resulting
in tumour growth inhibition and regression of established subcutaneous tumours derived
from four human cell-lines known to co-express ErbB receptors.
HER2 mutations are identified in about 2% of non-small-cell lung cancers (NSCLC) and
appear to be critical for lung carcinogenesis. There are very few data available that describe
the clinical course of HER2 mutated NSCLC patients. Mazieres and colleagues recently
retrospectively identified 65 NSCLC patients diagnosed with a HER2 in-frame insertion in
exon 20. The HER2 mutation was almost an exclusive driver, except one single case with a
concomitant KRAS mutation. All tumours were adenocarcinomas and 50% were stage IV at
diagnosis. For these latter cases, 22 anti-HER2 treatments were administered after
conventional chemotherapy in 16 patients. Subsequently, four progressive disease, seven
disease stabilizations and eleven partial responses (overall response rate ORR 50%; disease
control rate DCR 82%) were observed. Specifically, they observed a DCR of 93% for
trastuzumab-based therapies (n = 15), 100 % DCR for afatinib (n = 3), but no response to
other HER2-targeted drugs (n = 3). Progression free survival for patients with HER2-
therapies was 5.1 months. Median survival was of 89.6 and 22.9 months for early stage and
stage IV patients, respectively. This study, the largest to date dedicated to HER2-mutated
NSCLC,
reinforced
the
importance
of
screening
for
HER2-mutations
in
lung
adenocarcinomas, and suggested the potential efficacy of HER2-targeted drugs in this
population. Additionally, single case reports suggest that HER2 mutations may be predictive
for HER2 targeting therapies in lung cancer. Some ongoing clinical trials are enrolling
patients with HER2 mutated NSCLC, mixed together with HER2 amplified or EGFR


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mutated NSCLC cases. Large biomarker screening programs such as the French National
Program or the US Lung Cancer Mutation Consortium (LCMC) thus propose testing for
HER2 mutations.
Afatinib presents a manageable toxicity profile and potentially offers a significant activity in
terms of disease control and long term outcome. Therefore this treatment option offers a
good benefit to risk ratio in patients with HER2-mutated advanced NSCLC.
Objectives and endpoints:
The primary objective is to evaluate the ability of afatinib to control disease in pretreated
patients with advanced NSCLC harbouring HER2 exon 20 mutations.
Primary endpoint: disease control at 12 weeks
Secondary endpoints:

Progression-free survival by RECIST 1.1

Objective response determined by RECIST 1.1

Overall survival

Adverse events graded according to CTCAE V4.0
Most important eligibility criteria (see protocol section 7 for complete list):
Inclusion criteria at enrolment:

Histologically or cytologically confirmed, non-predominant squamous subtype,
stage IIIB (non amenable to curative-intent multimodal treatment) or IV NSCLC,
according to 7th TNM classification

Tumour is platinum-refractory

Measurable or evaluable disease (according to RECIST 1.1 criteria)

Locally documented HER2 mutation

Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

Life expectancy >3 months

Adequate haematological, renal and hepatic function

Effective contraception, no pregnancy
Exclusion criteria at enrolment:

Mixed small-cell and non-small-cell histologic features

Uncontrolled lepto-meningeal metastatic disease

Previous treatment with HER2 targeted antibody or tyrosine kinase inhibitor

Any previous (in the past 3 years) or concomitant malignancy EXCEPT adequately
treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix
or bladder, in situ ductal carcinoma of the breast

History or presence of clinically relevant cardiovascular abnormalities

Other serious diseases or clinical conditions, including but not limited to
uncontrolled active infection and any other serious underlying medical processes that
could affect the patient’s capacity to participate in the trial

Interstitial lung disease or pulmonary fibrosis

Any concurrent systemic anticancer therapy


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Treatment:
Afatinib 40 mg p.o./day until tumour progression or lack of tolerability
Statistical considerations:
Simon’s two stage phase II design is adopted. A Disease Control Rate (DCR) of 50% is
considered as unacceptable, targeting a DCR of 75%. Hence the null hypothesis under
consideration is that the DCR≤50% versus the alternative that DCR≥75%. For a one-sided
type I error of 10% and power of 80%, a total of 22 patients are needed, with 9 patients in
the first stage. If in the first stage, 6 out of the 9 patients achieve Disease Control, then the
trial will proceed to the second stage and recruit an additional 13 patients for a total of 22
patients. If at least 14 out of the 22 patients achieve Disease Control, then this finding will
indicate that it would be reasonable to proceed to a Phase III trial.
Total trial duration: 40 months from enrolment of the first patient, including 6 months of
follow-up from enrolment of the last patient.


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2.
Trial schedule
(refer to section 15 for details)
Screening
and eligibi-
lity within
28 days prior
to enrolment
Afatinib
treatment
visits13
End of treat-
ment visit
(within 30
days after
treat. stop
Follow-
up before
progress-
ion14
Follow-
up after
progress-
ion14
Written informed consent 1
X
Medical history
X
Physical exam 2, PS, weight
X
X
X3
Local HER2-testing 15
X
Haematology (WBC, haemoglobin,
platelets, neutrophils)
X4
X
X
Chemistry: Na, K, calcium, albumin,
magnesium
X4
X5
X
Renal function: serum creatinine,
calculated creatinine clearance
X
X
X
Hepatic function: ALT, AST,
bilirubin, GGT
X
X
X
Electrocardiogram
X
Pregnancy test if applicable 6
X
X
CT thorax and upper abdomen7
X
X
X8
X9
Brain MRI or CT
X
FFPE block (or 5-10 slides) from
(primary or metastatic) biopsy for
retrospective central HER2-testing
X10
Adverse events11
X
X12
X
X
X
Record concomitant medication11
X
X
X
X
Afatinib 40mg p.o. daily until PD
X12
Survival status
X
1 –
Any time before any trial-specific intervention
2 –
Physical exam according to local standards, including blood pressure
3 –
Blood pressure does not need to be reported at end of treatment visit.
4 –
If haematology and/or chemistry were done more than 7 days prior to first dose, they need to be repeated before
starting afatinib treatment.
5 –
Will be repeated if clinically indicated according to local standards
6 –
Women of childbearing potential (< 1 year without menstruation or < 2 years without menstruation following
chemotherapy) must have a negative serum or urine pregnancy test before enrolment to the trial; the test has to be
repeated within 7 days before starting afatinib treatment. Pregnancy tests should be repeated within 30 days after
afatinib treatment stop. Any pregnancy occurring during treatment or within 6 months after treatment stop must be
reported including its outcome.
7 –
All patients must have a CT thorax and upper abdomen at baseline during screening, 6 and 12 weeks after first dose
of trial treatment and then every 8 weeks (weeks 20, 28, 36 etc) until progression.
8 –
CT to be repeated if not done within 6 weeks prior to end of treatment visit.
9 –
In case of treatment stop for reason other than progressive disease, CT needs to be repeated every 8 weeks until
progression.
10 – Tissue collection for central histological subtype pathology review; mutation for HER2; potential future translational
research.
11 – Symptoms present at baseline will be recorded on the adverse event form as well from date of informed consent. In
follow-up, AEs and concomitant medication will be recorded until 90 days after stop of trial treatment.
12 – During the first cycle of 3 weeks, regular contact with patient to monitor adverse events, especially diarrhea (phone
contact allowed).
13 – Visits will be planned at start of treatment (week 0), week 3, 6, 9, 12 and then every 4 weeks. Patient diary should be
checked and tablets returned should be counted.
14 – Follow-up visits after treatment stop, before progression: every 8 weeks, coinciding with imaging visits; after
progression, record survival status every 3 months until 6 months after inclusion of the last patient.
15 – Can be from mutation test done prior to screening phase.


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3.
List of abbreviations
ADL
Activities of Daily Living
ADR
Adverse Drug Reaction
AESI
Adverse event of special interest
ALK
Anaplastic Lymphoma Kinase
ALT
Alanine transaminase
AST
Aspartate transaminase
AUC
Area Under the Curve
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease Control Rate
DILI
Drug-induced liver injury
DSUR
Development Safety Update Report
ECOG
Eastern Cooperative Oncology Groupe
eCRF
Electronic Case Report Form
EEA
European Economic Area
EGFR
epidermal growth factor receptor
EOT
End of Treatment
ERB
Ethical Review Board
FFPE
Formalin fixed, paraffin embedded
FISH
Fluorescence in situ Hybridization
GCP
Good Clinical Practice
GGT
Gamma Glutamyl Transferase
HER2/ ERBB2
Human Epidermal growth factor 2 Receptor
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
IC
Informed Consent
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Institutional Ethics Committee
IHC
Immunohistochemistry
ILD
Interstitial Lung Disease
IP
Investigational Product
IRB
Institutional Review Board
IUD
Intrauterine Device
KRAS
Kirsten Rat Sarcoma
LCMC
Lung Cancer Mutation Consortium
MEK-ERK
Mitogen-Activated Protein Kinase/Extracellular-Signal Regulated Kinase


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MRI
Magnetic Resonance Imaging
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer
NYHA
New York Heart Association
ORR
Objective Response Rate
OS
Overall Survival
PCR
Polymerase Chain Reaction
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression Free Survival
P-GP
Permeability Glycoprotein
PIK-AKT
Phosphatidylinositide 3-Kinases and Protein Kinase B
PK
Pharmacokinetics
PR
Partial Response
RDE
Remote Data Entry
RECIST
Response Evaluation Criteria In Solid Tumours
SAR
Serious Adverse Reaction
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCLC
Small cell lung carcinoma
SD
Stable Disease
SPF
Sun Protection Factor
SUSAR
Suspected Unexpected Serious Adverse Reaction
TKI
Tyrosine Kinase Inhibitor
TNM
Tumour, Nodes, Metastasis
ULN
Upper limit of normal lab value
WBC
White Blood Cells


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4.
Background and Rationale
4.1.
Disease background
Primary lung cancer is the most common malignancy after non-melanocytic skin cancer
with deaths from lung cancer exceeding those from any other type of malignancy
worldwide [1]. While it has been the most important cause of cancer mortality in men since
the 1960s, it has equalled breast cancer as a cause of mortality in women since the 1990s.
Lung cancer accounts for 12% of all incident cases of cancer. Non-small cell lung cancers
(NSCLC) account for 80-85% of lung cancers, while small cell lung cancer (SCLC) has
been decreasing in frequency in many countries over the last 2 decades [2].
Advanced stage NSCLC is traditionally treated by systemic palliative chemotherapy.
Several distinct chemotherapy regimens have shown comparable efficacy with different
toxicity profiles that are taken into account for treatment selection [3]. Fundamentally,
chemotherapy efficacy seems to have reached a plateau. Since 1978, cisplatin has been the
basis of chemotherapy treatment of NSCLC. However, in unselected patients, response rates
are only 15-30% and median survival is 10-12 months, while the majority of patients suffer
severe side effects with no therapeutic benefit. The treatment of cancer patients is
characterized by great inter-individual variability in outcome and evidence indicates that
response is determined in part by patient-specific alterations in the somatic cancer genome
and changes in gene expression. The use of a platinum-based chemotherapy combination is
the backbone of first-line treatment for epidermal growth factor (EGFR) or ALK (anaplastic
lymphoma kinase)-wild-type advanced NSCLC patients. There is an unmet need for
molecular predictive markers that could identify both patients most likely to benefit from
platinum-based treatment and those resistant to treatment, thus optimizing chemotherapy
approach in NSCLC. Since 1994, molecular research has centered on the identification of
predictive biomarkers that can be successfully used to tailor treatment in these patients. To
date, however, no genetic marker has been validated in a biomarker-directed randomised
trial.
4.2.
Targeted agents in non-small cell lung cancer
Human cancers usually evolve through multistep processes. These processes are driven by
the accumulation of abundant genetic and epigenetic abnormalities. However, some lung
cancers depend on a single activated oncogene by somatic mutation, termed “driver
oncogenic mutations”, for their proliferation and survival. EGFR mutations and ALK
rearrangement are typical examples of such driver oncogenic mutations found in lung
adenocarcinomas. EGFR-tyrosine kinase inhibitors (TKIs) like erlotinib, gefitinib or afatinib
or ALK-TKIs, like crizotinib, ceritinib or alectinib, significantly improved treatment
outcomes compared with conventional cytotoxic chemotherapy in patients with lung cancers
harboring EGFR mutations or ALK-rearrangement, respectively. Therefore, treatment
strategies for lung cancers have dramatically changed from a “general and empiric” to a
“personalized and evidence-based” approach according to the driver oncogenic mutation.


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Several novel driver oncogenic mutations, which are candidates as novel targets, such as
HER2, BRAF, ROS1, and RET, have been discovered. Some drugs have been shown to
inhibit more than one of the quite homologous cancer-related human kinases. For example,
crizotinib also achieves high response rates in anaplastic lymphoma kinase (ALK)-
translocated and ROS1-translocated NSCLC patients.
4.3.
HER2
Human epidermal growth factor 2 (HER2, erbB-2/neu) is a member of the erbB receptor
tyrosine kinase family. The ERBB2 gene which encodes for HER2 is a major proliferative
driver
that
activates
downstream
signaling
through
PI3K-AKT
and
MEK-ERK
pathways [4]. No ligand has been described for this receptor, which is activated by homo-
dimerization or hetero-dimerization with other members of the erbB family.
HER2 mutations consist of in-frame insertions in exon 20, leading to constitutive activation
of the receptor and downstream AKT and MEK pathways. HER2-mutations respond to the
genetic « driver » and preclinical models have proved the concept of transforming property
of such a genetic alteration [5].
Inducible expression of a HER2 mutant (HER2YVMA) in
lung epithelium of mice results in the emergence of invasive adenosquamous carcinomas,
with tumour maintenance requiring the continuous expression of the driver, as observed
with EGFR-driven cancer.
HER2 protein overexpression and gene amplification are present in 6–35% and in 10-20%,
respectively, of NSCLC. HER2 mutations were identified in about 2-4% of NSCLC. In the
selected population of EGFR/KRAS/ALK negative patients, HER2 mutations can reach up
to
6%.
This
mutation
is
predominantly
observed
in
females,
non-smokers
and
adenocarcinoma subtype, similar to EGFR mutated NSCLC. HER2 mutations have never
observed concomitantly with EGFR mutations or ALK rearrangement [6].
Among reported lung cancer biomarkers, HER2 as a target remains poorly described. HER2
overexpression or gene amplification is widely known to be associated with sensitivity to
HER2-targeting drugs (trastuzumab, lapatinib, pertuzumab and T-DM1) in breast cancer [7].
Involvement of HER2 in lung carcinogenesis has been known for many years, but clinical
research was slowed down when the first clinical trials with trastuzumab were negative.
Indeed, the addition of trastuzumab to gemcitabine-cisplatin or to docetaxel failed to show
any survival benefit in HER2 Immuno-Histo-Chemistry-positive (IHC) lung cancer
patients [8]. However, HER2 mutations may be more relevant in lung carcinogenesis than
HER2 amplification or overexpression.
Clinically relevant HER2 mutations are clustered in exon 20 of the HER2 gene and
commonly include small exon 20 insertions (majority of patients), clustered or single amino
acid substitutions all nested in the most proximal region of the exon, between codons 775
and 881. In the study of Arcila et al, the frequency of HER2 mutations among lung
adenocarcinoma patients was 26/1478 (approx. 2%). HER2 insertions identified in this study
included A775_G776insYVMA (80% of tumours), G776>VC, V777_G778insCG and
P780_Y781insGSP and point mutations included L755S and G776C [9].


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4.4.
Afatinib
Afatinib (BIBW2992) is a small molecule, selective and irreversible erbB family blocker. In
preclinical models it effectively inhibits EGFR, HER2 and HER4 phosphorylation resulting
in tumour growth inhibition and regression of established subcutaneous tumours derived
from four human cell-lines known to co-express ErbB receptors.
For the latest information on the drug profile of afatinib, please refer to the current
Investigator’s Brochure (IB) (U03-3218). All references in this protocol concerning afatinib
refer to the free base compound afatinib which is used as the oral formulation.
Afatinib is moderately fast
absorbed
after
oral administration. Maximum plasma
concentrations of afatinib were achieved mainly at 2 to 5 hours after oral drug
administration. Afatinib maximum plasma concentrations and area under the curve
increased slightly over-proportional with increasing doses in the therapeutic range of 20-50
mg. Moderate to high inter- and intra-individual differences in plasma concentration were
seen. Afatinib is highly distributed out of the blood and has a moderate to high clearance.
The overall geometric mean terminal half-life at steady state was 37.2 hours in cancer
patients. Steady state was reached no later than 8 days after the first administration. The
major route of elimination of afatinib was via faeces. After food intake, a decreased
systemic exposure was observed compared to administration under fasted conditions.
Therefore, afatinib should be taken without food (i.e. food should not be consumed for at
least 3 hours before and at least 1 hour after taking afatinib). The PK characteristics in
Caucasian cancer patients were comparable to those observed in Japanese cancer patients.
Afatinib binds covalently to proteins to a variable extent and covalent protein adducts were
the major circulating metabolites in the plasma. Afatinib did not show relevant inhibition or
induction of cytochrome P450 isoenzymes, and it appears unlikely that drug-drug
interactions based on this mechanism will occur.
Afatinib is a substrate of the P-gp transporter. Concomitant administration of the potent P-
gp inhibitor ritonavir did not relevantly change the exposure to 40 mg afatinib when taken
simultaneously with or 6 h after afatinib but increased the bioavailability of afatinib (single
dose of 20 mg) by 48% and 39% for AUC0-∞and Cmax when given 1 h before afatinib,
respectively. Pretreatment with the potent P-gp inducer rifampicin decreased the plasma
exposure of 40 mg afatinib by 34 % afatinib (AUC0-∞) and 22 % (Cmax), respectively.
Caution should be exercised when combining afatinib with potent P-gp modulators. In pre-
clinical studies afatinib is not irritant to intact skin but an ocular irritant. Afatinib is
mutagenic in a single bacteria strain, but did not show genotoxic potential in vivo when
tested up to overt toxic/lethal doses. Studies on embryo-foetal development in rats and
rabbits up to life-threatening doses have revealed no indication of teratogenicity.
Two phase I open label dose-escalation studies determined the MTD with continuous dosing
of afatinib in patients with advanced solid tumours at 40 mg and 50 mg daily, respectively
[10, 11]. Adverse events (AE) observed with afatinib are consistent with those reported for
other EGFR and dual EGFR/HER2 inhibitors. The most frequent investigator defined drug-
related AEs were associated with gastrointestinal disorders (including diarrhoea, and


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stomatitis), skin and subcutaneous tissue disorders (rash, dry skin, pruritus, acneiform rash,
acne), nail effects, epistaxis, fatigue and decreased appetite. Early and proactive
management of diarrhoea, and skin rash together with treatment interruptions and dose
reductions is recommended in line with recent guidelines in the management of common
toxicities of EGFR and EGFR/HER2 TKIs and monoclonal antibodies [12-16].
4.5.
Rationale for trial design
HER2 mutations are identified in about 2% of non-small-cell lung cancers (NSCLC) and
appear to be critical for lung carcinogenesis. There are very few data available that describe
the clinical course of HER2 mutated NSCLC patients. Mazieres and colleagues recently
retrospectively identified 65 NSCLC patients diagnosed with a HER2 in-frame insertion in
exon 20 [6]. The HER2 mutation was almost an exclusive driver, except one single case
with a concomitant KRAS mutation. The trial population presented with a median age of 60
years (range 31-86), a high proportion of women (45 vs. 20 men, 69%), and of never
smokers (34, 52.3%). All tumours were adenocarcinomas and 50% were stage IV at
diagnosis. For these latter cases, 22 anti-HER2 treatments were administered after
conventional chemotherapy in 16 patients. Subsequently, four progressive disease, seven
disease stabilizations and eleven partial responses (overall response rate ORR 50%; disease
control rate DCR 82%) were observed. Specifically, they observed a DCR of 93% for
trastuzumab-based therapies (n = 15), 100 % DCR for afatinib (n = 3), but no response to
other HER2-targeted drugs (n = 3). Progression free survival for patients with HER2-
therapies was 5.1 months. Median survival was of 89.6 and 22.9 months for early stage and
stage IV patients, respectively. This study, the largest to date dedicated to HER2-mutated
NSCLC,
reinforced
the
importance
of
screening
for
HER2-mutations
in
lung
adenocarcinomas, and suggested the potential efficacy of HER2-targeted drugs in this
population. Additionally, single case reports suggest that HER2 mutations may be predictive
for HER2 targeting therapies in lung cancer [17-19]. Some ongoing clinical trials are
enrolling patients with HER2 mutated NSCLC, mixed together with HER2 amplified or
EGFR mutated NSCLC cases. Large biomarker screening programs such as the French
National Program or the US Lung Cancer Mutation Consortium (LCMC) thus propose
testing for HER2 mutations.
4.6.
Overall Risk/Benefit Assessment
Distinct subtypes of NSCLC are driven by a specific genetic alteration and are thus sensitive
to inhibition of the corresponding activated oncogenic pathway. This new paradigm has
substantially impacted lung cancer treatment: early treatment for advanced NSCLC
consisted of chemotherapy tailored for patients according to the expected toxicity and more
recently according to histologic subtype. Nowadays, NSCLC can be further subdivided into
clinically relevant molecular subsets, according to their driving genetic alterations affecting
tumour proliferation and survival.
HER2 mutations offer a new treatment strategy beyond the standard chemotherapy. Afatinib
is a relatively well tolerated drug, for which we have rapidly learned to manage related
toxicities. Biologically, its transversal inhibition of the ERB family receptor offers an


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interesting blockade of interconnected cancer pathways and might prevent some early
compensatory feedback or resistance mechanisms. Indeed, in the small series available to
date, afatinib looks like being the most promising anti HER2 treatment. Based on available
data, stabilization and response to afatinib is comparable or superior to classical second line
chemotherapy (docetaxel), with a significantly better toxicity profile. This trial aims at
confirming the role of afatinib in HER2 mutated advanced NSCLC patients previously
treated with platinum based chemotherapy.
Afatinib presents a manageable toxicity profile and potentially offers a significant activity in
terms of disease control and long term outcome. Therefore this treatment option offers a
good benefit to risk ratio in patients with HER2-mutated advanced NSCLC.
5.
Objectives and endpoints
5.1.
Primary objective
Evaluate the ability of afatinib to control disease in pretreated patients with advanced
NSCLC harbouring HER2 exon 20 mutations.
5.2.
Secondary objectives
5.2.1.
To evaluate secondary measures of clinical efficacy including progression free
survival (PFS), objective response rate (ORR) and overall survival (OS).
5.2.2.
To assess the safety and the tolerability of the treatment.
5.3.
Primary endpoint
5.3.1.
Disease control defined as complete or partial response, or disease stabilisation
lasting at least 12 weeks (see section 14.1).
5.4.
Secondary endpoints
5.4.1.
Progression-free survival by RECIST 1.1
5.4.2.
Objective response determined by RECIST 1.1
5.4.3.
Overall survival
5.4.4.
Adverse events graded according to CTCAE V4.0
For definitions, see section 14.
6.
Trial design, duration and termination
This is a phase II, two-stage single-arm trial evaluating the efficacy of afatinib treatment in
pretreated patients with advanced NSCLC harbouring HER2 exon 20 mutations.


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Participating sites will screen patients for HER2 exon 20 mutations in their local laboratory.
One FFPE tumor block must be sent to the central laboratory for later confirmation of the
mutations.
Trial patients will receive afatinib 40 mg p.o./day until documented progression or
unacceptable toxicity.
Patient accrual is expected to be completed within 24 months including a run-in-period of 6
months. Recruitment will not be stopped after enrolment of the first 9 patients into stage 1
of the 2-stage design. Follow-up will continue until 6 months from enrolment of the last
patient. The final report will be prepared 40 months after the inclusion of the first patient.
Trial duration is therefore expected to be 40 months.
Approximately six sites from five European countries will participate.
7.
Patient selection
Written Informed Consent (IC) must be signed and dated by the patient and the investigator
prior to any trial-related intervention or test for eligibility.
7.1.
Inclusion criteria for enrolment
7.1.1.
Histologically or cytologically confirmed non small cell lung cancer
7.1.2.
Stage IIIB (non amenable to curative-intent multimodal treatment) or IV NSCLC,
according to 7th TNM classification.
-
Contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney,
adrenals);
-
brain MRI or CT
within 28 days before the date of enrolment.
7.1.3.
Non-predominant squamous subtype (<50% squamous cells).
7.1.4.
Previous treatment with a platinum based chemotherapy for advanced disease;
or
Disease relapse or progression within <6 months after adjuvant platinum based
chemotherapy, or (definitive) platinum-based chemo(radio)therapy for stage I-III
NSCLC
Stage
IIIB / IV
NSCLC,
pretreated
HER2
mutation
confirmed
locally
CT T&A
CT or MRI brain
Trial treatment
Screening, eligibility
and enrolment
Afatinib 40mg daily p.o.
until PD or unacceptable toxicity
CT week 20, then every 8 weeks until PD
For 6 months
after enroll-
ment of last
patient
Progression
Follow up
…….
…….
CT
week 6
CT
week 12


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7.1.5.
Measurable or evaluable disease (according to RECIST 1.1 criteria). Not eligible:
patients with only one measurable or evaluable tumour lesion which was resected
or irradiated prior to enrolment.
7.1.6.
Locally documented HER2 mutation
7.1.7.
Age ≥18 years
7.1.8.
Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 (see Table 1
below)
7.1.9.
Life expectancy >3 months.
7.1.10. Adequate haematological function:
-
WBC ≥2000/μL
-
haemoglobin ≥9 g/dL
-
neutrophils count ≥1.5×109/L
-
platelet count ≥100 × 109/L
7.1.11. Adequate liver function:
-
Total bilirubin ≤1.5 × ULN (except subjects with Gilbert
Syndrome, who can have total bilirubin < 3.0 mg/dL)
-
ALT < 2.5 × ULN
-
AST < 2.5 × ULN
-
GGT < 2.5 × ULN.
7.1.12. Adequate renal function: Calculated creatinine clearance ≥45mL/min (Cockroft-
Gault)
7.1.13. Patient capable of proper therapeutic compliance, and accessible for correct follow-
up.
7.1.14. Women of childbearing potential (< 1 year without menstruation or < 2 years
without menstruation following chemotherapy) must have a negative serum or
urine pregnancy test within 7 days before beginning trial treatment.
7.1.15. Sexually active men and women of childbearing potential must use an effective
contraceptive method (two barrier methods or a barrier method plus a hormonal
method) during the trial treatment and for a period of at least 28 days following the
last administration of trial drug.
7.1.16. Recovered from any previous therapy related toxicity to ≤Grade 1 at date of
enrolment (except for recovery to ≤Grade 2 of alopecia, fatigue, creatinine
increased, lack of appetite as well as stable sensory neuropathy)


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7.1.17. Written Informed Consent (IC) for trial treatment must be signed and dated by the
patient and the investigator prior to any trial-related intervention.
7.1.18. Tumour block available for central review of HER2 mutation status.
Table 1. ECOG Performance Status
PS 0
Fully active, able to carry on all pre-disease performance without restriction
PS 1
Restricted in physically strenuous activity but ambulatory and able to carry out work
of a light or sedentary nature, e.g., light housework, office work
PS 2
Ambulatory and capable of all self-care but unable to carry out any work activities.
Up and about more than 50% of waking hours
PS 3
Capable of only limited self care, confined to bed or chair more than 50% of waking
hours
PS 4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
7.2.
Exclusion criteria for enrolment
7.2.1.
Patient with mixed small-cell and non-small-cell histologic features
7.2.2.
Uncontrolled lepto-meningeal metastatic disease. Radiotherapy-treated or
asymptomatic brain metastases are allowed (no systematic screening).
Patients with brain or subdural metastases are not eligible, unless they have
completed local therapy and have discontinued the use of corticosteroids or have
been on stable dose of corticosteroids for at least 4 weeks before starting trial
treatment. Any symptoms attributed to brain metastases must be stable for at least 4
weeks before date of enrolment.
7.2.3.
Previous treatment with HER2 targeted antibody or tyrosine kinase inhibitor
including afatinib.
7.2.4.
Major surgery within 4 weeks before starting trial treatment or scheduled for
surgery during the projected course of the trial.
7.2.5.
Patient who has had in the past 3 years any previous or concomitant malignancy
EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ
carcinoma of the cervix or bladder, in situ ductal carcinoma of the breast.
7.2.6.
History or presence of clinically relevant cardiovascular abnormalities such as
uncontrolled hypertension, congestive heart failure NYHA classification of III or
IV (see Table 2 below), unstable angina or poorly controlled arrhythmia as
determined by the investigator. Myocardial infarction within 6 months prior to
enrolment.


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7.2.7.
Patient with other serious diseases or clinical conditions, including but not limited
to uncontrolled active infection and any other serious underlying medical processes
that could affect the patient’s capacity to participate in the trial.
7.2.8.
Known HIV, active Hepatitis B or Hepatitis C infection (screening not required).
7.2.9.
Known or suspected hypersensitivity to afatinib or any of its excipients.
7.2.10. Interstitial lung disease or pulmonary fibrosis.
7.2.11. Women who are pregnant or in the period of lactation.
7.2.12. Patients with any concurrent systemic anticancer therapy.
7.2.13. Any history or presence of poorly controlled gastrointestinal disorders that could
affect the absorption of the trial drug (e.g. Crohn’s disease, ulcerative colitis,
chronic diarrhea, malabsorption.
7.2.14. Patient who received treatment with an investigational drug agent during the 3
weeks before enrolment in the trial.
Table 2. NYHA functional classification
Class
Functional Capacity: How a patient with cardiac disease feels during
physical activity
I
Patients with cardiac disease but resulting in no limitation of physical activity.
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or
anginal pain.
II
Patients with cardiac disease resulting in slight limitation of physical activity.
They are comfortable at rest. Ordinary physical activity results in fatigue,
palpitation, dyspnea or anginal pain.
III
Patients with cardiac disease resulting in marked limitation of physical activity.
They are comfortable at rest. Less than ordinary activity causes fatigue,
palpitation, dyspnea or anginal pain.
IV
Patients with cardiac disease resulting in inability to carry on any physical
activity without discomfort. Symptoms of heart failure or the anginal syndrome
may be present even at rest. If any physical activity is undertaken, discomfort
increases
8.
Patient screening and enrolment
This trial will use a web-based registration system. Each participating centre will access the
system directly to enrol patients. Specific details for enrolment of patients are in the NICHE
Procedures Manual which will be available on the ETOP website (www.etop-eu.org).
8.1.
Screening
Note that written informed consent has to be obtained from the patient prior to any trial-
specific intervention including any examination done specifically for screening purposes.
The participating site should keep a screening log.


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8.2.
HER2 mutation testing
The presence of HER2 mutation needs to be confirmed according to the standard assay used
in the local laboratory.
Appropriate molecular tests to detect clinically relevant HER2 mutations should include
direct sequencing of exon 20 of the HER2 gene, validated PCR-based techniques, and
clinically validated next generation sequencing methods, according to the standards of each
laboratory. One block of FFPE material (or alternatively, 5-10 slides) from biopsy of
primary tumor or metastatic lesion for each patient with HER2 exon 20 mutation identified
in the local laboratory will be subsequently sent for confirmation to the central laboratory at
Medical University of Gdansk (Dr. Bartosz Wasag, Dept. of Biology and Genetics,
Collegium Biomedicaum, Medical University of Gdansk, Poland), see NICHE procedures
manual for details. This biological material will be stored at the central laboratory for
potential targeted next generation sequencing that includes HER2 and other lung cancer
relevant driver mutations, such as EGFR, KRAS, ALK, ROS1, RET and BRAF. Clinical
impact of other coexistent molecular alterations (if they are identified) would be analysed in
exploratory analyses.
For the purpose of the patient enrolment into the trial, local testing is sufficient.
8.3.
Enrolment
Verify eligibility, and then enrol the patient by entering the relevant information into the
RDE facility ETOPdata according to the information in the ETOPdata User Manual. The
date the Informed Consent was signed by the patient and the date signed by the investigator
are both required to complete the eligibility checklist.
8.4.
Start of afatinib
Afatinib treatment should start within 7 days after enrolment of the patient.
9.
Investigational product
Afatinib is the Investigational Product (IP) used in this trial. Boehringer Ingelheim will
provide the IP at no cost for the entire duration of this trial.
The Drug Supply Manual will describe detailed drug supply logistics as well as labelling,
packaging, handling, drug accountability and destruction of unused drugs.
9.1.
Summary of the safety profile
The types of adverse drug reactions (ADRs) were generally associated with the EGFR
inhibitory mode of action of afatinib. The summary of all ADRs is shown in Table 3 below,
with ADRs pooled from all NSCLC trials with daily afatinib doses of 40 mg (N=497) or 50
mg (N=1638) as monotherapy. The most frequent ADRs were diarrhoea and skin related
adverse events as well as stomatitis and paronychia. Interstitial Lung Disease (ILD)-like
adverse reactions were reported in 0.7% of afatinib treated patients. Overall, dose reduction
led to a lower frequency of common adverse reactions.


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In patients treated with once daily afatinib 40 mg, dose reductions due to ADRs occurred in
57% of the patients. Discontinuation due to ADRs diarrhoea and rash/acne was 1.3% and
0%, respectively.
Bullous, blistering and exfoliative skin conditions have been reported including rare cases
suggestive of Stevens-Johnson syndrome although in these cases there were potential
alternative aetiologies.
Although rare, drug-induced liver injury (DILI) is under constant surveillance by sponsors
and regulators and is considered an Adverse Event of Special Interest, see section 9.2.
Timely detection, evaluation, and follow-up of laboratory alterations of selected liver
laboratory parameters to distinguish an effect of the underlying malignancy on liver function
from other causes are important for patient safety.
Table 3. Summary of ADRs per frequency category
System organ class
(CTCAE v.4)
Very common
(≥10%)
Common
(1% to <10%)
Uncommon
(0.1% to <1%)
Infections and
infestations
Paronychia 1
Cystitis
Metabolism and
nutrition disorders
Decreased appetite
Dehydration
Hypokalaemia
Nervous system
disorders
Dysgeusia
Eye disorders
Conjunctivitis
Dry eye
Keratitis
Respiratory, thoracic
and mediastinal
disorders
Epistaxis
Rhinorrhoea
Interstitial lung
disease
Gastrointestinal
disorders
Diarrhea
Stomatitis 2
Dyspepsia
Cheilitis
Hepatobiliary
disorders
Alanine amino-
transferase
increased
Aspartate amino-
transferase incr.
Skin and
subcutaneous tissue
disorders
Rash 3
Dermatitis acneiform 4
Pruritus 5
Dry skin 6
Palmar-plantar
erythrodysaesthesia
syndrome
Musculoskeletal and
connective tissue
disorders
Muscle spasms
Renal and urinary
disorders
Renal impairment /
renal failure
General disorders
and administration
site conditions
Pyrexia
Investigations
Weight decreased
1 – includes paronychia, nail infection, nail bed infection


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2 – includes stomatitis, aphthous stomatitis, mucosal inflammation, month ulceration, oral mucosa erosion,
mucosal erosion, mucosal ulceration
3 – includes group of rash preferred terms
4 – includes acne, acne pustular, dermatitis acneiform
5 – includes pruritus, pruritus generalised
6 – includes dry skin, skin chapped
Very common ADRs in afatinib-treated patients occurring in at least 10% of patients in trial
LUX-Lung 3 are summarised in Table 4:
Table 4. Very common ADRs in trial LUX-Lung 3
Afatinib (40mg/day)
N=229
Pemetrexed/Cisplatin
N=111
NCI-CTC Grade
Any
grade
3
4
Any
grade
3
4
MedDRA Preferred Term
%
%
%
%
%
%
Infections and infestations
Paronychia1
57.6
11.4
0
0
0
0
Metabolism and nutrition disorders
Decreased appetite
20.5
3.1
0
53.2
2.7
0
Respiratory, thoracic and mediastinal disorders
Epistaxis
13.1
0
0
0.9
0.9
0
Gastrointestinal disorders
Diarrhoea
Stomatitis2
Cheilitis
95.2
69.9
12.2
14.4
8.3
0
0
0.4
0
15.3
13.5
0.9
0
0.9
0
0
0
0
Skin and subcutaneous tissue disorders
Rash3
Dermatitis acneiform4
Dry skin5
Pruritus6
70.3
34.9
29.7
19.2
14.0
2.6
0.4
0.4
0
0
0
0
6.3
0
1.8
0.9
0
0
0
0
0
0
0
0
Investigations
Weight decreased
10.5
0
0
9.0
0
0
1 – Includes Paronychia, Nail infection, Nail bed infection
2 – Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Oral mucosa erosion,
Mucosal erosion, Mucosal ulceration
3 – Includes group of rash preferred terms
4 – Includes Acne, Acne pustular, Dermatitis acneiform
5 – Includes Dry skin, Skin chapped
6 – Includes Pruritus, Pruritus generalised


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9.2.
Adverse Events of Special Interest
Drug-induced liver injury (DILI):

For patients with normal liver function at baseline:
Hepatic injury defined by an elevation of AST and/or ALT >3 × ULN
combined with an elevation of bilirubin >2 ×ULN measured in the same
blood draw sample.

For patients with impaired function tests at baseline:
Hepatic injury defined by an elevation of AST and/or ALT >5 × ULN
combined with an elevation of bilirubin >2 ×ULN measured in the same
blood draw sample.
Adverse Events of Special Interest are to be reported in an expedited manner like Serious
Adverse Events, even if they do not meet any of the seriousness criteria. Please submit the
completed SAE Initial Report Tab in the RDE system within 24 hours after awareness of the
event, and choose “yes” in the “description” section if this is a “non-serious adverse event of
special interest”. Please submit the SAE Follow-up Report within 14 days after the Initial
Report.
10.
Trial treatment
10.1.
Administration
Treatment with afatinib 40 mg p.o./day should start within 7 days after enrolment of the
patient.
Afatinib should be taken without food, approximately at the same time of the day. Food
should not be consumed for at least 3 hours before and at least 1 hour after taking this
medicinal product.
The tablets should be swallowed whole with water. If swallowing of whole tablets is not
possible, these can be dispersed in approximately 100 ml of noncarbonated drinking water.
No other liquids should be used. The tablet should be dropped into the water without
crushing it, and stirred occasionally for up to 15 min until it is broken up into very small
particles. The dispersion should be consumed immediately. The glass should be rinsed with
approximately 100 ml of water which should also be consumed. The dispersion can also be
administered through a gastric tube.
Missed dose:
If a dose is missed, it should be taken within the same day as soon as the patient remembers.
However, if the next scheduled dose is due within 8 hours then the missed dose must be
skipped.
Patient diary:
The patient should document each self-administration of afatinib on the patient diary.


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10.2.
Delay and dose modification for toxicity
Treatment related toxicities will be managed by treatment interruptions and subsequent dose
reductions of afatinib according to the schedule described in Table 5. Dose reductions will
apply to individual patients only. Once the dose has been reduced, it cannot be increased
later.
To prevent the development of more severe adverse events, treatment related diarrhoea,
nausea and vomiting or rash should be managed early and proactively as described in
Section 11.3.
Table 5. Dose reduction scheme for afatinib
AE type and CTCAE Grade
Action
Dose reduction scheme
Events related to trial drug:
Diarrhoea
Grade 2 persisting for 2 or
more consecutive days (48
hours) despite adequate anti-
diarrhoeal medication/
hydration
Reduced renal function
to ≥Grade 2 as measured by
serum creatinine, proteinuria
or decrease in glomerular
filtration rate of more than
50% from baseline
Any drug related AE
Grade ≥3
Pause
treatment
until
patient has recovered to
Grade ≤1 or baseline1.
Resume
treatment
at
reduced dose according
to dose reduction scheme
(next column).
If
patient
has
not
recovered to Grade ≤1 or
baseline1 within 14 days,
trial treatment must be
permanently
discontinued2.
If patient was receiving
40 mg, resume treatment
at a dose of 30 mg.
If patient was receiving
30 mg, resume treatment
at a dose of 20 mg.
If patient was receiving
20 mg, discontinue
afatinib.
Acute onset and/or unexplained
worsening of pulmonary
symptoms (dyspnoea, cough,
fever)
Pause afatinib while
clinical assessment to
exclude ILD is
completed.
If ILD is ruled out as a
cause of symptoms, grade
symptoms and relatedness
and report as AEs. If AEs
are not related, resume
afatinib at current dose. If
AEs are drug related,
follow instructions in row
above.
If ILD is confirmed,
discontinue afatinib
1 – Baseline is defined as the CTCAE Grade at the start of treatment
2 – In the event that the patient is deriving obvious clinical benefit according to the investigator’s
judgement, further treatment with afatinib will be decided in agreement between ETOP and the
investigator.


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Adverse reactions of grade 1 should not lead to interruption or dose reduction.
Similarly, adverse reactions of grade 2 but not prolonged (i.e. <48h of diarrhea and <7 days
of rash) should not lead to interruption or dose reduction. See section 11.3 for management
of diarrhea and section 11.4 for management of dermatological adverse reactions.
In case of any unrelated adverse events, the investigator may choose to interrupt the
medication for up to 14 days, but no dose reduction should occur. If the medication is
interrupted for more than 14 days, the decision to continue with afatinib will be made by
ETOP in agreement with the investigator; please contact NICHE@etop-eu.org.
If the medication is interrupted for more than a cumulative interval of 3 weeks, the decision
to continue with afatinib will be made by ETOP in agreement with the investigator; please
contact NICHE@etop-eu.org.
11.
Management of adverse events, concomitant therapy, restrictions
and rescue treatment
11.1.
Rescue medication, emergency procedures, and additional treatment(s)
11.1.1. Rescue medication
Rescue medications to reverse the actions of afatinib are not available. There is no specific
antidote for overdosage with afatinib. Potential adverse events should be treated
symptomatically. Common adverse events of treatment with afatinib with specified
management recommendations and/or requirements include diarrhoea, and rash/acne. To
improve tolerability and the probability of clinical benefit, patients should receive prompt
and appropriate supportive care at the first signs of symptoms. Suggested treatments for AEs
are described below.
11.1.2. Concomitant treatment(s)
Concomitant medications or therapy to provide adequate supportive care may be given as
clinically necessary.
After trial enrollment, palliative radiotherapy may be given for bone pain or for other
reasons (e.g. bronchial obstruction, skin lesions), provided that the total dose delivered is in
a palliative range according to institutional standards. The irradiated area can not be used for
tumour response assessment. During palliative radiotherapy, trial treatment should be
delayed and may be resumed once the patient has recovered from any radiation associated
toxicity. If medication is interrupted for more than 14 days, the decision to continue will be
made by ETOP in agreement with the investigator; please contact NICHE@etop-eu.org.
Continuous interruption of >28 days due to palliative radiotherapy will not be allowed.
All concomitant therapy, including anaesthetic agents, vitamins, homeopathic/herbal
remedies, nutritional supplements, must be recorded in the eCRF during the screening and
treatment period, starting from the date of signature of informed consent, and ending at the


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EOT visit. After the EOT visit, only concomitant therapy indicated for treatment of an AE
has to be reported.
In case of major elective surgery (as judged by the investigator), it is recommended to stop
treatment with afatinib one week prior to the surgery, and to restart treatment after complete
wound healing. If afatinib is interrupted for more than 14 days, the decision to continue will
be made by ETOP in agreement with the investigator.
11.1.3. Emergency procedures
Careful assessment of all patients with an acute onset and/or unexplained worsening of
pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude interstitial
lung disease (ILD). Trial drug should be interrupted pending investigation of these
symptoms. If interstitial lung disease is diagnosed, trial drug must be permanently
discontinued and appropriate treatment instituted as necessary.
Patients who present with symptoms of keratitis, such as acute or worsening eye
inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should
be referred promptly to an ophthalmic specialist. If a diagnosis of ulcerative keratitis is
confirmed, treatment with afatinib should be interrupted or discontinued. If keratitis is
diagnosed, the benefits and risks of continuing treatment with afatinib should be carefully
considered. Afatinib should be used with caution in patients with a history of keratitis,
ulcerative keratitis or severe dry eye. Contact lens use is a risk factor for keratitis and
ulceration.
11.2.
Management of expected adverse events
Dermatologic adverse events and diarrhoea are the most common side-effects associated
with treatment with afatinib. Treatment of these side-effects should be proactive and should
be started as early as possible after onset of symptoms.
11.3.
Management of diarrhoea and dehydration
Diarrhoea occurs at a high frequency and generally begins within 2 weeks of exposure to
afatinib. Although usually mild to moderate, diarrhoea may lead to dehydration and compel
treatment modification or discontinuation, so early management is essential (Table 6). At
the time of initiation of treatment with afatinib patients should be given a supply of
loperamide to keep with them at all times or access to loperamide should be confirmed; and
patients should be counselled on the appropriate use of loperamide.
Patients must be advised to drink an adequate amount of fluids to make up for the fluid lost
through diarrhoea.


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Table 6. Grade specific treatment recommendations for afatinib related diarrhoea
Severity
(CTCAE Grading)
Description
Intervention
concerning afatinib
treatment
Specific intervention
Mild (Grade 1)
Increase of < 4 stools per
day over baseline; mild
increase in ostomy output
compared with baseline
Continue same dose
Stop laxatives and advise
patient to drink at least 8-10
glasses of water of clear fluids
per day;
4 mg (2 tablets) of loperamide
to be taken immediately,
followed by 2 mg (1 tablet)
after each loose stool until
bowel movements cease for 12
hours
Moderate (Grade 2)
Increase of 4-6 stools per
day over baseline; i.v.
fluids indicated < 24
hours; moderate increase
in ostomy output
compared with baseline;
not interfering with ADL
Continue same dose
unless Grade 2
diarrhoea continues for
≥2 days (48 hours) in
which case treatment
must be interrupted
until recovered to ≤
Grade 1 followed by
dose reduction
Continue loperamide;
assess for dehydration and
electrolyte imbalance;
consider IV fluids and
electrolyte replacement
Severe (Grade 3)
Increase of ≥7 stools per
day over baseline;
incontinence; IV fluids >
24 hours; hospitalisation;
severe increase in ostomy
output compared with
baseline; interfering with
ADL
Dose interruption until
recovered to ≤Grade 1
followed by dose
reduction*
See Grade 2; plus:
an infectious process should be
ruled out with stool cultures;
aggressive iv fluid replacement
≥24 hours; hospitalisation to
monitor progress;
consider prophylactic
antibiotics if patient is also
neutropenic;
Life threatening
(Grade 4)
Life-threatening
consequences (e.g.
haemodynamic collapse)
Dose interruption until
recovered to ≤Grade 1
followed by dose
reduction*
See Grade 3
* If despite optimal supportive care and a treatment interruption, diarrhoea does not resolve
to CTC AE Grade ≤1 within 14 days, treatment with afatinib must be permanently
discontinued. In the event that the patient is deriving obvious clinical benefit according to
the investigator’s judgement, further treatment with afatinib will be decided in agreement
between ETOP and the investigator.
11.4.
Management recommendations for dermatological AEs
Dermatologic AEs of afatinib include rash, acne, dermatitis acneiform, and dry skin.
General recommendations for prophylaxis are summarized in Table 7 and grade-specific
treatment recommendations are summarized in Table 8. For dose adjustment of afatinib
refer to Table 5 section 10.2.
Specific interventions should be reassessed at least after 2 weeks or at any worsening of
symptoms, in which case the specific intervention should be adjusted and, depending on
own clinical experience, early involvement of a dermatologist should be considered.


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Table 7. General recommendations for prophylaxis while receiving afatinib
Personal hygiene
Use of gentle soaps and shampoos for the body, e.g. pH5 neutral bath and
shower formulations and tepid water.
Use of very mild shampoos for hair wash.
Only clean and smooth towels are recommended because of potential risk of
infection. The skin should be patted dry after a shower, whereas rubbing the skin
dry should be avoided.
Fine cotton clothes should be worn instead of synthetic material.
Shaving has to be done very carefully.
Manicure, i.e. cutting of nails, should be done straight across until the nails no
longer extend over the fingers or toes. Cuticles are not allowed to be trimmed
because this procedure increases the risk of nail bed infections
Sun protection
Sunscreen should be applied daily to exposed skin areas regardless of season.
Hypoallergenic sunscreen with a high SPF (at least SPF30, PAPA free,
UVA/UVB protection), preferably broad spectrum containing zinc oxide or
titanium dioxide are recommended
Patients should be encouraged to consequently stay out of the sun.
Protective clothing for sun protection and wearing a hat should be
recommended.
Moisturizer
treatment
It is important to moisturize the skin as soon as anti-EGFR therapy is started.
Hypoallergenic moisturizing creams, ointments and emollients should be used
once daily to smooth the skin and to prevent and alleviate skin dryness.
Note: avoid greasy creams (e.g. petrolatum, soft paraffin, mineral oil based) and
topical acne medications
Prevention of
paronychia
Patients should keep their hands dry and out of water if ever possible.
They should avoid friction and pressure on the nail fold as well as picking or
manipulating the nail.
Topical application of petrolatum is recommended around the nails due to its
lubricant and smoothing effect on the skin.
Table 8. Grade specific treatment recommendations of skin reactions to afatinib
Severity
(CTCAE
Grading)
Description
Specific intervention
ACNEIFORM RASH
Mild
(Grade 1)
Macular or papular eruptions or
erythema without associated
symptoms
Consider topical antibiotics, e.g. clindamycin
2% or topical erythromycin 1% cream of
metronidazole 0.75% or topical nadifloxacin
1%;
Isolated scattered lesion: cream preferred
Multiple scattered areas: lotion preferred


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Severity
(CTCAE
Grading)
Description
Specific intervention
Moderate
(Grade 2)
Macular or papular eruptions with
pruritus or other associated
symptoms; localized desquamation
or other lesions covering <50% of
BSA
Topical treatment as for Grade 1 1
plus short term topical steroids, e.g.
prednicarbate cream 0.02% plus
an oral antibiotic (for at least 2 weeks) e.g.
Doxycycline 100mg b.i.d. or Minocycline
hydrochloride 100mg b.i.d
Severe
(Grade 3)
Severe, generalized erythroderma
or macular, popular or vesicular
eruption; desquamation covering ≥
50% of BSA; associated with pain,
disfigurement, ulceration or
desquamation
Topical and systemic treatment as for Grade 2.1
Consider referral to dermatologist
Consider systemic steroids
Life
threatening
(Grade 4)
Generalized exfoliative, ulcerative,
or bullous dermatitis
See Grade 3
Systemic steroids are recommended
EARLY AND LATE XEROTIC SKIN REACTIONS – PRURITUS
Mild
(Grade 1)
Mild or localized
Topical polidocanol cream.
Consider oral antihistamines, e.g.
diphenhydramine, dimethindene, cetirizine,
levocetirizine, desloratidine, fexofenadine or
clemastine)
Moderate
(Grade 2)
Intense or widespread
See Grade 1 plus oral antihistamines;
Consider topical steroids, e.g. topical
hydrocortisone
Severe
(Grade 3)
Intense or widespread and
interfering with activities of daily
living (ADL)
See Grade 2.
XEROSIS (DRY SKIN)
Mild
(Grade 1)
Asymptomatic
Soap-free shower gel and/or bath oil.
Avoid alcoholic solutions and soaps.
Urea- or glycerin-based moisturizer.
In inflammatory lesions consider topical
steroids (e.g. hydrocortisone cream)
Moderate
(Grade 2)
Symptomatic, not interfering with
ADL
See Grade 1.
In inflammatory lesions consider topical
steroids (e.g. hydrocortisone cream)
Severe
(Grade 3)
Symptomatic,
interfering with ADL
See Grade 2.
Topical steroids of higher potency (e.g.
prednicarbate, mometasone furoate)
Consider oral antibiotics
FISSURES


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Severity
(CTCAE
Grading)
Description
Specific intervention
Mild
(Grade 1)
Asymptomatic
Petroleum jelly, Vaseline® or Aquaphor for 30
minutes under plastic occlusion every night,
followed by application of hydrocolloid
dressing; antiseptic baths (e.g. potassium
permanganate therapeutic baths, final
concentration of 1:10,000, or povidone-iodine
baths)
Topical application of aqueous silver nitrate
solutions to fissures
Moderate
(Grade 2)
Symptomatic, not interfering with
ADL
See Grade 1.
Consider oral antibiotics.
Severe
(Grade 3)
Symptomatic,
Interfering with ADL
See Grade 2.
1 If Grade 2 rash persists for ≥7 days despite treatment and is poorly tolerated by the patient, the investigator
may choose to pause treatment up to 14 days followed by a reduction in the dose of afatinib according to the
dose reduction scheme in Table 5
11.5.
Management of mucositis/stomatitis
General and grade specific recommendations are described in Table 9. For dose adjustment
refer to Table 5 and for restrictions on concomitant therapies refer to Sections 11.6.
Treatment is supportive and aimed at symptom control. These may include atraumatic
cleansing and rinsing with non-alcoholic solutions such as normal saline, diluted salt and
baking soda solution (e.g. one-half teaspoonful of salt and one teaspoon of baking soda in
one quart of water every four hours); avoidance of agents containing iodine, thyme
derivatives and prolonged use of hydrogen peroxide; dietary manoeuvres such as promotion
of soft, non irritating foods like ice-creams, mashed/cooked vegetables, potatoes and
avoidance of spicy, acidic or irritating foods such as peppers, curries, chillies, nuts and
alcohol. If the patient is unable to swallow foods or liquids, parenteral fluid and/or
nutritional support may be needed. Examples of some of the agents suggested in Table 9
include: topical analgesics – viscous lidocaine 2%; mucosal coating agents – topical
kaolin/pectin; oral antacids, maltodextrin, sucralfate; topical antifungals – nystatin
suspension (adapted from [20]).


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Table 9. Grade specific treatment recommendations of trial-drug related
mucositis/stomatitis
Severity
(CTCAE
grading)
Description
Treatment recommendations
Intervention
concerning afatinib
treatment / dose
modification
Mild
(Grade 1)
Minimal
symptoms;
normal diet
Oral rinses with agents such as non-
alcoholic mouth wash, normal saline,
diluted salt and baking soda solution .
No change .
Moderate
(Grade 2)
Symptomatic,
but can eat and
swallow
modified diet
Addition of topical analgesic mouth
treatments, topical corticosteroids,
antiviral therapy if herpetic infection
confirmed, antifungal therapy
preferably topical on a case by case
basis.
Maintain dose if tolerable;
Hold dose if intolerable
until recovery to grade ≤1,
then restart at the same
dose.
Severe
(Grade 3)
Symptomatic
and unable to
adequately
aliment or
hydrate orally
Same as for Grade 2; institute
additional symptomatic therapy
(topical or systemic) as clinically
indicated .
Hold dose until recovery to
grade ≤1 or baseline, then
restart at the reduced dose
according to Table 5.
Life
threatening
(Grade 4)
Symptoms
associated with
life-threatening
consequences
Same as for Grade 2; institute
additional symptomatic therapy
(topical or systemic) as clinically
indicated
Hold dose until recovery to
grade ≤1 or baseline, then
restart at the reduced dose
according to Table 5
11.6.
Restrictions
11.6.1. Restrictions regarding concomitant treatment
Additional experimental anti-cancer treatment and/or standard chemo-, immunotherapy,
hormone treatment (with the exception of megestrol acetate and use of anti-androgens
and/or gonadorelin analogues for treatment of prostate cancer), or radiotherapy (other than
palliative radiotherapy for symptom control) is not allowed concomitantly with the
administration of trial treatment.
Afatinib is a substrate of the P-gp (permeability glycoprotein) transporter. Caution should be
exercised when combining afatinib with P-gp modulators.


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Table 10. List of potent inhibitors and inducers of P-glycoprotein (MDR1)
Inhibitors
Inducers
Amiodarone
Azithromycin
Captopril
Carvedilol
Clarithromycin
Conivaptan
Cyclosporine
Diltiazem
Dronedarone
Erythromycin
Felodipine
Itraconazole
Ketoconazole
Lopinavir
Nelfinavir
Ritonavir
Quinidine
Ranolazine
Saquinavir
Tacrolimus
Ticagrelor
Verapamil
Carbamazepine
Phenytoin
Rifampicin
St John’s Wort
Phenobarbital Salt
Tipranavir
Ritonavir
The information on potent inhibitors and inducers of P-glycoprotein may evolve. It is
important for the investigator to record the administration of such modulators on the
concomitant medications form.
11.6.2. Restrictions on diet and life style
Patients should be advised to avoid any foods known to aggravate diarrhoea.
To prevent skin related adverse events it is recommended to avoid intense irradiation with
UV light and harsh detergents, see also Section 11.4.
11.7.
Women of Child-Bearing Potential and Pregnancy Prevention
Female patients who are not of childbearing potential due to being postmenopausal (1 year
without menstruations without an alternative medical cause or at least 2 years without
menstruation following chemotherapy) or surgically sterilised (oophorectomy, hysterectomy
and/or tubal ligation) do not need to use contraception to be eligible for the trial.
All other patients are considered to be of childbearing potential and must use adequate
contraception throughout the trial (from screening until end of trial participation or at least
28 days after last dose of trial medication, whichever is later).
Acceptable methods of contraception include surgical sterilisation and double barrier
method, and must be in accordance with local regulations where applicable. Double barrier
method of contraception is defined as two barrier methods used simultaneously each time


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the patient has intercourse. Accepted barrier methods include diaphragm, female condom,
cervical cap, male condom and intrauterine device (IUD) (the diaphragm and cervical cap
must be used in conjunction with spermicidal jelly/cream). Those using hormonal
contraceptives, or with partners using hormonal contraceptives, must also be using an
additional approved method of contraception (as described above). Partner vasectomy,
natural "rhythm" and spermicidal jelly/cream are not acceptable methods of contraception.
Similarly, male patients must use acceptable methods of contraception mentioned above.
Women who become pregnant while participating in the trial must discontinue trial
medication immediately. The pregnancy must be reported following procedures detailed in
section 12.2.1
11.8.
Treatment compliance
The trial medication will be given in accordance with the protocol and the instructions of a
site investigator.
The appropriate number of afatinib tablets for treatment cycles (3 weeks for the first four
cycles, then 4 weeks) will be provided to patients to be self-administered at home. Patients
should be instructed to use the Patient Diary to record every self-administration as well as
any symptoms and to bring the Patient Diary to every visit at the clinic.
Patients will be asked to bring the remaining trial medication at the end of each cycle to the
investigator site for a compliance check. The remaining film-coated tablets will be counted
by the investigator/site staff and recorded at the investigator site. Discrepancies between the
number of tablets remaining and the calculated number of tablets the patients should have
taken as well as the information recorded in the patient diary must be documented and
explained. At the end of each cycle, any remaining medication will be collected. If the
patient is eligible for further treatment, a new bottle of trial medication must be dispensed.
The investigator and/or ETOP can withdraw a patient from the trial in the event of serious
and persistent non-compliance which jeopardizes the patient’s safety or render trial results
for this patient unacceptable. Patients who do not attend a minimum of 75% of scheduled
trial visits, unless due to exceptional circumstances, should be discussed with ETOP and be
evaluated for compliance.
11.9.
Treatment duration
Patients remain on treatment until one of the following events, whichever occurs first:

Documented progression according to RECIST v1.1

Secondary malignancy resulting in need of systemic treatment

Unacceptable toxicity

Medical condition that prevents further treatment

Patient withdraws consent

Patient becomes pregnant

Trial treatment interrupted for too long


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
Patient is not compliant with protocol
If the IP has been stopped for any reason, the patient enters the follow-up phase of the trial.
Patients who discontinue trial treatment should be assessed by the investigator who must
document the case on the appropriate CRF.
12.
Adverse events and reporting
12.1.
Adverse event reporting
The main criterion for tolerability is the occurrence of toxicities and adverse events. The
severity and causality will be classified according to the NCI CTCAE Version 4. The
CTCAE
is
available
for
downloading
on
the
internet
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html).
An adverse event is defined as any untoward medical occurrence that occurs from the date
of informed consent until 90 days after the final dose of afatinib, regardless of whether it is
considered related to the trial treatment. The relationship of the adverse event with the
administered trial treatment has to be indicated (unrelated – unlikely – possible – probable –
definite).
In addition, any known untoward event that occurs subsequent to the adverse event
reporting period that the investigator assesses as possibly related to the protocol treatment
should be considered an adverse event.
Symptoms of the targeted cancer (if applicable) and hospitalisations for the management of
the underlying disease should not be reported as adverse events.
The adverse event severity grade provides a qualitative assessment of the extent or intensity
of an adverse event, as determined by the investigator or as reported by the subject. The
severity grade does not reflect the clinical seriousness of the event, only the degree or extent
of the affliction or occurrence (e.g. severe nausea, mild seizure), and does not reflect the
relationship to trial drug.
Severity grade for other adverse events not covered in the toxicity grading scale:
1 = Grade 1
Mild
2 = Grade 2
Moderate
3 = Grade 3
Severe
4 = Grade 4
Life-threatening
5 = Grade 5
Fatal
Note:

Report the highest grade observed within one period.

Baseline symptoms will be recorded on the CRF and changes in grade as well as
resolution of an AE during treatment have to be reported.

Laboratory abnormalities for non-safety parameters will be documented on the AE
CRF from grade ≥3 only


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
AEs should not be reported in a narrative description.
12.2.
Definition of Serious Adverse Event (SAE)
12.2.1. SAEs during trial treatment
An SAE is defined in general as any undesirable medical occurrence/adverse drug
experience that occurs during or within 90 days after stopping trial treatment that results in
any of the following:

is fatal (any cause except progression of disease)

life-threatening,

requires or prolongs inpatient hospitalisation,

results in persistent or significant disability/incapacity

is a congenital anomaly or birth defect

is a secondary malignancy

is a medically important event

Overdose, only if associated with a symptom or AE
Second (non-NSCLC) malignancies are always considered SAEs, no matter when they are
diagnosed. These events should be reported on the Serious Adverse Event Forms.
Other significant/important medical events which may jeopardise the patient are also
considered serious adverse events.
An overdose is defined as the accidental or intentional administration of any dose of a
product that is considered both excessive and medically important. All occurrences of
overdose must be reported as an SAE.
Serious also includes any other event that the investigator or the ETOP Safety Office judges
to be serious or which is defined as serious by the regulatory agency in the country in which
the event occurred.
An unexpected adverse event is one that is not listed as a known toxicity of the
investigational drug in the summary of product characteristics.
A related adverse event is one for which the investigator assesses that there is a reasonable
possibility that the event is related to the investigational drug. All adverse events judged as
having a reasonable suspected causal relationship to the trial medication qualify as adverse
reactions.
Events not considered to be serious adverse events are hospitalisations occurring under the
following circumstances:

elective surgery;

occur on an outpatient basis and do not result in admission (hospitalisation < 24 h);

are part of the normal treatment or monitoring of the studied treatment;

progression of disease (by convention, clinical events related to the primary cancer
being studied or to the primary cancer progression are not to be reported as SAEs,


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even if they meet any of the seriousness criteria from the standard SAE definition,
unless the event is more severe than expected and therefore the investigator
considers that their clinical significance deserves reporting).
12.2.2. SAEs after end of trial treatment
For 90 days after stop of afatinib, the following events have to be reported as SAE:

fatal, life-threatening and other medically significant events possibly, probably or
definitely related to late effects of trial treatment

disabling events

second primary cancer

congenital anomaly
In the case of pregnancy occurring during trial treatment or within 1 year after treatment
discontinuation, the investigator shall immediately notify this by completing the pregnancy
reporting form. The investigator shall ensure that the case is followed up to the end of the
pregnancy and supply a final report on the outcome.
12.3.
Definition of Serious Adverse Reaction (SAR)
SARs are all SAEs considered to be related (possibly, probably, definitely) to the trial
treatment.
12.4.
Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR)
A SUSAR is a serious adverse reaction that is assessed as unexpected on the basis of the
applicable Swiss product information, the European summary of product characteristics, and
the Investigators’ Brochure.
12.5.
Reporting SAEs and Adverse Events of Special Interest
Drug-induced liver injuries as defined in section 9.2 are considered to be Adverse Events of
Special Interest (AESIs) and are to be reported on the SAE form, within 24 hours of
awareness.
Following the subject’s written consent to participate in the trial, all SAEs, whether related
or not related to trial drug, must be collected, including those thought to be associated with
protocol-specified procedures. All SAEs must be collected that occur within 90 days of
discontinuation of dosing.
All SAEs must be collected that occur during the screening period. If applicable, SAEs must
be collected that relate to any protocol-specified procedure (eg, a follow-up skin biopsy).
The investigator should report any SAE that occurs after these time periods that is suspected
to be related to trial drug or protocol-specified procedure.
Any SAE or AESI must be reported by submitting the completed SAE Initial Report Tab in
the RDE system within 24 hours of awareness.


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Submission is done via the remote data entry system, or in case of unavailability, by sending
the SAE form by fax to the ETOP Safety Office:
+41 31 389 92 29
Once the remote data entry system is available again, the SAE Tab has to be completed by
the site.
The SAE/AESI outcome must be reported within 14 days after onset by online submitting
the SAE/AESI Follow-up Report Tab. In case the SAE is reported as ongoing after 14 days,
the follow-up report has to be submitted again with the final outcome.
The ETOP Safety Office will forward each SAE to the trial chairs and notify principal
investigators of any SAR meeting the criteria for expedited reporting (SUSAR) within the
timelines specified in GCP.
The local Ethics Committee must be informed by the principal investigator about SAEs
according to local regulations.
The ETOP Safety Office will inform Boehringer Ingelheim Regional Drug Safety and other
appropriate persons about all SAEs and AESIs at least possibly related to trial medication
(per either investigator or ETOP Safety Office review) within 24 hours of receipt.
The ETOP Safety Office will record the SAE and prepare an annual safety report (DSUR,
Development Safety Update Report). Listings of SAEs will be prepared as required.
12.6.
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a
patient is pregnant or may have been pregnant at the time of investigational product
exposure, the investigational product will be permanently discontinued in an appropriate
manner (eg, dose tapering if necessary for subject safety).
The investigator must inform ETOP within 24h of awareness by completing and submitting
the Pregnancy Form in ETOPdata.
Follow-up information regarding the course of the pregnancy, including perinatal and
neonatal outcome and, where applicable, offspring information must be reported on the
Pregnancy Form.
In case the pregnancy is associated with a serious adverse event (fetal death, congenital
anomaly, abortion, complication requiring hospitalisation), this has to be reported on the
SAE form within 24h.
Any pregnancy that occurs in a female partner of a male trial participant should be reported
to ETOP. Information on this pregnancy will be collected on the Pregnancy Form.


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13.
Response evaluation
13.1.
RECIST 1.1 criteria
The patient’s response to protocol treatment will be assessed by RECIST 1.1 criteria (see
appendix 2).
13.2.
Determination of time point response
Table 11. Determination of time point response
Target lesions
Non-target lesions
New lesions
Resulting Overall
response
CR
CR
No
CR
CR
Non-CR / non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
unless
the
sum
of
diameters of evaluated
lesions indicates PD 1)
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
1)
From ref. 1 in Appendix 2, p.234: When no imaging/measurement is done at all at a particular time
point, the patient is not evaluable (NE) at that time point. If only a subset of lesion measurements are
made at an assessment, usually the case is also considered NE at that time point, unless a convincing
argument can be made that the contribution of the individual missing lesion(s) would not change the
assigned time point response. This would be most likely to happen in the case of PD. For example, if
a patient had a baseline sum of 50mm with three measured lesions and at follow-up only two lesions
were assessed, but those gave a sum of 80 mm, the patient will have achieved PD status, regardless of
the contribution of the missing lesion.
13.3.
Determination of best overall response
Best overall response is defined as best response across all time points. Confirmation of
partial or complete response by an additional scan is not requested in this trial. Response at
week 6 assessment will be confirmed by the week 12 assessment; response at week 12
assessment will be confirmed by the week 20 assessment.


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14.
Endpoints definition
14.1.
Disease control
This is the primary endpoint. It is defined as complete or partial response, or disease
stabilisation lasting at least 12 weeks.
14.2.
Progression-free survival
This is defined as the time from the date of enrolment until documented progression or
death, if progression is not documented. Censoring will occur at the last tumour assessment
only if patient is lost to follow-up.
14.3.
Objective response
Objective response is defined as best overall response (CR or PR) across all assessment
time-points during the period from enrolment to termination of trial treatment. Objective
response to afatinib treatment will be determined using RECIST 1.1 criteria (see section 13).
14.4.
Overall survival
Defined as time from the date of enrolment until death from any cause. Censoring will occur
at the last follow-up date.
14.5.
Toxicity
Adverse events classified according to NCI CTCAE version 4.
15.
Trial procedures
This section gives an overview of procedures, clinical and laboratory evaluations and
follow-up investigations.
15.1.
Baseline evaluations (within 28 days prior to enrolment)
The following examinations should be done within a maximum of 28 days before
enrolment. If examinations were done prior to 28 days before enrolment, they have to be
repeated.
15.1.1. Obtain written informed consent prior to any trial-specific evaluations or
interventions
15.1.2. Local HER2 mutation testing (test may have been done prior to 28 days)
15.1.3. Medical history including symptoms, smoking history, medications, comorbidities
and allergies
15.1.4. Physical examination according to local standards, including blood pressure
[mmHg], ECOG performance status, body weight [kg]
15.1.5. Haematology: WBC, haemoglobin, platelets, neutrophils. Needs to be repeated


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prior to first dose of afatinib if done more than 7 days prior to first dose.
15.1.6. Chemistry: sodium (Na), potassium (K), calcium, albumin, magnesium. Needs to
be repeated prior to first dose of afatinib if done more than 7 days prior to first
dose.
15.1.7. Renal function: serum creatinine and creatinine clearance calculated according to
Cockroft-Gault
15.1.8. Hepatic function: ALT, AST, bilirubin, GGT
15.1.9. Electrocardiogram
15.1.10. Pregnancy test for women of childbearing potential within 7 days before trial
treatment start
15.1.11. CT thorax and upper abdomen. PET-CT thorax and upper abdomen can be used
instead of CT scan if contrast-enhanced
15.1.12. Brain MRI or CT
15.1.13. Ascertain availability of FFPE tumour material for later central review of HER2
mutation
15.2.
At trial treatment start visit
Week 0 is the week of trial treatment start. The following evaluations should be done at the
week 0 visit:
15.2.1. If not done within 7 days prior to first dose, repeat haematology and chemistry
before first dose: WBC, haemoglobin, platelets, neutrophils; sodium, potassium,
calcium, albumin, magnesium (to be reported on baseline form)
15.2.2. Record current symptoms, and all adverse events which have occurred after signing
informed consent, on adverse event CRF
15.2.3. Record all concomitant medication from date of signed informed consent.
15.3.
During first 3 weeks of afatinib treatment
15.3.1. Regular contact with patient to monitor adverse events, especially diarrhoea (phone
contact allowed) according to treatment tolerability and investigator’s decision.
15.4.
Every visit during afatinib treatment
Visits will take place at 3, 6, 9 and 12 weeks after first dose, then every 4 weeks until stop
of treatment.
15.4.1. Physical examination according to local standards, including blood pressure,
performance status, and body weight
15.4.2. Check patient diary and count remaining tablets


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15.4.3. Recording of symptoms / adverse events
15.4.4. Haematology: WBC, haemoglobin, platelets, neutrophils
15.4.5. If clinically indicated according to local standards: Chemistry; sodium (Na),
potassium (K), calcium, albumin, magnesium
15.4.6. Serum creatinine and creatinine clearance calculated according to Cockroft-Gault
15.4.7. Hepatic function: ALT, AST, bilirubin, GGT
15.4.8. Record all concomitant medication
15.4.9. Give to the patient the afatinib tablets for the next treatment cycle (3 or 4 weeks)
15.5.
Imaging
The following imaging will be done on weeks 6 and 12 from day of first dose of trial
treatment, and then every 8 weeks (weeks 20, 28, 36 etc) until progression:
15.5.1. CT thorax and upper abdomen
15.6.
End of treatment visit
At the end of all trial treatment and irrespective of the reason for stopping treatment, an
end of treatment visit at the centre is to be scheduled within 30 days following the last dose
of trial treatment or within 30 days after planned treatment start if treatment never started.
This visit has to be done for all patients, including those who did not start afatinib treatment.
The following procedures should be performed:
15.6.1. Physical examination according to local standards, performance status, and body
weight
15.6.2. Recording of symptoms / adverse events
15.6.3. Haematology: WBC, haemoglobin, platelets, neutrophils
15.6.4. Chemistry: sodium (Na), potassium (K), calcium, albumin, magnesium
15.6.5. Serum creatinine and creatinine clearance calculated according to Cockroft-Gault
15.6.6. Hepatic function: ALT, AST, bilirubin, GGT
15.6.7. Pregnancy test for women of childbearing potential
15.6.8. CT thorax and upper abdomen, if not done within the last 6 weeks
15.6.9. Record all concomitant medication
15.7.
Follow up after treatment stop, before progression
Follow up visits after trial treatment stop but before progression will take place every 8
weeks until progression; and should be scheduled at the same time as the CT scans


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15.7.1. Report any pregnancy occurring within 6 months after treatment stop
15.7.2. Report any adverse event occurring within 90 days after treatment stop
15.7.3. Report any concomitant medication within 90 days after treatment stop
15.8.
Follow up after progression
Follow up visits after progression will take place every 3 months until death or until 6
months from enrolment of the last patient, whatever occurs first.
15.8.1. Record survival status
15.8.2. Report any pregnancy occurring within 6 months after treatment stop
15.8.3. Report any adverse event occurring within 90 days after treatment stop
15.8.4. Report any concomitant medication within 90 days after treatment stop
16.
Case report forms and documentation
16.1.
Case report forms schedule
CRFs will only be available on-line at the Remote Data Entry (RDE) facility ETOPdata. No
paper forms will be used, with the exception of paper SAE initial and follow-up forms in
case of system unavailability.
Table 12. Case report forms
Tab in ETOPdata
To be completed
Eligibility for Enrolment
Within 28 days of start of baseline assessments
Baseline
Until 7 days after start of afatinib
Concomitant Medication
Continuously from signed informed consent to 90 days after
end of trial treatment
Within 7 days after each afatinib visit.
Trial Treatment Start Visit
Within 7 days after trial treatment start visit.
Afatinib Treatments
Within 7 days of the end of each cycle
Tumour Assessment
Baseline: Within 7 days after start of afatinib;
Within 14 days after every imaging (weeks 6, 12 after start
of afatinib treatment, and then every 8 weeks until
progression)


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Tab in ETOPdata
To be completed
Adverse Events
Continously from signed informed consent to 90 days after
end of afatinib treatment:
Within 7 days after enrolment (to record symptoms present
at enrolment);
Within 7 days after each afatinib treatment visit;
End of treatment: Within 14 days after end-of-treatment visit
if patient has been treated with afatinib.
In follow-up for 90 days after treatment stop
Pregnancy
Within 24h of first documentation of pregnancy;
Within 14 days of end of pregnancy.
Serious Adverse Event
Initial Report
Within 24h of awareness of SAE or AESI;
Can be submitted via ETOPdata or via fax to ETOP Safety
Office in case of unavailability of ETOPdata.
Serious Adverse Event
Follow-up Report
Within 14 days of completion of initial report.
If event was not resolved after 14 days, submit an additional
report again within 7 days of resolution/final outcome of
event.
End of Treatment
Within 14 days after end of treatment visit (which is to take
place within 30 days after end of treatment)
Follow-up
To be completed within 14 days after each follow-up visit
and at death.
Consult the CRF completion guideline for detailed instructions on how to complete, save
and submit the electronic CRFs.
17.
Statistical considerations
17.1.
Primary objective
To evaluate the ability of afatinib to control disease in pretreated patients with advanced
NSCLC harbouring HER2 exon 20 mutations. Disease control is defined as complete or
partial response, or disease stabilisation lasting at least 12 weeks.
17.2.
Sample size determination
For sample size determination, a Simon’s two stage phase II design [21] is adopted. A
Disease Control Rate (DCR) of 50% is considered as unacceptable, targeting a DCR of
75%. Hence the null hypothesis under consideration is that the DCR≤50% versus the
alternative that DCR≥75%. For a one-sided type I error of 10% and power of 80%, a total of


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22 patients need to enter the trial, with 9 patients in the first stage. If in the first stage, 6 out
of the 9 patients achieve Disease Control, then the trial will proceed to the second stage and
recruit an additional 13 patients for a total of 22 patients. If at the end of trial, at least 14
patients achieve Disease Control, then this finding will indicate that it would be reasonable
to proceed to a Phase III trial.
17.3.
Evaluation of primary and secondary objectives
The total trial duration will be approximately 40 months including a 6 months start-up
period, 24 months accrual, 6 months follow-up after inclusion of the last patient, and 4
months for preparation of the final trial report.
The final evaluation of the trial will be performed approximately 40 months after the
inclusion of the first patient.
The binomial exact one-sample test will be used for evaluation of the primary endpoint
(DCR) at both the interim and final analysis (if trial continues to completion) [22-25]. The
conclusion will be based on examining whether or not the observed number of patients who
have achieved complete response, partial response and stable disease crosses the
corresponding O’Brien-Fleming boundary. Results will be presented in terms of rates
together with the corresponding exact binomial 90% confidence intervals.
The secondary endpoints of Progression free survival (PFS) and overall survival (OS) will
be estimated by the Kaplan Meier method. Clinical efficacy will also be described by
objective response rate (ORR).
Safety and tolerability of the afatinib treatment will be presented by tabulation of the
CTCAE V4 grade. The safety cohort will encompass all patients who have received at least
one dose of trial treatment.
Statistical analysis of both the primary and secondary endpoints will be described in detail
in the Statistical Analysis Plan (SAP) document
17.4.
Early stopping rules
An early look will take place at the end of the first stage, when 9 patients are evaluable for
the primary endpoint. This report will be submitted to the Independent Data Monitoring
Committee (IDMC), see section 20.3. If less than 6 patients achieve Disease Control, then
the results will be reported immediately and the Steering Committee will decide whether the
patients still on treatment should stop it. Otherwise the trial will continue as planned until
the final evaluation. The recruitment into the trial will continue during the preparation of the
analysis of the first stage.


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18.
Criteria for termination of the trial
18.1.
General criteria for termination of the trial
The trial may be discontinued early in parts or completely if the information on the product
leads to doubt as to the benefit/risk ratio, by decision of ETOP or Trial Steering Committee,
or at the suggestion of the IDMC based on the interim safety evaluations.
The trial can be terminated at any time if the authorization and approval to conduct the trial
is withdrawn by Ethics Committee or regulatory authority decision, insufficient accrual,
emerging new data impacting the scientific value of the trial or ethical grounds.
18.2.
Discontinuation of protocol treatment for individual patients
Protocol treatment should be stopped in the following situations:

Disease progression.

Occurrence of unacceptable toxicities. Stopping protocol treatment is determined
by medical judgment of the treating physician.

Inter-current severe illnesses which would in the judgment of the investigator affect
assessments of the clinical status to a significant degree and require discontinuation
of protocol therapy. Note: Diagnosis of another neoplastic disease (second
malignant tumour) does not mandate a stop of trial therapy; patients may continue
to receive protocol treatment after appearance of a second primary tumour,
stopping protocol treatment is determined by the medical judgment of the treating
physician.

Request by the patient. Patients have the right to refuse further trial treatment at
any time during the trial. Such patients will remain in the trial and will be
transferred to the follow-up phase.

If a patient refuses to have the treatments or follow-up examinations and tests
needed to determine whether the treatment is safe and effective.
The decision for discontinuation of protocol treatment of individual patients is taken by the
treating physician based on his medical evaluation and taking into account the patient’s
individual situation.
18.3.
Withdrawal of consent
Patients have the right to withdraw consent for further trial participation at any time without
having to specify the reason. The data recorded up to the timepoint of withdrawal will
continue to be evaluated in the trial. The investigator should ask the patient for consent to
continue to collect information on her/his disease and survival status.
It should be documented in both the medical records and in the eCRF, according to the
instructions in the CRF completion guidelines, if the patient accepts to be contacted for
survival status despite withdrawing the trial consent. For the patient’s safety, an end of
treatment visit should be performed and documented in the eCRF.


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19.
Ethics aspects, regulatory approval, and Patient Informed Consent
The Investigator will ensure that this trial is conducted in full conformance with the
principles of the “Declaration of Helsinki” or with the laws and regulations of the country in
which the research is conducted, whichever affords the greater protection to the individual.
The trial must fully adhere to the principles outlined in “Guideline for Good Clinical
Practice” ICH Tripartite Guideline (January 1997) or with local law if it affords greater
protection to the patient. For studies conducted in the EU/EEA countries, the Investigator
will ensure compliance with the EU Clinical Trial Directive (2001/20/EC).
19.1.
Ethical Review Board/Ethics Committee
All protocols and the patient informed consent forms must have the approval of a properly
constituted committee or committees responsible for approving clinical trials. The ERB/IRB
decision must contain approval of the designated investigator, the protocol (identifying
protocol title and version number), and of the patient informed consent.
The ERB/IRB written, signed approval letter/form must contain approval of the designated
investigator, the protocol (identifying protocol title and version number), and of the patient
informed consent. Documentation of Ethics Committee approval must be sent to the ETOP
Coordinating Office prior to enrolment of the first patient.
Any modifications made to the protocol must be submitted to the appropriate ERB/IRB for
information or approval in accordance with local procedures and regulatory requirements
and to Health Authorities if required.
Once approved or acknowledged by the appropriate ERB/IRB and by the Health Authorities
(if required), the investigator shall implement the protocol modifications. Protocol
modifications for urgent safety matters may be directly implemented following the
instructions of ETOP.
19.2.
Regulatory approval procedures
If applicable, in addition to the approval of the Ethics Committee according to national
legislation, the protocol, other protocol related documents including patient information and
informed consent and other documents as required locally must be submitted to and be
approved by the health authority. Documentation of health authority approval must be sent
to the ETOP Coordinating Office prior to Participating Centre activation.
19.3.
Informed consent
Informed consent for each patient will be obtained prior to initiating any trial procedures in
accordance with the “Patient Information and Informed Consent" (See Appendix I). One
signed and dated copy of the informed consent must be given to each patient and the
original copy must be retained in the investigator's trial records. The informed consent form
must be available to monitors and in the case of data audits. Verification of signed informed
consent and the date signed are required for inclusion to this trial.


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The "Declaration of Helsinki" recommends that consent be obtained from each potential
patient in biomedical research trials after the aims, methods, anticipated benefits, and
potential hazards of the trial, and discomfort it may entail, are explained to the individual by
the physician. The potential patient should also be informed of her/his right to not
participate or to withdraw from the trial at any time. The process of obtaining the informed
consent must be documented in the patient record.
If the patient is in a dependent relationship to the physician or gives consent under duress,
the informed consent should be obtained by an independent physician.
By signing this
protocol, the investigator agrees to conduct the trial in accordance with Good Clinical
Practice and the "Declaration of Helsinki."
ETOP recognises that each institution has its own local, national, and international
guidelines to follow with regard to informed consent. Therefore, we provide a template
information sheet and informed consent form (Appendix I), which can be edited to
incorporate information specific to your institution. The template Patient Information Sheet
and Informed Consent has been written according to ICH guidelines which state the
Informed Consent should adhere to GCP and to the ethical principles that have origin in the
“Declaration of Helsinki”. The final version needs to receive the Institutional Review
Board/ Local Ethics Committee approval in advance of its use. Centres need to send their
locally modified PIS/IC to ETOP for review and approval before submitting to their Ethics
Committee.
20.
Governance and administrative issues
20.1.
Final report
A final clinical trial report will be written and distributed to Health Authorities as required
by applicable regulatory requirements.
20.2.
Steering Committee
A Steering Committee will be constituted for this trial. The Steering Committee is
responsible for maintaining the scientific integrity of the trial, for example, by
recommending changes to the protocol in light of emerging clinical or scientific data from
other trials. Membership will include the trial chair and co-chair, trial coordinators, trial
statisticians, ETOP officials, representatives from some participating institutions and
groups, and a representative from Boehringer Ingelheim.
20.3.
Independent Data Monitoring Committee
The trial will be presented for review to the ETOP IDMC at each of their semi-annual
meetings. Accrual and safety will be monitored. The Stage 1 Report will be reviewed by the
IDMC which will make a recommendation to continue or stop the trial based on the results.
20.4.
Publication
The results of the trial will be published according to the ETOP publication policy.


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20.5.
Clinical trial insurance
ETOP will contract the appropriate liability insurance for this trial. Patients who suffer
injuries due to the trial should report them immediately to their physician. The local
group/institution should report all alleged claims immediately to the ETOP Coordinating
Office.
20.6.
Quality Assurance
ETOP conducts trials according to the ICH Good Clinical Practice (GCP) guidelines. The
Trial Data Manager reviews each CRF as it is received. In addition, the ETOP Medical
Reviewer reviews each case at specific timepoints. ETOP conducts periodic audit visits to
ensure proper trial conduct, verify compliance with GCP, and perform source data
verification.
The Investigator should ensure that source documents are made available to appropriately
qualified personnel from ETOP or its designees, or to Ethics Committee and health authority
inspectors after appropriate notification.
At regular intervals during the clinical trial, the centre will be contacted, through monitoring
visits, letters or telephone calls, by a representative of the monitoring team to review trial
progress, investigator and patient compliance with clinical trial protocol requirements and
any emergent problems. These monitoring visits will include but not be limited to review of
the following aspects: patient informed consent, patient recruitment and follow-up, SAE
documentation and reporting, AEs with pre-specified monitoring documentation and
reporting, AE documentation, dispensing IP, compliance with protocol, drug accountability,
concomitant therapy use, and quality of data.
20.7.
Protocol adherence
Investigators ascertain that they will apply due diligence to avoid protocol deviations. Under
no circumstances should the investigator contact ETOP or personnel monitoring the trial to
request approval of a protocol deviation, as no deviations are permitted. The investigator
should document and explain any deviations from the approved protocol. The investigator
should promptly report any deviations to ETOP and to the EC concerned in accordance with
the applicable EC policies and procedures. If the investigator feels a protocol deviation
would improve the conduct of the trial this must be considered a protocol amendment, and
unless such an amendment is developed and activated by ETOP and approved by the
IRB/IEC/REB it cannot be implemented. All protocol deviations will be recorded.
20.8.
Data protection
The samples and data collected will be coded to protect patient confidentiality. Each patient
will have a unique identifier assigned by the RDE facility ETOPdata. Sites are responsible
to keep a patient log locally in order to be able to link the unique identifier to the record of
the patient.
Biological material will be assigned the same unique identifier. No identifiable / personal
data will be stored in the trial database or the tissue repositories in the central lab.


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Biological material will be transferred outside the treating institution for central review.
Results of the assays will be coded only by the patient identifier.
Regulatory authorities and pertinent Ethics Committees (IRB/ERB) may have access to
patient data on-site. ETOP audit or monitoring personnel will also have access to such data
on-site.
20.9.
Record Retention
The centre must retain all essential documents according to ICH GCP. This includes copies
of the patient trial records, which are considered as source data, patient informed consent
statement, laboratory printouts, drug inventory and destruction logs, and all other
information collected during the trial. These documents are to be stored until at least 15
years after the termination of the trial. ETOP guarantees access and availability of the data
entered into ETOPdata for at least 15 years after the termination of the trial.
Longer retention may be required for participating centres according to national regulations.
In the event that the Principal Investigator retires or changes employment, custody of the
records may be transferred to another competent person who will accept responsibility for
those records. Written notice of such transfer has to be given to ETOP and the local Ethics
Committee at least one month in advance.


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21.
References
1.
Jemal, A., et al., Global cancer statistics. CA Cancer J Clin, 2011. 61(2): p. 69-90.
2.
National, C.I.B., SEER Cancer Statistics Review, 1975-2006. Available at
http://seer.cancer.gov/csr/1975_2006, 2009.
3.
Schiller, J.H., et al., Comparison of four chemotherapy regimens for advanced non-
small-cell lung cancer. N Engl J Med, 2002. 346(2): p. 92-8.
4.
Spector, N.L. and K.L. Blackwell, Understanding the mechanisms behind
trastuzumab therapy for human epidermal growth factor receptor 2-positive breast
cancer. J Clin Oncol, 2009. 27(34): p. 5838-47.
5.
Perera, S.A., et al., HER2YVMA drives rapid development of adenosquamous lung
tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy.
Proc Natl Acad Sci U S A, 2009. 106(2): p. 474-9.
6.
Mazieres, J., et al., Lung cancer that harbors an HER2 mutation: epidemiologic
characteristics and therapeutic perspectives. J Clin Oncol, 2013. 31(16): p. 1997-
2003.
7.
Arteaga, C.L., et al., Treatment of HER2-positive breast cancer: current status and
future perspectives. Nat Rev Clin Oncol, 2012. 9(1): p. 16-32.
8.
Gatzemeier, U., et al., Randomized phase II trial of gemcitabine-cisplatin with or
without trastuzumab in HER2-positive non-small-cell lung cancer. Ann Oncol, 2004.
15(1): p. 19-27.
9.
Arcila, M.E., et al., Prevalence, clinicopathologic associations, and molecular
spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas.
Clin Cancer Res, 2012. 18(18): p. 4910-8.
10.
Ould-Kaci, M., Investigator’s brochure. Afatinib (BIBW 2992). Version 14, 1200.P1
- 1200.P10. , 2013.
11.
Temple, G., S. Bell, and P. Stopfer, A Phase I open-label dose escalation study of
continuous once-daily oral treatment with BIBW 2992 in patients with advanced
solid tumours. Trial 1200.3. . 2010.
12.
Lynch, T.J., Jr., et al., Epidermal growth factor receptor inhibitor-associated
cutaneous toxicities: an evolving paradigm in clinical management. Oncologist,
2007. 12(5): p. 610-21.
13.
Lacouture, M.E., et al., Dermatologic adverse events associated with afatinib: an
oral ErbB family blocker. Expert Rev Anticancer Ther, 2013. 13(6): p. 721-8.
14.
Yang, J.C., et al., Diarrhea associated with afatinib: an oral ErbB family blocker.
Expert Rev Anticancer Ther, 2013. 13(6): p. 729-36.
15.
Moy, B. and P. Goss, Lapatinib-associated toxicity and practical management
recommendations. Oncologist 1007. 12(7): p. 756-765.
16.
Giaccone, G., B. Melosky, and M. Reck, Epidermal growth factor receptor inhibitor
(EGFRI)-associated rash: a suggested novel management paradigm. A consensus
position from the EGFRI dermatologic toxicity forum. , in ECCO2007: Barcelona.
17.
Cappuzzo, F., L. Bemis, and M. Varella-Garcia, HER2 mutation and response to
trastuzumab therapy in non-small-cell lung cancer. N Engl J Med, 2006. 354(24): p.
2619-21.
18.
De Greve, J., et al., Clinical activity of afatinib (BIBW 2992) in patients with lung
adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer,
2012. 76(1): p. 123-7.
19.
Tomizawa, K., et al., Prognostic and predictive implications of HER2/ERBB2/neu
gene mutations in lung cancers. Lung Cancer, 2011. 74(1): p. 139-44.
20.
Porta, C., et al., Management of adverse events associated with use of everolimus in
patients with advance renal cell carcinoma. . Eur J Cancer, 2011. 47: p. 1287-1298.


ETOP 7-14 NICHE V 1.0 01Dec2014
56/56
21.
Simon, R., Optimal two-stage designs for phase II clinical trials. Control Clin Trials,
1989. 10(1): p. 1-10.
22.
Corporation, C.S., EaSt: a software package for the design and interim monitoring
of group sequential clinical trials. , 2011, Cytel Software Corporation, Cambridge,
MA.
23.
Fleming, T.R., ONE-SAMPLE MULTIPLE TESTING PROCEDURE FOR PHASE-II
CLINICAL-TRIALS. Biometrics, 1982. 38(1): p. 143-151.
24.
Jennison, C. and B.W. Turnbull, Group sequential designs with applications to
clinical trials. 2000: Chapman & Hall/CRC, Boca Raton.
25.
Schultz, J.R., et al., Multiple-stage procedures for drug screening. Biometrics, 1973.
29(2): p. 293-300.

SAP_000.pdf: 
Statistical Analysis Plan 
 
ETOP 7-14 NICHE 
 
 
Page 1 of 17 
 
 
 
ETOP 7-14 NICHE 
 
Afatinib in pretreated patients with advanced NSCLC 
harbouring HER2 exon 20 mutations  
 
 
Sponsor: European Thoracic Oncology Platform (ETOP) 
 
 
STATISTICAL ANALYSIS PLAN – FINAL ANALYSIS 
 
 
SAP VERSION 
2.1 
SAP VERSION DATE 
23 January 2017 
TRIAL STATISTICIANS 
Urania Dafni, Zoi Tsourti 
TRIAL PRIMARY INVESTIGATORS 
Rafal Dziadziuszko, Solange Peters 
SAP AUTHOR 
Zoi Tsourti 
APPROVED BY 
Urania Dafni 
 


Statistical Analysis Plan 
 
ETOP 7-14 NICHE 
 
 
Page 2 of 17 
TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................................................................... 3 
1.1 
Preface .................................................................................................................................... 3 
1.2 
History of the Study ............................................................................................................... 3 
1.3 
Purpose of the present Statistical Analysis Plan ................................................................. 4 
2. 
GENERAL CONSIDERATIONS FOR THE ANALYSIS ............................................................................ 4 
2.1 
Timing of Analysis ................................................................................................................. 4 
2.2 
Analysis Populations ............................................................................................................. 4 
2.3 
Statistical Considerations ..................................................................................................... 5 
2.4 
Missing Data ........................................................................................................................... 5 
3. 
SUMMARY OF STUDY DATA ............................................................................................................ 5 
3.1 
MAIN OUTCOME .................................................................................................................... 5 
3.2 
Baseline characteristics ........................................................................................................ 6 
3.3 
Follow-up and treatment administration ............................................................................ 6 
3.4 
Translational results ............................................................................................................. 6 
4. 
EFFICACY ANALYSIS ......................................................................................................................... 6 
5. 
SAFETY ANALYSIS ............................................................................................................................ 7 
6. 
REPORTING CONVENTIONS ............................................................................................................ 8 
7. 
TECHNICAL DETAILS ........................................................................................................................ 8 
8. 
LISTING OF TABLES AND FIGURES ................................................................................................... 8 
APPENDIX .............................................................................................................................................. 16 
 
 
 


Statistical Analysis Plan 
 
ETOP 7-14 NICHE 
 
 
Page 3 of 17 
1. INTRODUCTION 
 
1.1 
Preface 
Afatinib presents a manageable toxicity profile and potentially offers a significant activity 
in terms of disease control and long-term outcome. Therefore this treatment option offers 
a good benefit to risk ratio in patients with HER2-mutate advanced NSCLC. 
The primary objective of the study is to evaluate the ability of afatinib to control disease 
in pretreated patients with advanced NSCLC harbouring HER2 exon 20 mutations. More 
particularly, the primary endpoint is disease control at 12 weeks.  
The secondary objectives of the study are:  
• To evaluate secondary measures of clinical efficacy including progression-free 
survival (PFS),  
• To assess the safety and the tolerability of the treatment.  
 
1.2 
History of the Study 
ETOP/7-14 NICHE trial was activated in December 2014 and the first patient was 
enrolled on September 2015. 
The ETOP IDMC reviewed the trial safety data during its scheduled bi-annually meetings, 
in April 2016 (n=5 patients enrolled; no safety issues identified) and October 2016 
(n=13) when the interim analysis was presented. Follow-up was suspended based on the 
interim analysis and an unscheduled follow-up IDMC meeting in November 2016 on the 
13 enrolled patients enrolled).   
At the IDMC meeting of October 2016, the interim analysis (1st stage of Simon’s two-stage 
design) was presented. Among the first 9 patients, 5 patients (55.6%) had not reached 
week 12 free of progression. Thus, the stopping threshold of the 1st stage of Simon’s two-
stage design was reached, since more than the maximum allowed of 3 patients had a 
progression by 12 weeks. Based on these results, the IDMC recommended suspending 
further recruitment into the trial while continuing the treatment and close follow-up for 
the enrolled patients. 
A follow-up analysis, once all enrolled patients reached the 12-week assessment, was 
performed in November 2016. Among all 13 enrolled patients, 6 patients (46.2%) had not 
reached week-12 free of progression.  


Statistical Analysis Plan 
 
ETOP 7-14 NICHE 
 
 
Page 4 of 17 
Based on the data and results of the interim analysis and considering the protocol 
specified early stopping rule, the IDMC recommended that: 
- The ETOP 7-14 NICHE trial should be permanently closed to accrual. 
- Treatment and follow-up of enrolled patients may continue based on the 
judgement of the treating physician.  
- Patients should be informed. 
 
1.3 
Purpose of the present Statistical Analysis Plan  
The purpose of the present Statistical Analysis Plan (SAP) is to provide an analytic and 
solid framework for the final analysis of the patients enrolled in the NICHE study. 
More details on the planned final evaluation in terms of methods, reporting conventions 
and formats are described in detail in the following sections. 
The overall objectives and methods of the study, as dictated by its protocol, may be found 
in the Appendix. 
 
 
2. GENERAL CONSIDERATIONS FOR THE ANALYSIS 
 
2.1 
Timing of Analysis 
The final analysis will be performed at least six months after the last patient was enrolled 
and as soon as the database is formally locked.  
 
2.2 
Analysis Populations 
Interim evaluation Cohort 
The interim evaluation cohort will include the first 9 patients enrolled in the study, which 
were used for the evaluation of Simon’s stage one. 
Efficacy Cohort 
The efficacy cohort will include all eligible patients enrolled in the study until trial 
termination. 
Safety Cohort 
The safety cohort will encompass all eligible enrolled patients who have received at least 
one dose of trial treatment.  
 


Statistical Analysis Plan 
 
ETOP 7-14 NICHE 
 
 
Page 5 of 17 
2.3 
Statistical Considerations 
Primary endpoint is disease control (DC), defined as complete (CR) or partial response 
(PR), or disease stabilisation (SD) lasting at least 12 weeks. 
Simon’s two stage phase II design has been adopted. A Disease Control Rate (DCR) of 50% 
was considered as unacceptable, targeting a DCR of 75%. Hence the null hypothesis under 
consideration was that the DCR≤50% versus the alternative that DCR≥75%. For a one-
sided type I error of 10% and power of 80%, a total of 22 patients were needed, with 9 
patients in the first stage. If in the first stage, 6 out of the 9 patients achieved Disease 
Control, then the trial would proceed to the second stage and recruit an additional 13 
patients for a total of 22 patients. If at least 14 out of the 22 patients achieved Disease 
Control, then this finding would indicate that it would be reasonable to proceed to a Phase 
III trial. 
Secondary endpoints include objective response (OR), defined as best overall response 
(CR or PR, using RECIST 1.1 criteria) across all assessment time-points during the period 
from enrolment to termination of trial treatment, progression-free survival (PFS), 
defined as the time from the date of enrolment until documented progression or death, 
overall survival (OS), defined as time from the date of enrolment until death from any 
cause (censoring occurring at the last follow-up date), and toxicity as specified by the 
adverse events classified according to NCI CTCAE version 4.  
 
2.4 
Missing Data 
Missing values will not be replaced by any statistics calculated over non-missing data. 
 
3. SUMMARY OF STUDY DATA 
3.1 
MAIN OUTCOME 
The primary endpoint according to study’s protocol, is the DCR.  
DCR will be calculated along with 90% exact binomial confidence interval (CI) for the 
efficacy cohort. 
PFS and OS (medians and rates) will be estimated based on the product-limit Kaplan-
Meier method, while the corresponding 95% CIs for the median values will be based on 
the complementary log–log transformation.  
 


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3.2 
Baseline characteristics  
Baseline characteristics will be summarized and presented overall for all enrolled 
patients. 
All continuous variables will be summarised using the following descriptive statistics: n 
(non-missing sample size), mean, 95% CI for the mean, median, maximum and minimum. 
The frequency and percentages (based on the non-missing sample size) of observed 
levels will be reported for all categorical measures. 
 
3.3 
Follow-up and treatment administration  
Follow-up time will be defined as time between the minimum of enrolment and start 
treatment date and last contact date. The median follow-up will be estimated based on 
reverse censoring of overall survival.   
Time-to-Treatment Failure (TTF) will also be calculated based on the Kaplan-Meier 
method, and the specific reasons of treatment failures will be provided.   
 
3.4 
Translational results  
The results of all translational analyses (of the tests performed centrally) in the frame of 
the study we be analytically presented in tabular format.  
 
4. EFFICACY ANALYSIS 
The primary efficacy analysis will include all eligible enrolled patients. 
The primary endpoint is disease control, defined as complete or partial response or 
disease stabilisation lasting at least 12 weeks.  
Results on the primary endpoint will be presented for the whole efficacy cohort as well 
as for the ‘interim analysis’ cohort. 
Objective response, progression-free survival and overall survival, the secondary 
efficacy endpoints of the NICHE trial, will also be evaluated for the whole efficacy 
cohort. 
Best overall response, defined as best response across all assessment time-points, 
during the period from enrolment to termination of trial treatment, and objective 
response rate, defined as the best overall response (complete or partial response) will 
be summarized in table format. 


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PFS (defined as the time between the minimum of enrolment and start treatment date 
until documented progression or death) and OS (defined as the time between the 
minimum of enrolment and start treatment date until death or last contact date for 
censored patients) will be summarized through tables as well as graphically depicted 
via Kaplan-Meier curves and alternative graphical illustrations if possible (spider plot, 
swimmer plot). 
 
As an exploratory analysis, the association of the primary endpoint (Disease control at 12 
weeks) with patients’ baseline characteristics, prior treatments received as well as with 
translational results will be also investigated.  
More particularly, the distribution of patients’ baseline characteristics and prior 
treatments will be presented separately for the group of patients that achieved disease 
control at 12th week versus the group of patients that did not achieve disease control and 
corresponding Fisher’s exact tests will be provided. 
In a similar manner, all translational results will be presented separately for the groups 
of patients that achieved or not disease control. Also, PFS and OS results will be provided 
for selected subgroups of patients with particular interest (type of ERBB2 mutation, 
Gender and Smoking status). Log-rank test comparing the survival curves between 
subgroups will be also presented. 
 
5. SAFETY ANALYSIS 
The safety cohort will encompass all patients who have received at least one dose of trial 
treatment. Safety and tolerability of the afatinib treatments will be described by 
tabulation of the CTCAE V4 grade. In particular, safety analysis will include assessment 
of the experience of adverse events (AE) and serious adverse events (SAE), the frequency 
of AEs, the numbers of patients experiencing specific number of adverse events and their 
distribution by CTCAE V4 grade. Further exploration on AEs, with respect to their grade 
will include the presentation of maximum severity of AEs for each patient as well as the 
distribution of worst degree of severity by patient.  
Note: If the same adverse event is recorded more than once for a specific patient, it will 
be counted only once keeping the one with the higher grade. 
 


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For a closer investigation and for purposes of medical review, information on AEs will 
also be provided by patient. This information will consist of AE description and grade, 
date of AE onset and end date (if the event is resolved), its potential relation to treatment 
and his/ her specific outcome.  
A summary table of all the narratives of patients with SAE will also be provided. 
Furthermore, the baseline symptoms experienced by some of the patients, which are not 
counted as adverse events –unless their grade was increased or they appeared as new 
events at a later period of time- will be presented separately. 
 
 
6. REPORTING CONVENTIONS 
P-values≥0.001 will be reported with two significant digits (e.g. p=0.26, p=0.026, 
p=0.003); p-values less than 0.001 will be reported as “<0.001”. The mean, 95% 
confidence limits, quantiles, and any other statistics, will be reported to one decimal. 
Hazard ratios (HRs) and their 95% CI’s will be reported to two decimals. Estimated 
parameters, not on the same scale as raw observations (e.g. regression coefficients) will 
be reported to 3 decimals.  
 
7. TECHNICAL DETAILS 
Data will be analyzed using the SAS software package (version 9.4). The use of R language 
will also be considered for the production of specific plots. 
A second statistician, the reviewing statistician will independently reproduce all 
analysis and summary statistics. The reviewing statistician will have an overview of the 
entire analysis and will explicitly check the code producing tables and figures as well as 
any other pieces of code as desired. 
 
 
8. LISTING OF TABLES AND FIGURES 
Table 1 gives a tabulation of the following aspects unique to each table: 
▪ Title 
▪ Numbering 
▪ Population 
▪ Endpoint(s) 


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▪ Time Points or details of how to conglomerate multiple observations 
▪ Covariates or Subgroups used to break down summary statistics 
▪ Which summary statistics will be calculated 
 
 
For figures the equivalent information is summarized in Table 2 and includes the 
following: 
▪ Title 
▪ Numbering 
▪ Population 
▪ Type of figure  
▪ Endpoint(s), and which is used for horizontal and vertical co-ordinates 
▪ Statistic(s) used in calculating co-ordinate values used in the figure 
▪ Covariates used within the figure used to determine colours or symbols 
 


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Table 1. Listing of Tables 
 
Table title 
Number 
Population 
Endpoint 
Time Points 
or how to 
conglomerate 
Covariates or 
Subgroups 
Summary 
Statistics 
Formal 
Analysis 
Notes 
Section I: Patient Accrual & Baseline Characteristics 
Accrual by center 
1 
Efficacy 
cohort 
Accrual 
NA 
center 
n (%) 
NA 
Sorted by 
descending “n” 
Patient and tumor 
baseline characteristics 
2 
Efficacy 
cohort 
Gender  
Smoking history 
ECOG Performance status (at 
enrolment) 
TNM staging 
Age (yrs at enrollment) 
Baseline 
- 
n (%) 
NA 
 
Information on 
previous and 
subsequent lines of 
treatment 
3 
Efficacy 
cohort 
Type of prior platinum 
treatment 
Afatinib Treatment Line 
Further treatment 
Type of further treatment 
Baseline, 
Follow-up 
- 
n (%) 
NA 
 
History of previous 
diseases/conditions 
4 
Efficacy 
cohort 
Types of previous diseases and 
conditions 
Baseline 
- 
n (%) 
NA 
 
Results of HER2 central 
testing 
5 
Efficacy 
cohort 
HER2 (ERBB2) mutation 
Baseline 
- 
n (%) 
NA 
 
Section II: Follow-up & Treatment Administration 
Time on follow-up and 
Time on treatment 
6 
Efficacy 
cohort 
No. of patients still on f-up, no. 
of discontinuations 
End of follow-
up 
- 
n (%) 
median, interq. 
range  
Reverse 
Censoring 
based on 
OS (f-up) 
Kaplan – 
Meier 
analysis 
(both) 
 
 
Reasons of treatment 
failures 
7 
Efficacy 
cohort 
Reasons of treatment failures 
 
 
n (%) 
NA 
 
Section III: Analysis of Primary Endpoint 


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Table title 
Number 
Population 
Endpoint 
Time Points 
or how to 
conglomerate 
Covariates or 
Subgroups 
Summary 
Statistics 
Formal 
Analysis 
Notes 
Disease Control Rate 
(DCR) at 12 weeks 
8 
Interim 
evaluation 
cohort 
& 
Efficacy 
cohort 
Disease Control (Yes / No) 
12-week 
evaluation 
(tumor 
assessment) 
- 
n (%) 
NA 
 
Section IV: Analysis of Secondary Efficacy Endpoints 
Best Overall Response 
and Objective Response 
Rate (ORR) for all 
enrolled patients 
(N=13) 
9 
Efficacy 
cohort 
Best Overall Response, ORR 
OR: The best 
overall 
response (CR 
or PR) across 
all assessment 
time-points 
according to 
RECIST 
Criteria 1.1, 
during the 
period from 
enrolment to 
termination of 
trial 
treatment.  
 
n (%) 
 
 
Progression-free 
Survival (PFS) for all 
enrolled patients 
(N=13) 
10 
Efficacy 
cohort 
PFS 
PFS: time from 
the date of 
enrolment 
until 
documented 
progression or 
death without 
documented 
progression  
- 
KM estimates: 
no. of patients, 
n(%) of PFS 
events, 12-week 
PFS (%) (95% 
CI), median PFS 
(in weekw)  
Kaplan – 
Meier 
analysis 
 
Overall Survival (OS) 
for all enrolled patients 
(N=13) 
11 
Efficacy 
cohort 
OS 
OS: time from 
the date of 
enrolment 
until death 
- 
KM estimates: 
no. of patients, 
n(%) of deaths, 
xx-weeks OS 
Kaplan – 
Meier 
analysis  
 


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Table title 
Number 
Population 
Endpoint 
Time Points 
or how to 
conglomerate 
Covariates or 
Subgroups 
Summary 
Statistics 
Formal 
Analysis 
Notes 
from any 
cause 
(%) (95% CI), 
median OS (in 
weeks)  
Section V: Translational Results 
Translational results of 
central testing 
12 
Efficacy 
cohort 
All biomarkers included in the 
central testing (wild-type, 
mutation detected, type of 
mutation detected) 
Baseline 
- 
n (%) 
 
 
Section VI: Exploratory Analysis of Efficacy Endpoints  
Primary endpoint by 
baseline characteristics 
13 
Efficacy 
cohort 
DC at 12w achieved or not for 
each value of baseline 
characteristics 
12-week 
assessment 
Different values 
of baseline 
characteristics 
n (%) 
Fisher’s 
exact test 
 
Primary endpoint by 
prior treatment 
14 
Efficacy 
cohort 
DC at 12w achieved or not for 
each value of prior treatment 
12-week 
assessment 
Different types 
of prior 
treatment 
n (%) 
Fisher’s 
exact test 
 
Primary endpoint by 
translational results 
15 
Efficacy 
cohort 
DC at 12w achieved or not for 
each value of biomarkers 
centrally tested 
12-week 
assessment 
Different status 
of biomarkers 
tested 
n (%) 
Fisher’s 
exact test 
 
Progression-free 
survival (PFS) for 
selected subgroups of 
patients 
16 
Efficacy 
cohort 
PFS 
PFS: time from 
the date of 
enrolment 
until 
documented 
progression or 
death without 
documented 
progression  
ERBB2, gender, 
smoking status 
KM estimates: 
no. of patients, 
n(%) of PFS 
events, 12-week 
PFS (%) (95% 
CI), median PFS 
(in weekw)  
Kaplan – 
Meier 
analysis 
 
Overall survival (OS) 
for selected subgroups 
of patients 
17 
Efficacy 
cohort 
OS 
OS: time from 
the date of 
enrolment 
until death 
from any 
cause 
ERBB2, gender, 
smoking status 
KM estimates: 
no. of patients, 
n(%) of deaths, 
xx-weeks OS 
(%) (95% CI), 
median OS (in 
weeks)  
Kaplan – 
Meier 
analysis  
 


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Table title 
Number 
Population 
Endpoint 
Time Points 
or how to 
conglomerate 
Covariates or 
Subgroups 
Summary 
Statistics 
Formal 
Analysis 
Notes 
Section VII: Safety Analysis 
 (Serious) Adverse 
event overview 
18 
Safety 
cohort 
AE / SAE 
At the end of 
each 
treatment 
visit, Within 
24h of 
occurrence of 
SAE 
- 
n (%) of 
persons who 
have 
experienced 
>=1 AE or SAE 
- 
 
Number of patients 
experiencing specific 
number of adverse 
events 
19 
Safety 
cohort 
AE 
At the end of 
each 
treatment visit 
- 
n (%) 
- 
 
Number of patients 
experiencing specific 
number of serious 
adverse events 
20 
Safety 
cohort 
SAE 
At the end of 
each 
treatment 
visit, Within 
24h of 
occurrence of 
SAE 
- 
n (%) 
- 
 
Maximum severity of 
adverse events 
(AE/SAE) per patient 
21 
Safety 
cohort 
AE / SAE 
At the end of 
each 
treatment 
visit, Within 
24h of 
occurrence of 
SAE 
- 
n (%) 
 
 
Distribution of adverse 
events (AE/SAE) by 
Grade 
22 
Safety 
cohort 
AE / SAE 
At the end of 
each 
treatment 
visit, Within 
24h of 
occurrence of 
SAE 
Severity grade 
(NCI CTCAE 
version 4) 
 
n (%) 
- 
In case of 
multiple reports 
of the same 
AE/SAE 
(grouped 
according to 
CTCAE V4) for a 
particular 
patient, the 


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Table title 
Number 
Population 
Endpoint 
Time Points 
or how to 
conglomerate 
Covariates or 
Subgroups 
Summary 
Statistics 
Formal 
Analysis 
Notes 
event is counted 
once. 
Baseline symptoms by 
patient 
23 
Safety 
cohort 
AE 
At baseline 
- 
- 
- 
Patients ordered 
by enrolment 
date 
 
Adverse event 
information by patient 
24 
Safety 
cohort 
AE / SAE 
At the end of 
each 
treatment 
visit, Within 
24h of 
occurrence of 
SAE 
- 
- 
- 
Patients ordered 
by enrolment 
date 
 
Narratives of patients 
with SAE 
25 
Safety 
cohort 
SAE 
At the end of 
each 
treatment 
visit, Within 
24h of 
occurrence of 
SAE 
- 
- 
- 
Patients ordered 
by enrolment 
date 
 
 
 
 
 
 


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Table 2. Listing of Figures 
Title 
Number 
Population 
Type of 
graph 
Horizontal 
Variables 
Vertical 
Variables 
Groupings 
Notes 
Section I: Patient Accrual & Baseline Characteristics 
Expected vs Observed 
Accrual 
1 
Efficacy cohort 
Line graph 
time 
cumulative 
number of 
patients 
- 
- 
Section II: Follow-up & Treatment Administration 
Kaplan Meir plot for 
Time-to-Treatment 
Failure (TTF) 
2 
Efficacy cohort 
KM 
time 
probability 
- 
- 
Section IV: Analysis of Secondary Efficacy Endpoints 
Plot of tumor response 
3 
patients in efficacy 
cohort evaluable for 
tumor-response 
Spider plot 
time 
% change (in 
sum of 
diameter of 
target 
lesions) from 
baseline 
 
It depends on the data 
whether it will be 
feasible to produce it 
Plot of duration of 
tumor response 
4 
patients in efficacy 
cohort evaluable for 
tumor-response 
Swimmer 
plot 
Duration of 
response (in 
weeks) 
Patient id 
- 
It depends on the data 
whether it will be 
feasible to produce it 
Kaplan Meir plot for 
Progression Free 
Survival (PFS)  
5 
Efficacy cohort 
KM 
time 
probability 
- 
- 
Plot of Progression-free 
Survival by patient, 
according to primary 
endpoint (disease 
achieved at 12 weeks) 
6 
Efficacy cohort 
Bar-plot 
Patient id 
PFS (in 
weeks) 
- 
Additional patients’ 
characteristics will be 
shown below the bars 
Kaplan Meir plot for 
Overall Survival (OS)  
7 
Efficacy cohort 
KM 
time 
probability 
- 
- 
 


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APPENDIX 
IMPORTANT INFORMATION AS DESCRIBED IN THE PROTOCOL 
 
Objectives 
The primary objective of the study is to evaluate the ability of afatinib to control disease in pretreated patients 
with advanced NSCLC harbouring HER2 exon 20 mutations. More particularly, the primary endpoint is disease 
control at 12 weeks. 
Secondary objectives 
The secondary objectives of the study are: 
• 
To evaluate secondary measures of clinical efficacy including progression-free survival (PFS),  
• 
To assess the safety and the tolerability of the treatment. 
 
Endpoints 
1. Primary endpoint: Disease control at 12 weeks 
2. Secondary endpoints: 
a. 
Progression-free survival by RECIST v1.1 
b. Objective response rate by RECIST v1.1 
c. 
Overall survival  
d. Adverse events graded according to CTCAE V4.0 
 
Most important eligibility criteria 
Inclusion criteria at enrolment: 
• 
Histologically or cytologically confirmed, non-predominant squamous subtype,  
• 
Stage IIIB (non amenable to curative-intent multimodal treatment) or IV NSCLC, according to 7th TNM 
classification 
• 
Tumour is platinum-refractory 
• 
Measurable or evaluable disease (according to RECIST 1.1 criteria) 
• 
Locally documented HER2 mutation 
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 
• 
Life expectancy >3 months 
• 
Adequate haematological, renal and hepatic function 
• 
Effective contraception, no pregnancy 
Exclusion criteria at enrolment: 
• 
Mixed small-cell and non-small-cell histologic features 
• 
Uncontrolled lepto-meningeal metastatic disease 
• 
Previous treatment with HER2 targeted antibody or tyrosine kinase inhibitor 
• 
Any previous (in the past 3 years) or concomitant malignancy EXCEPT adequately treated basal or 
squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ ductal carcinoma 
of the breast 
• 
History or presence of clinically relevant cardiovascular abnormalities 


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• 
Other serious diseases or clinical conditions, including but not limited to uncontrolled active infection 
and any other serious underlying medical processes that could affect the patient’s capacity to participate 
in the trial 
• 
Interstitial lung disease or pulmonary fibrosis 
• 
Any concurrent systemic anticancer therapy 
 
Treatment 
Afatinib 40 mg p.o./day until tumour progression or lack of tolerability 
 
SCHEMA 1. Trial design 
 
Population: Advanced stage NSCLC, harbouring HER2 exon 20 mutations. 
Design:  A Phase II single-arm multicenter trial 
Planned sample size: 22 patients 
Total trial duration: 40 months from enrolment of the first patient, including 6 months of follow-up from 
enrolment of the last patient 
 
Statistical considerations 
Simon’s two stage phase II design is adopted. A Disease Control Rate (DCR) of 50% is considered as 
unacceptable, targeting a DCR of 75%. Hence the null hypothesis under consideration is that the 
DCR≤50% versus the alternative that DCR≥75%. For a one-sided type I error of 10% and power of 
80%, a total of 22 patients are needed, with 9 patients in the first stage. If in the first stage, 6 out of 
the 9 patients achieve Disease Control, then the trial will proceed to the second stage and recruit an 
additional 13 patients for a total of 22 patients. If at least 14 out of the 22 patients achieve Disease 
Control, then this finding will indicate that it would be reasonable to proceed to a Phase III trial.