Conditions: Neuroectodermal Tumors Rhabdomyosarcoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 56
Healthy volunteers: no

Brief summary:
Open-label, dose escalation, monotherapy, basket trial with biomarker specific MTD expansion cohort/Phase II part.

The trial will consist of 2 parts:

1. Dose finding part to determine the MTD
2. Biomarker specific MTD expansion cohort/Phase II part to assess clinical anti-tumour activity in included tumour types

Detailed description:

Arms:
arm 1: dose escalation

Interventions: intervention 1: afatinib
Intervention descriptions: intervention 1: None

Protocol document:
Prot_001.pdf: 
Clinical Trial Protocol
Doc. No.: c02332639-05
EudraCT No.:
BI Trial No.:
2014-002123-10
1200.120
BI Investigational
Product(s):
Giotrif®, Gilotrif®, Afatinib Capsules and Solvent for Oral Solution
Title:
Phase I/II open label, dose escalation trial to determine the MTD, 
safety, PK and efficacy of afatinib monotherapy in children aged ≥1 
year to <18 years with recurrent/refractory neuroectodermal tumours,
rhabdomyosarcoma and/or other solid tumours with known ErbB 
pathway deregulation regardless of tumour histology
Clinical Phase:
I/II
Trial Clinical 
Monitor:
Phone: 
Fax:
Co-ordinating 
Investigator:
Phone: 
Fax: 
Status:
Final protocol (based on global amendment 3)
Version and Date:
Version: 4
           
Date: 02 June 2017  
Version: 1 (initial 
protocol)
12 December 2014
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TITLE PAGE


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Giotrif®, Gilotrif®, Afatinib Capsules and 
Solvent for Oral Solution
Name of active ingredient:
Afatinib
Protocol date:
Trial number:
Revision date:
02 June 2017
12 Dec 2014
1200.120
Title of trial:
Phase I/II open label, dose escalation trial to determine the MTD, safety, PK and 
efficacy of afatinib monotherapy in children aged ≥1 year to <18 years with 
recurrent/refractory neuroectodermal tumours, rhabdomyosarcoma and/or other 
solid tumours with known ErbB pathway deregulation regardless of tumour 
histology
Co-ordinating 
Investigator:
Trial site(s):
International, multi-centre trial with participation of ITCC trial sites specialized in 
paediatric oncology and new drug development
Clinical phase:
I/II


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Giotrif®, Gilotrif®, Afatinib Capsules and 
Solvent for Oral Solution
Name of active ingredient:
Afatinib
Protocol date:
Trial number:
Revision date:
02 June 2017
12 Dec 2014
1200.120
Objective(s):
Dose finding part
-
To determine the maximum tolerated dose (MTD) of afatinib in patients ≥2 
to <18 years by assessing dose limiting toxicity (DLT). The MTD will be 
determined as the highest dose at which no more than 1/6 patients 
experienced DLT. 
-
To assess safety
-
To describe the pharmacokinetics (PK) after first dose and at steady state in 
children. 
-
To investigate objective response (OR) to treatment 
MTD expansion cohorts/Phase II part
-
Patients aged ≥1 year to <18 years included into the MTD expansion 
cohorts/Phase II
part
will be selected by biomarker(s)
for ErbB 
deregulation, which were previously identified in the biomarker prevalence 
study outside of this clinical trial protocol, i.e. fulfil at least two of the 
below criteria:
o
EGFR gene amplification (FISH) and/or
o
HER2 gene amplification (DDISH) and/or
o
EGFR protein expression (H score >150) and/or
o
HER2 protein expression (H-score > 0)
Patients aged ≥1 year to <18 years with proven genomic, transcriptomic or 
proteomic ErbB alterations which are not defined above will be included in 
an exploratory cohort (for further information see section 5.6)
-
To investigate objective response (OR) to treatment, progression free 
survival (PFS) and duration of objective response (DoR)
-
To collect further safety, PK and efficacy data 


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Giotrif®, Gilotrif®, Afatinib Capsules and 
Solvent for Oral Solution
Name of active ingredient:
Afatinib
Protocol date:
Trial number:
Revision date:
02 June 2017
12 Dec 2014
1200.120
Methodology:
Open-label, dose escalation, monotherapy trial with biomarker specific MTD 
expansion cohorts/ Phase II part.
The trial will consist of 2 parts:
1)
Dose finding part to determine the MTD 
2)
MTD expansion cohorts/Phase II part to assess clinical anti-tumour activity 
in patients selected by any two of the above detailed biomarkers for ErbB 
deregulation; i.e. EGFR FISH positive and/or EGFR H-score >150 and/or 
HER2-DDISH positive and/or HER2 H-score >0. Patients with proven
genomic, transcriptomic or proteomic ErbB alterations which are not 
defined above will be included in an exploratory cohort.
No. of patients: 
total entered:
Approximately up to 550 patients will need to be screened to allow for up to55 
patients who are entered and evaluable for response/MTD
each treatment:
- Dose finding part: 17 patients were entered to determine the MTD (c09990672-01)
- MTD expansion cohorts/Phase II part: Up to 38 patients evaluable for OR will be 
entered.

A minimum of 5 patients in each of the four following cohorts, i.e. high grade 
glioma (HGG), diffuse intrinsic pontine glioma (DIPG), ependymoma (EM)
and a mixed histology agnostic cohort of patients with refractory tumours, will 
be accrued. All patients must fulfil two of the biomarker screening criteria, i.e. 
EGFR FISH positive and/or EGFR H-score >150 and/or HER2-DDISH 
positive and/or HER2 H-score >0. 

An exploratory histology agnostic patient cohort with proven genomic, 
transcriptomic or proteomic ErbB alterations which are not defined above will 
be added.
Diagnosis :
Paediatric patients with recurrent/refractory HGG, DIPG, low grade astrocytoma,
neuroblastoma, EM, medulloblastoma/primitive neuroectodermal tumours (PNET),
rhabdomyosarcoma (RMS) and/or other solid tumours with known ErbB pathway 
deregulation regardless of tumour histology will be included during the dose finding 
part. 
From the MTD expansion cohorts/phase II part onwards, patients with either HGG, 
DIPG, EM or any other solid tumour selected by biomarkers for ErbB deregulation; 
i.e. EGFR FISH positive and/or EGFR H-score >150 and/or HER2-DDISH positive 
and/or HER2 H-score >0 and patients regardless of tumour indication but with
proven genomic, transcriptomic or proteomic ErbB alterations which are not defined 
above will be included.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Giotrif®, Gilotrif®, Afatinib Capsules and 
Solvent for Oral Solution
Name of active ingredient:
Afatinib
Protocol date:
Trial number:
Revision date:
02 June 2017
12 Dec 2014
1200.120
Main criteria
for inclusion:
-
Paediatric patients 
-
presenting with recurrent/refractory disease after they received at least one 
prior standard treatment regimen and for whom no effective conventional 
therapy exists
Dose finding part 
-
aged ≥2 years - <18 years at the time of informed consent
-
Patients with a diagnosis of HGG, DIPG, low grade astrocytoma,
neuroblastoma, EM, medulloblastoma/PNET, RMS, and/or solid tumours 
with known ErbB pathway deregulation regardless of tumour histology. 
MTD expansion cohorts/phase II part:
- aged ≥1 year to <18 years at the time of informed consent
-
patients with HGG, DIPG, EM and any other solid tumour which fulfil at 
least two of the below criteria:
o
EGFR gene amplification (FISH): Either EGFR/Cen7 ≥ 2.0 or
≥10% of cells with ≥15 copies or ≥40% of cells with ≥ 4 copies or 
gene cluster in ≥10% of cells 
and/or
o
HER2 gene amplification (DDISH): Her2/CEP17 ≥ 2.0 
and/or
o
EGFR protein expression: H-score > 150 (membrane staining)
and/or
o
HER2 protein expression: H-score > 0 (membrane staining)
-
patients with proven genomic, transcriptomic or proteomic ErbB alterations 
which are not defined above regardless of tumour histology
Test product(s):
Giotrif®, Gilotrif®, Afatinib
dose:
Once daily dosing of afatinib using film coated tablets 20, 30, 40 or 50mg afatinib 
or age appropriate oral liquid dosage form at a concentration of 4mg/ml. The dose 
will be calculated by allometric scaling per m2BSA.
Dose escalation starts at 80% of recommended adult dose (40mg once daily) based 
on allometric scaling per m²BSAwith escalation levels to 100%, 125% and 150%; in 
case 80% is exceeding the MTD, dose level “-1” will allow dose de-escalation to 
50%
mode of admin.:
Oral 


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Giotrif®, Gilotrif®, Afatinib Capsules and 
Solvent for Oral Solution
Name of active ingredient:
Afatinib
Protocol date:
Trial number:
Revision date:
02 June 2017
12 Dec 2014
1200.120
Comparator products:
Not applicable
Duration of treatment:
Therapy with afatinib will continue as long as the individual patient benefits from
therapy, does not develop secondary malignancy and does not meet one of the 
criteria requiring withdrawal from treatment 
Criteria for efficacy:
- Anti-tumour activity measured as objective response (OR) assessed by the 
investigator according to the institution’s tumour response evaluation criteria for 
the given tumour type
- Duration of objective response (DoR) for those patients with a response (CR or 
PR)
- Progression free survival (PFS) 
Criteria for 
pharmacokinetics
- PK parameters of afatinib based on noncompartmental analysis (NCA) after 1st
dose and at steady state (AUCτ(,ss), Cmax(,ss), tmax(,ss) and accumulation (or effective) 
half-life) for patients with extensive PK sampling
- PK parameters of afatinib based on population PK modeling (Cmax,ss, AUCτ,ss, 
CL/F, Vd/F) for all patients with sparse and extensive PK sampling
Criteria for safety:
- Evaluation of safety and tolerability of afatinib by incidence and severity of 
adverse events according to Common Terminology Criteria for Adverse
Events (CTCAE v3.0)
- Assessment of the MTD of afatinib in the dose finding part
The recommended safe paediatric dose will take all safety assessments during dose 
finding part and MTD expansion cohorts/phase II part into consideration
Statistical methods:
Descriptive statistics, frequency tables for DLTs
Objective response rate will be calculated with exact 95% confidence interval. DoR
for patients with response and PFS will be evaluated using Kaplan-Meier estimate. 
The analyses will be exploratory and descriptive in nature


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FLOW CHART
Trial periods
screen
Treatment Course 1
Treatment
Course 21
Treatment 
Course 3 and 
onwards1
Day of period
-28 to 
0
1
2
8
±2
15 
±2
22 
±2
1
±2
151
±2
1
±2
EOT2
FU3
OP4
Visit
1
2
3
4
1
2
1
Informed consent /patient 
assent
x5
Demographics
x
Medical history
x
Physical examination
including neurological 
exam in patients with 
brain tumours
x
x
x
x
x
x
x
x
x
x
Ophthalmologic 
examination
x
x
Pulmonary examination6
x
x
x
x
x
Performance score22
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height 7
x
x7
Weight
x
x
x
x
x
x
x
x
Safety laboratory tests8-9
x
x8
x9
x9
x9
x
x9
x
x8
Pregnancy test (if appl.)10
x
x
12 lead-ECG11
x
x
x11
x
LVEF echo
x
x
x12
x
Disease assessment
imaging13
x
x13
x
Tumour marker(s) 14
x
x
x
x
Tumour sample tissue 
availability23
x
Review in-/ex- criteria
x
Dose assessment
x
x15
x15
x15
Dispense trial drug16
x
x
x
Afatinib administration
Continuous oral once daily, fasted
Pharmacokinetics
x17
x17
x17
x17
Adverse events
x
x
x
x
x
x18
x
x
x
x
x19
Concomitant therapies
x
x
x
x
x
x
x
x
x
x
Compliance check
x
x
x
x
Patient diary check
x
x
x
x
x
x
x
Eligibility for treatment 
continuation
x
x
Conclusion of treatment
x
Conclusion  of patient 
participation
x
Survival status
x
1
All courses are of 4 weeks duration (28 days). Day 1 of a new course should take place on day 29. Patients may continue 
on treatment for unlimited courses until the criteria for stopping medication are met (see Section 3.3.4). Visits are 
performed weekly for the first course. At course 2, visits will take place every 2 weeks (Visit 2 day 8 and visit 4 day 22 
are no longer requested). From course 3 onwards, only visits “1” are required.
2
EOT= end of treatment – When the decision is taken to permanently discontinue the study medication, the EOT visit 
must be performed within 7 days after last administration of afatinib. If the decision is taken at a scheduled visit, the 
EOT visit will be performed instead of the scheduled visit. Examinations performed at this time may need to be renamed 
for the actual visit conducted.
3
FU= safety follow-up 28 to 30days after last afatinib administration. With the FU visit the patient will have completed 
his/her trial participation.
4
OP= observation (post-trial) period. Collection of information on vital status every 3 months. Information could be 
collected from the patient’s notes or by telephone contact. A formal visit is not required.


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5
Before any trial procedure, both the patient and/or parent/legal guardian have to give informed consent/assent according 
to the local regulatory requirements. At each moment along the trial, the site staff must disclose and discuss any new 
information that might affect willingness to continue trial participation with the patient and/or parent/legal guardian. For 
the MTD expansion cohorts/phase II part a high rate of screening failures is expected. Therefore a pre-screening
informed consent may be used to allow collection and testing of tumour tissue for ErbB deregulations (see section 3.3.2). 
Upon confirmation of positivity for selection biomarkers and before to proceed with trial procedures the informed 
consent/assent for trial entry, as mentioned earlier in this footnote, must be signed.
6
Pulmonary examination must include transdermal O2 saturation at screening, at visit 1 of each course and EOT. It should 
be repeated as clinically indicated during the trial and may be supplemented by a chest X-ray if clinically indicated.
7
Measurement of height (in cm) will be performed on day1 every other courses.
8
Safety lab tests should not be repeated if previous tests are not older than 48 hours.
9
Safety lab test at visits 2, 3, 4 of courses 1 and 2 to be limited as described in Section 5.2.3.
10 Mandatory for female patients of child bearing potential (post menarchal) within 7 days prior to first treatment and at 
EOT. To ensure early detection of pregnancy, test might be repeated as necessary during the treatment period depending 
on the local law.
11 ECG is required at screening, at C1V2, V1 every third course thereafter (i.e. C4V1, C7V1…) and EOT.  
12 Left ventricular ejection fraction (LVEF) at screening, at end of course 1 (C2V1 visit) and to be repeated C4V1, every 
3rd course thereafter (C7V1…) and EOT.
13 Imaging (CT or MRI for CNS tumours or soft tissue lesions) assessment is to be performed every 8 weeks until 
progression of disease. In case of objective response, the latter has to be confirmed 4 to 6 weeks after initial OR 
observation. Consecutive imaging assessment will be performed every 8 weeks. In exceptional cases when patients have 
been stable on treatment for at least 2 consecutive images (i.e. 16 weeks), imaging intervals may be extended to 12 
weeks upon discussion between the investigator and the sponsor.
14 Tumour marker(s) in urine or blood as indicated depending on tumour type (e.g. catecholamines (VMA/HVA, 
dopamine), NSE in neuroblastoma)
15 Intra-patient dose escalation might be allowed as soon as the next higher dose tier is completed and considered safe
(applicable to dose finding part only). A dose reduction can also be applied in case of drug-related toxicity (see Section 
4.1.4.3)
16 New kit(s) of trial drug must be dispensed at visit 1 of each course. If needed (e.g. in case a dose adaptation has to be 
applied during treatment course), new kit(s) of trial drug might be dispensed outside of the planned visit schedule 
17 A full PK profile (extensive PK sampling) is to be taken at course 1, day 1: pre-dose before afatinib administration then 
1h, 2h, 3h, 4h, 5h, 6h, 8h and 24h after administration and to be repeated at steady state on day8. In exceptional cases 
where extensive PK sampling is not possible, a limited sampling approach must be applied with blood sampling before, 
1h and 3 h after afatinib administration. An additional trough sample is to be taken on day 15 to confirm steady state 
exposure to afatinib. In addition, trough CSF sampling (from Rickham, Ommaya reservoirs or from lumbar puncture 
performed for clinical reasons not related to the trial) may be taken on day 8 or later. This CSF sampling is optional. 
Each trough CSF sample has to be accompanied by a trough plasma sample taken at the same time-point. For further 
details on time points and sampling volumes, see Section 5.5.2 and Appendix 10.3 .
18 During the dose escalation part, a DLT confirmation fax has to be sent to the sponsor before start of course 2.
19 AE/SAE after the 28-30 days FU period have to be reported only if considered relevant by the investigator.
22 Lansky for patients ≤ 12 years or Karnofsky for patients older than 12 years at time of informed consent
23 Tumour samples must be assessed for ErbB deregulation with start of recruitment into the MTD expansion cohorts/phase 
II part see Section 3.3.1. For patients with proven genomic, transcriptomic or proteomic ErbB alterations a confirmatory 
analytical laboratory report has to be provided to the sponsor. Inclusion will be dependent on ErbB deregulation from 
that time point onwards, for details see Section 4.1.2 and Section 5.6.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................7
TABLE OF CONTENTS ...................................................................................9
ABBREVIATIONS.......................................................................................... 13
1.
INTRODUCTION.................................................................................... 16
1.1
MEDICAL BACKGROUND............................................................................16
1.2
DRUG PROFILE...............................................................................................21
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 24
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................24
2.2
TRIAL OBJECTIVES.......................................................................................25
2.3
BENEFIT - RISK ASSESSMENT ...................................................................26
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 28
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................28
3.1.1
Administrative structure of the trial...................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................30
3.3
SELECTION OF TRIAL POPULATION ......................................................31
3.3.1
Main diagnosis for study entry............................................................31
3.3.2
Inclusion criteria...................................................................................32
3.3.3
Exclusion criteria ..................................................................................33
3.3.4
Removal of patients from therapy or assessments.............................34
3.3.4.1
Removal of individual patients................................................34
3.3.4.2
Discontinuation of the trial by the sponsor..............................35
4.
TREATMENTS........................................................................................ 37
4.1
TREATMENTS TO BE ADMINISTERED....................................................37
4.1.1
Identity of BI investigational product.................................................37
4.1.2
Method of assigning patients to treatment groups ............................38
4.1.3
Selection of doses in the trial................................................................38
4.1.4
Drug assignment and administration of doses for each patient .......39
4.1.4.1
Dose escalation of afatinib for MTD determination................41
4.1.4.2
Intra-patient dose escalation of afatinib...................................43
4.1.4.3
Dose reduction of afatinib........................................................43
4.1.5
Blinding and procedures for unblinding ............................................45


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4.1.5.1
Blinding....................................................................................45
4.1.5.2
Procedures for emergency unblinding .....................................45
4.1.6
Packaging, labelling, and re-supply ....................................................45
4.1.7
Storage conditions.................................................................................45
4.1.8
Drug accountability ..............................................................................46
4.1.9
Drug acceptability.................................................................................47
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................47
4.2.1
Rescue medication, emergency procedures, and additional 
treatment(s) ...........................................................................................47
4.2.2
Management of expected adverse events............................................48
4.2.2.1 Management of diarrhoea and hydration status following 
treatment with afatinib.............................................................48
4.2.2.2
Management recommendations for dermatological AEs 
following treatment with afatinib.............................................50
4.2.2.3
Management of mucositis/stomatitis .......................................53
4.2.3
Restrictions............................................................................................54
4.2.3.1
Restrictions regarding concomitant treatment .........................54
4.2.3.2
Restrictions on diet and life style.............................................55
4.2.3.3
Boys and girls with reproductive potential – contraception and 
pregnancy prevention...............................................................55
4.3
TREATMENT COMPLIANCE.......................................................................55
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 57
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................58
5.1.1
Endpoint(s) of efficacy..........................................................................58
5.1.1.1    Primary endpoint.....................................................................58
5.1.1.2   Secondary endpoints ................................................................58
5.1.2
Assessment of efficacy...........................................................................58
5.2
SAFETY..............................................................................................................58
5.2.1
Endpoint(s) of safety.............................................................................58
5.2.2
Assessment of adverse events...............................................................59
5.2.2.1
Definitions of adverse events...................................................59
5.2.2.2
Adverse event and serious adverse event reporting.................62
5.2.2.3
Pregnancy reporting.................................................................63
5.2.3
Assessment of safety laboratory parameters......................................64
5.2.4
Electrocardiogram................................................................................65
5.2.5
Assessment of other safety parameters...............................................65
5.2.5.1
Physical examination, vital signs, height and weight, 
performance score....................................................................65
5.2.5.2
Left ventricular function ..........................................................65
5.2.5.3
Ophthalmologic examination...................................................65


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5.2.5.4
Pulmonary examination ...........................................................65
5.3
OTHER...............................................................................................................66
5.3.2
Other assessment(s) ..............................................................................66
5.3.3
Pharmacogenomic evaluation..............................................................66
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................66
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................67
5.5.1
Pharmacokinetic endpoint(s)...............................................................67
5.5.2
Methods of sample collection...............................................................68
5.5.3
Analytical determinations ....................................................................68
5.6
.68
5.6.1
Endpoints based on biomarker(s) .......................................................72
5.6.2
Methods of sample collection...............................................................72
5.6.3
Analytical determinations ....................................................................72
5.7
PHARMACODYNAMICS................................................................................72
5.7.1
Pharmacodynamic endpoints...............................................................72
5.7.2 Methods of sample collection...............................................................72
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....72
6.
INVESTIGATIONAL PLAN.................................................................. 73
6.1
VISIT SCHEDULE............................................................................................73
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................73
6.2.1
Screening period....................................................................................73
6.2.2
Treatment period(s)..............................................................................74
6.2.3
End of treatment and follow-up period ..............................................77
6.2.4
Observational period ............................................................................78
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 79
7.1
STATISTICAL DESIGN - MODEL................................................................79
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................79
7.3
PLANNED ANALYSES....................................................................................79
7.3.1
Primary analyses...................................................................................79
7.3.2
Secondary analyses ...............................................................................80
7.3.3
Safety analyses.......................................................................................81
7.3.4
Interim analyses ....................................................................................82
7.3.5
Pharmacokinetic analyses ....................................................................82
7.3.6
Pharmacodynamic analyses.................................................................84
7.3.7
Pharmacogenomic analyses..................................................................84
7.3.8
Biomarker Analyses..............................................................................84


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7.4
HANDLING OF MISSING DATA ..................................................................84
7.5
RANDOMISATION ..........................................................................................85
7.6
DETERMINATION OF SAMPLE SIZE ........................................................85
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 87
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................87
8.2
DATA QUALITY ASSURANCE .....................................................................88
8.3
RECORDS..........................................................................................................89
8.3.1
Source documents .................................................................................89
8.3.2
Direct access to source data and documents.......................................89
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................90
8.4.1
Listedness...............................................................................................90
8.4.2
Expedited reporting to health authorities and IECs/IRBs................90
8.5
STATEMENT OF CONFIDENTIALITY.......................................................90
8.6
COMPLETION OF TRIAL..............................................................................90
9.
REFERENCES......................................................................................... 91
9.1
PUBLISHED REFERENCES...........................................................................91
9.2
UNPUBLISHED REFERENCES...................................................................103
10. APPENDICES ........................................................................................ 104
10.2
CLINICAL EVALUATION OF LIVER INJURY .......................................105
10.2.1 Introduction.........................................................................................105
10.2.2 Procedures ...........................................................................................105
10.3
FLOW CHART (PK SAMPLING) ................................................................108
10.4
P-GLYCOPROTEIN INHIBITORS AND INDUCERS .............................110
10.5
TUMOUR DIAGNOSIS AND TREATMENT OF PAEDIATRIC 
TUMOURS .......................................................................................................111
10.6 DATA OF THE RELATIVE BIO-EQUIVALENCE STUDY 1200.35 ......114
10.7
BODY SURFACE AREA CALCULATION.................................................115
10.8 EXAMPLE FOR FORMULA APPROPRIATE FOR GFR ESTIMATION 
IN CHILDREN.................................................................................................116
11. DESCRIPTION OF GLOBAL AMENDMENT(S)............................ 117


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ABBREVIATIONS
ADL
AE
AESI
ALT
ANC
AST
Activity of Daily Life
Adverse Event
Adverse Event of Special Interest
Alanine Aminotransferase
Absolute Neutrophil Count
Aspartate Aminotransferase
AUC
BA
BSA
CA
CHMP
Area under the Curve
Bio-Availability
Body Surface Area
Competent Authority
Committee for Medicinal Products for Human use
CI
Cmax
Confidence Interval
Maximum measured concentration of the analyte in plasma
CML
CNS
CPK
Local Clinical Monitor
Central nervous system
Creatine Phosphokinase
CRA
Clinical Research Associate
CRF
CRO
CRP
CSF
CT
Case Report Form
Clinical research organization
C-Reactive Protein
Cerebrospinal Fluid
Computer tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
DFS
DILI
DIPG
DLT
Clinical Trial Report
Disease free survival
Drug Induced Liver Injury
Diffuse intrinsic pontine glioma
Dose Limiting Toxicity
DMC
DNA
DoR
Data Monitoring Committee
Desoxyribonucleic Acid
Duration of Objective Response
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
EFS
EGFR
EM
EMA
ErbB
Electronic Data Capture
Event free survival
Epidermal Growth Factor Receptor
Ependymoma
European Medicines Agency
Erythroblastic leukaemia viral oncogene homolog of the human 
EGFepidermal growth factor family of receptors
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set


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FDA
FDG-PET
FF tablet
FISH
FU
Food and Drug Administration
Fluoro-2-desoxy-D-glucose positron emission tomography
Film-Coated Tablet
Fluorescence In Situ Hybridation
Follow-up
GCP
GFR
GGT
Hb
HCG
HER2
HGG
HIV
HNSCC
Good Clinical Practice
Glomerular Filtration
Gamma-Glutamyl Transferase
Haemoglobin
Human chorionic gonadotropin
Human epidermal growth factor receptor 2
High grade glioma
Human immunodeficiency virus
Head and Neck Squamous Cell Carcinoma
HPC
HPLC-MSMS
HVA
Human Pharmacology Centre
High performance liquid chromatography tandem mass spectrometry
Homovanillic acid
IB
Investigator’s Brochure
IEC
IHC
ILD
Independent Ethics Committee
Immunohistochemistry
Interstitial lung disease
IRB
Institutional Review Board
ISF
ITCC
Investigator Site File
Innovative Therapies for Children with Cancer
i.v.
intravenous
LDH
LVEF
Mab
Lactate dehydrogenase
Left ventricular ejection fraction
Monoclonal antibody
MedDRA
MIBG
MIC2
µm
MRI
Medical Dictionary for Drug Regulatory Activities
Meta-Iodbenzylguanidine
Synonyme for CD99 (Cluster of differentiation 99)
Micrometer
Magnetic resonance imaging
MST
MTD
NCI
NSCLC
NSE
Medical Subteam
Maximum Tolerated Dose
National Cancer Institute
Non-Small Cell Lung Cancer
Neuron specific enolase
OPU
OR
ORR
OS
Operative Unit
Objective Response
Objective response rate
Overall Survival
p.o.
per os (oral)
PCC
PFS
P-gp
Protocol Challenge Committee
Progression Free Survival
P-glycoprotein


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PK
PNET
PR
Pharmacokinetics
Primitive neuroectodermal tumour
Partial response
RECIST
RMS
RNA
RPIID
Response evaluation criteria in solid tumours
Rhabdomyosarcoma
Ribonucleic acid
Recommended Phase II dose
SAE
SOP
Serious Adverse Event
Standard Operation Procedure
SPC
SUSAR
Summary of Product Characteristics
Suspected Unexpected Serious Adverse Reaction
TCM
Trial Clinical Monitor
TDMAP
TKI
Tmax
Trial Data Management and Analysis Plan
Tyrosine Kinase Inhibitor
Time from (last) dosing to the maximum measured
TMM
Team Member Medicine
TMW
TMZ
Trial Medical Writer
Temozolomide
TSAP
TTP
ULN
VMA
WBC
WHO
WOCBP
Trial Statistical Analysis Plan
Time to Progression
Upper Limit of Normal
Vanillylmandelic acid
White blood cells
World Health Organization
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Afatinib (Giotrif®, Gilotrif®) is an ErbB-family blocker. It binds to and efficaciously blocks 
signalling from all homo- and heterodimers formed by the ErbB family members EGFR 
(ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. It was approved  by EMA in 2013 for the 
indication of  “GIOTRIF monotherapy is indicated for the treatment of Epidermal Growth 
Factor Receptor (EGFR) TKI-naïve adult patients with locally advanced or metastatic non-
small cell lung cancer (NSCLC) with activating EGFR mutation(s)” and for the treatment of 
patients with metastatic, squamous NSCLC progressing after platinum-based chemotherapy (
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002280/WC500152392.pdf) and by 
US FDA as “GILOTRIF is indicated for the first-line treatment of patients with metastatic 
non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor 
(EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-
approved test” and for the treatment of patients with metastatic, squamous NSCLC 
progressing after platinum-based chemotherapy.
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/201292s010lbl.pdf ).
Neuroectodermal tumours and their aetiology: The neural crest which consists of a unique 
transient embryonic cell population was initially identified by the Swiss embryologist 
 in 1868, as a group of cells localized in between the neural tube and the 
epidermis in the vertebrate embryo. Neural crest cells after a phase of epithelial mesenchymal 
transition and extensive migration, settle down in different parts of the body to contribute to 
the formation of a plethora of different tissues and organs. Neural crest derivatives originate 
from four major segments of the neuraxis: Cranial, cardiac, vagal, and trunk neural crest. The 
cranial neural crest gives rise to the majority of the head connective and skeletal structures, 
nerves and pigment cells (R13-0505, R13-0511). 
An extensive line of research has revealed that ‘neuregulins’, a family of EGF-like ligands, 
are keys to nervous system development in mice (R13-0502, R13-1286). ErbB signalling also 
plays an important role in neural crest-derived melanophore differentiation during 
embryogenesis in zebra fish suggesting that this signalling system is conserved over species. 
Indeed, the picasso mutant zebra fish which lacks most metamorphic melanophores results 
from a homozygous deletion of the ErbB gene erbb 3b, which encodes an EGFR-like receptor 
tyrosine kinase (R13-0513).
With a limited capacity for self-renewal and a wide range of differentiation fates, neural crest 
cells bear many of the hallmarks of stem cells and persist throughout embryonic and adult 
development. These stem cells bear the potential for tissue-specific repair. Overall many 
ontogenetic studies have established the crucial role of ErbB-family signalling on neural crest 
cell development and homeostasis and it is thus not surprising that deregulation of the ErbB 
network can lead to proliferation and survival defects and thus can result in cancer. 
The ErbB pathway: Ontogenetically the ErbB pathway is highly conserved (R13-1286) and 
was associated with ectodermal and also with mesenchymal development at certain stages. 
Neuroectodermal tumours or tumours of neuroepithelial tissue per WHO classification (R14-


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1466) are originally derived from the ectoderm of the early embryo that gives rise to the 
central and peripheral nervous systems and comprise malignant neoplasms including a large 
variety of paediatric and adult malignancies (R13-1189, R13-1286, R13-0502, R13-0650) . 
These lineages give rise to astrocytomas, glioblastoma multiforme including diffuse intrinsic 
pontine glioma (DIPG) and high grade glioma (HGG), ependymomas (EM), 
medulloblastomas, primitive neuroectodermal tumours (PNET) and neuroblastomas (R13-
1286). For these tumours and also for rhabdomyosarcoma (RMS), a mesenchymal tumour, 
ErbB deregulation has been sparsely described in the literature. A recent study on 
ectomesenchymomas which are believed to arise from the widely distributed, pluripotential, 
migrating neural crest cell, or remnants thereof, the so-called ectomesenchyme, showed that 
these pluripotential cells form not only neuroectodermal tissues but also various 
mesenchymal tissues. Aside from primitive neuroblastic/neuroectodermal elements, 
mesenchymal elements which usually consist of rhabdomyosarcoma tissue (RMS) can be 
found (R13-4400). 
For years various molecular profiling programmes enriching trials with patients of certain 
molecular subtypes (R14-4092) have been integrated into adult oncology clinics. Similar 
programmes like MOSCATO (R14-4191; R14-4189) or INFORM (R14-4190; R14-4233; 
R14-4104) are now also being implemented into paediatric oncology and reshape the trial 
scene (R17-1692; R17-1805). The latter allow more targeted patient selection into future 
paediatric clinical trials with targeted agents. In line with the above, clinical trial 1200.120
will recruit paediatric patients suffering from tumours with ErbB pathway deregulations
regardless of tumour histology into the MTD expansion cohorts/Phase II part.
Tumours to be considered for treatment within this trial are recurrent or refractory
1. HGG
2. DIPG
3. Low grade astrocytomas
4. Neuroblastoma
5. EM
6. Medulloblastoma/PNET 
7. RMS
8. Other solid tumours with known ErbB pathway deregulation regardless of tumour 
histology
This group of tumours shares common aetiological features as described above and a poor 
prognosis once refractory or recurrent disease is diagnosed, i.e. the tumours progressed or 
relapsed despite initial anti-cancer treatment. A high unmet medical need requires new 
treatment options. Based on afatinib’s mode of action and the descriptions of ErbB pathway 
deregulations in paediatric tumours, it is expected that afatinib as an irreversible ErbB family 
blocker renders its maximum therapeutic effect in the condition of neuroectodermal 
paediatric tumours, rhabdomyosarcomas and other solid tumours with ErbB deregulation and 
may add a valuable choice to the treatment  armamentarium of these tumours.


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A brief description of all diseases is included below. For further details on clinical tumour 
presentation, diagnosis and treatment please refer to Table 10.5:1, Appendix 10.5.
High grade gliomas (HGG) include astrocytomas with histological documentation of either 
a WHO III or IV pathology, either of pure astroglial or mixed glial neuronal lineage, 
radiographically diagnosed diffuse intrinsic pontine gliomas (DIPGs) and others. Median age 
at diagnosis varies between 4-8 years (R13-0762, R13-0393). Malignant high grade gliomas 
account for 15% of all paediatric CNS tumours. Utilizing multimodality treatment with 
surgery, radiotherapy and chemotherapy, the 5-year survival increased over time from 47% 
(1975-1984) to 57% (1985-1994). At the time of relapse or recurrence treatment regimen to 
be considered are largely experimental. Prognosis and outcome tremendously deteriorate 
upon relapse. Gruber et al reported survival times of 4-6 months from relapse (R13-1360). 
Responses are very infrequently observed. Narayana et al report 16.7% of their patients 
experienced a partial response after the first MRI (R13-0403). No complete radiographic 
responses were seen. New treatment options combining the EGFR-targeting MAb 
nimotuzumab and radiotherapy, or using BRAF inhibitors and others are currently under 
investigation and show interesting results (R13-4931, R17-1805).
Diffuse intrinsic pontine glioma (DIPG) due to its location is one of the most devastating 
paediatric malignancies and one for which no effective therapy exists (R12-3163). Incidence 
rates are still largely unclear. Reports vary with between 5-10% (R13-0421) and 10-20% of 
all brain tumours (R13-0405) in children being DIPGs. Children are diagnosed between ages 
5 to 10 years (R13-5168). The use of hyper-fractionated radiotherapy, pre-irradiation 
chemotherapy, adjuvant chemotherapy, high dose chemotherapy, concurrent chemo-
radiotherapy and radio-sensitizers has not increased long-term OS (R12-1172). The 2-year 
OS-rates from relapse were 3.6% and 2.5%, respectively (R13-1355). Several AKT/mTOR 
and MEK pathway inhibitors are currently under clinical trial investigation (R17-1691; R17-
1690).
Astrocytoma (low grade) occurs with 2 peaks at median ages of 5 years and 12 years. 
Despite an increase in incidence from 4/106 to 19/106 over the past 30 years (R13-0762), 5-
year survival improved and was between 70%-80% (R12-3186; R13-0360, R13-0762). 
Overall these tumours have a very good prognosis (P13-01488). Grade I and II astrocytomas 
are curable by gross total resection. Recurrence-free survival is greater than 95% at 10 and 20 
years and extent of resection is strongly correlated with survival. Upon recurrence of disease 
or progression, however, treatment is challenging and several studies reported 4-year PFS and 
OS-rates of 17% (95% CI, 1 to 33%) and 71% (95% CI, 43 to 100%), partial or minimal 
response in only 12% of the patients, stable disease not requiring additional treatment in 30% 
of the patients (P13-01488). 
Neuroblastoma is the most frequent extra cerebral solid tumour in children with a total of
1240 children newly diagnosed in Germany over the past 10 years and 650 patients/year in 
the US ( R13-0393; R13-0762). The peak incidence is observed in children between 0-5 years 
of age (R13-0393). Patient survival is dependent on age at diagnosis with a better prognosis 
in younger children (R13-0393). Multimodality treatment includes chemotherapy 
combinations, radiotherapy, MIBG treatment, high dose chemotherapy with bone marrow 


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rescue and immunotherapy with anti-GD2 antibodies. Despite all these treatments, high risk 
stage patients with metastatic and recurrent disease face a 5-year survival of only 30-40% 
(R13-0491, R13-1190, R13-0762, R13-0468). According to Cole et al, high-risk 
neuroblastoma accounts for 12% of paediatric cancer deaths but only for 4% of all paediatric 
cancer diagnoses. New therapies are clearly needed (R13-0472). Lately encouraging results 
were published for the ALK inhibitor crizotinib in a subset of neuroblastoma patients 
carrying ALK oncogenic mutations (R13-5080).
Ependymoma (EM) is the third most common neuroepithelial tumour in children (R13-
0435). The incidence of ependymoma lies between 0.2 and 0.34/100000. It comprises 
approximately 9% of all childhood brain tumours with approximately 200 cases per year in 
the US (R12-1174, Central Brain Tumour Registry of the United States (CBTRUS) 2011).
Median age at diagnosis ranges from 51 to 71 months (R13-1648, R12-1159, R12-3173, R13-
1524) and 25-40% are diagnosed in children less than 3 years of age. The majority of 
paediatric ependymomas is of intracranial location. This tumour remains difficult to treat due 
to the high frequency of chemotherapy and radiation resistance (P13-04039). Surgery, if 
feasible, remains the approach with the most curative potential. Patients frequently 
experience multiple recurrences with a median 5-year PFS-rate of 18–55% (R13-0410). 
Zacharoulis et al. report that survival is very poor (0%-25%) after relapse post primary 
treatment (R13-0388). Data for chemotherapy of recurrent ependymomas are limited to few 
small retrospective series and results vary significantly as do PFS and OS (R13-0412; R13-
0418). Median Time to Progression (TTP) in several series is between 4.4 months and 10 
months (R13-0388). Recent molecular characterization ependymoma subtypes may give way 
to new and more effective targeted treatments (R17-1689).
Medulloblastoma and primitive neuroectodermal tumours (PNET): Medulloblastomas 
are derived from primitive neuroectodermal cells and as such are grouped together with 
PNETs occurring in the CNS. They account for 10-20% of primary CNS neoplasms (R13-
0388). Overall the incidence increased from 4/106 to 18/106 over past 30 years (R13-0762) 
and in the US an incidence of 462 patients/year with an age peak between 0-4 years is 
described for both tumours (R13-0393). Standard treatment includes surgery, radiation and 
chemotherapy. Although the five-year survival increased over time, and was 80% in 
Germany and 50-55% (1985-1994) in the US per SEER database (R13-0393, R13-1190, R13-
0414), patients with metastatic or recurrent disease have a 5-year survival of approximately 
20%. New treatment options targeting the Wnt and sonic hedgehog pathway, like LDE 225 
are currently under investigation in medulloblastoma (R13-4458).
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, accounts 
for approximately 3.5% of the cases of cancer among children aged 0 to 14 years and 2% of 
the cases among adolescents and young adults aged 15 to 19 years (R13-0392). The incidence 
is 4.5 per one million children and 50% of cases are seen in the first decade of life (R13-
1401). Like other sarcomas RMS tumours are molecularly diverse. Treatment is largely 
relying on chemotherapy (R13-1190, R13-0432), surgery and radiotherapy. The presence of 
distant metastases defines high-risk RMS which has a poor prognosis and treatment options 
are very limited. Patients with primary metastatic disease have a 5-year EFS of 20-30% with 
conventional treatment despite chemotherapy, surgery and radiotherapy. 


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Tumours with known ErbB pathway deregulation regardless of tumour histology will be 
included into this trial. Various molecular profiling programmes have been integrated into
adult oncology clinics aiming at enriching trials with patients of certain molecular subtypes 
(R14-4092). Similar programmes are now being implemented into paediatric oncology, e.g. 
MOSCATO (R14-4191; R14-4189) or INFORM (R14-4190; R14-4233; R14-4104) and 
reshape the trial scene (R17-1692; R17-1805). These programmes, like the biomarker 
prevalence study conducted in parallel to the dose finding part of this trial (c09990672-01)
aim at more targeted patient selection into paediatric oncology clinical trials and may support 
early inclusion of patients suffering from tumours with known ErbB pathway deregulation.


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1.2
DRUG PROFILE
Afatinib (BIBW2992) is a small molecule, selective and irreversible ErbB family blocker.
Afatinib covalently binds to and irreversibly blocks signalling from all homo- and 
heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 
and ErbB4. Due to its wide spectrum of inhibition across the ErbB family and the irreversible 
nature of this inhibition, afatinib belongs to the new generation ErbB TKIs. 
Afatinib is being developed in mutation positive non-small cell lung cancer (NSCLC), and 
head and neck squamous cell carcinoma (HNSCC). Marketing Authorisations have been 
granted by several regulatory authorities including the US FDA and the European 
Commission in patients with non-small cell lung cancer (NSCLC) with (certain) activating 
EGFR mutation(s) and for the treatment of patients with metastatic, squamous NSCLC 
progressing after platinum-based chemotherapy.
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 20-50mg. Moderate to high 
inter- and intra-individual differences in plasma concentration were seen. Afatinib has a 
moderate to high apparent clearance (CL/F= 1050 mL/min for single dose treatment and 898 
mL/min at steady state) and a high apparent volume of distribution (Vz/F= 1940 L for single 
dose treatment and 2770 L at steady state), suggesting that it is highly distributed out of the 
blood into tissues. However, values for CL/F and Vz/F should be considered with caution as 
the absolute bioavailability (F) of afatinib in humans is not known. The overall gMean 
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. The PK characteristics in Caucasian cancer patients 
were comparable to those observed in Japanese cancer patients. 
Afatinib is bound 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 


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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 % (AUC0-∞) and 22 % (Cmax), respectively. Caution 
should be exercised when combining afatinib with potent P-gp modulators, for further 
information see Appendix 10.4 .
Afatinib exposure is expected to be comparable for the film-coated tablets and the capsule 
and solvent for oral solution (both formulations are to be used in this trial). 
 
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. 
In adult cancer patients, the choice of the starting dose of 40 or 50 mg daily with afatinib 
monotherapy was based on the expected balance between patient’s tolerability and the 
required level of target inhibition. A dose of 40 mg daily has been used in patients with
NSCLC or HNSCC not previously exposed to EGFR-targeted treatments. A dose of 50 mg 


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has been largely limited to EGFR TKI pre-treated NSCLC patients with tumours that are 
expected to harbour resistant mutations.
In clinical studies, the pattern of AEs was as expected from EGFR inhibitors, including 
predominantly GI and dermatological AEs which were dose-dependent. Early and effective
management of these AEs is mandated in ongoing and forthcoming clinical trials with the
opportunity to reduce the dose where appropriate. The typical AEs associated with afatinib
treatment are diarrhoea (which in severe cases may lead to dehydration with or without renal
insufficiency) and effects on skin and its appendages: rash/acne/folliculitis, paronychia,
pruritus, dryness and eczema. Besides diarrhoea, GI AEs include stomatitis, mouth
ulceration, dry mouth, and oral pain. Other AEs seen in clinical trials of afatinib include
general disorders such as fatigue/asthenia; mucosal inflammation; respiratory disorders such
as epistaxis and rhinorrhoea; eye disorders such as conjunctivitis and keratitis.
Hepatic failure, including fatalities, has been reported during treatment with afatinib in less
than 1% of patients. 
Afatinib does not appear to have an adverse effect on cardiac contractility or QTcF 
parameter. The frequency of interstitial lung disease (ILD) -like AEs in all afatinib treated 
patients was low (approximately 1.5%) and similar to that observed with other EGFR TKIs
(c01802941). Considering reports of suspected cases of ILD on afatinib, afatinib trials 
exclude patients with known pre-existing ILD from treatment with afatinib and request 
assessment of all patients with acute onset and/or unexplained worsening of pulmonary 
symptoms (see Table 4.1.4.3:1).
Afatinib has been combined with various anti-cancer agents including chemotherapy and
targeted treatments. The pattern of AEs displayed in combination was consistent with the
respective monotherapy safety profiles and tolerable doses of afatinib in these combination
regimens varied between 20 to 50 mg (c01802941).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Several Phase I or Phase II studies on EGFR and/or HER2 inhibitors in paediatric cancers 
have been conducted (R10-4924, R10-4926, R11-4989, P11-14451, R10-4917, R11-5022, 
R10-4960, R10-4920, R11-5046, R11-4988) or are still ongoing (R10-4921, R11-5021). 
These trials established the safety profile, pharmacokinetics and MTDs for gefitinib (Iressa 
®) and erlotinib (Tarceva®, OSI-774) and lapatinib in children (R11-5022, R10-4926, R11-
4989). Overall, gefitinib, erlotinib and lapatinib were reported to be well tolerated in children, 
with a safety profile similar to that observed in adults and paediatric MTDs comparable with 
those associated with anti-tumour activity in adults (R11-5022, R10-4926, R11-4989).The 
clinical pharmacokinetics of gefitinib in children were similar to those observed in adults 
(P11-14451, R11-4987). Some signs of clinical anti-tumour activity were observed (R11-
4989, R11-5022).
Although the ErbB pathway ontogenetically is highly conserved (R13-1286) and is associated 
with ectodermal and mesenchymal development at certain stages (R14-1466), and despite 
ErbB deregulation being sparsely described in the literature, none of the above trials was 
dedicated to the in-depth assessment of the role of ErbB family deregulation neither (i) in the 
aetiology of paediatric cancers nor (ii) trying to make use of ErbB deregulation for the 
development of targeted treatment options.
Limited reports of clinical efficacy for ErbB pathway inhibitors in paediatric cancer patients 
may be due to the following: (1) ErbB network aberrations observed in the various tumour 
entities tested are contributing to tumour proliferation but are not essential to maintaining 
tumour growth. As most of these clinical studies were not conducted in pre-selected patients, 
it is possible that signs of clinical efficacy were diluted in the total patient population. (2) The 
tested drugs may only partially silence the ErbB network. Indeed, the mechanism of ErbB 
signalling relies on ligand-induced stabilization of homo- or heterodimers formed by the 
various ErbB-receptor tyrosine kinases. Currently available ErbB directed therapies do not 
inhibit all ErbB-family receptor members and possibly fail to block both partners in an active 
receptor complex. 
ErbB-family blockers, like afatinib, bind to and block signalling from all homo- and 
heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 
and ErbB4. This complete and irreversible blockage by afatinib may achieve greater efficacy 
than reversible inhibitors with selective ErbB1 (EGFR) and/or ErbB2 (HER2) inhibitory 
activity.
The proposed trial 1200.120 attempts to address the following questions:
1. Can afatinib be safely administered to paediatric patients with neuroectodermal 
tumours, rhabdomyosarcomas and/or solid tumours with known ErbB pathway 
deregulation regardless of tumour histology?


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2. Will the observed degree of ErbB receptor expression render the tumour types 
included in this trial a suitable condition for treatment with the ErbB family blocker 
afatinib? Thus will deregulated ErbB receptors be drugable targets, and as such will 
patients treated with afatinib show increased benefit from treatment?
3. Will patients’ benefit obtained from treatment with afatinib be considered meaningful 
by experts in the field of paediatric oncology? 
4. Will the biomarker selected patient population included in the MTD expansion 
cohorts/phase II part render a further biomarker driven development suitable and 
beneficial for patients?
2.2
TRIAL OBJECTIVES
The objective of the dose finding part is to determine the maximum tolerated dose (MTD), 
safety and pharmacokinetics of afatinib. The MTD of afatinib as single agent will be 
determined in the paediatric patient population across all applicable tumour entities, based on 
the occurrence of dose limiting toxicities (DLTs). 
The MTD expansion cohorts/Phase II part will provide insight into the clinical anti-tumour 
activity of afatinib, i.e. efficacy of afatinib evaluated by objective response (OR), duration of 
objective response (DoR), progression free survival (PFS) and more data on safety and
pharmacokinetics in a larger number of patients suffering from HGG, DIPG, EM and other 
solid tumours with ErbB pathway deregulation regardless of tumour histology will be 
generated.
In case the observed degree of efficacy in any of the above mentioned tumour indications 
within this phase I/II trial renders further development of afatinib in paediatrics suitable, 
additional trial(s) with single agent or combination therapy may proceed.


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2.3
BENEFIT - RISK ASSESSMENT
Standard treatment regimens for newly diagnosed neuroectodermal tumours, 
rhabdomyosarcomas and/or other tumours for which ErbB deregulation may play a role, do 
exist and result in acceptable disease free survival periods. Once patients develop 
recurrent/refractory disease, however, treatment options are limited and outcome dismal. The 
European Paediatric Medicine Regulation implemented by EMA in 2006 ((EC) No 
1901/2006) (R09-2583)  and Written Requests issued by US FDA attempt to improve access 
to new treatment modalities for paediatric patients, but little has changed for paediatric 
oncology (R13-1146).
At the start of this trial no safety or efficacy data for afatinib in paediatric patients existed, but 
in analogy to observations made for the reversible EGFR-inhibitors gefitinib and erlotinib in 
children, the safety profile of afatinib in paediatric patients was not expected to deviate from 
what was observed in adults. The safety and efficacy of afatinib is well described in adults. 
The known side effects of afatinib in adults are similar to EGFR inhibitors and largely consist 
of gastrointestinal side effects, mostly diarrhoea and stomatitis and skin related side effects. 
Side effects proved to be manageable with early and proactive concomitant treatment. 
Implementation of similar measures to control afatinib related side effects in this paediatric 
trial are expected to limit early treatment discontinuations due to toxicity, and thus positively 
impact compliance and efficacy. The dose finding part of this trial was completed; the MTD 
was established in children between ≥2 years to <18 years and the paediatric safety data were 
consistent with the known safety profile of afatinib in adults (c09990672-01).
The proposed paediatric phase I/II trial is following suggestions made by PDCO during the 
review of afatinib’s initial paediatric development plan and the FDA’s written request issued 
April 2017 (ra00865826). The MTD expansion cohorts /Phase II part will accrue patients 
with HGG, DIPG, EM and any other solid tumour with ErbB deregulation as defined in 
sections 3.3.2 and 5.6. In addition patients with proven genomic, transcriptomic or proteomic 
ErbB alterations in their tumours will be recruited to an exploratory cohort. Such biomarker 
driven, histology agnostic development is innovative for paediatric oncology and only little 
precedence exists in adults (SHIVA (R14-4174), MOSCATO (R14-4191; R14-4189)). More 
recently, however, genomic screening programs were implemented in paediatric oncology 
(INFORM (R14-4190; R14-4233; R14-4104)), allowing patients’ early assignment to 
targeted treatment regimen. To enable assessment of afatinib’s anti-tumour activity in this 
biomarker driven, largely histology agnostic approach, nevertheless a defined/ small number 
of patients per indication needs to be included (ra00865826). Assessment of antitumour 
activity for afatinib at the end of this phase I/II trial will determine future trial activities in   
close alignment with regulatory agencies and specialists in the field. 
The trial medication is available as oral formulations, i.e. film coated tablets of various 
strengths for older children and an oral liquid formulation at 4 mg/ml dose strength for 
younger children. These oral formulations will grant patients and their parents the advantage 
of out-patient treatment and increase flexibility to move on with their lives. A resulting 
increase in quality of life, with hopefully increased efficacy should impact positively on 
treatment compliance.


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The proposed treatment with the ErbB family blocker afatinib targets a deregulated ErbB 
pathway. If the latter proves as a suitable target in this phase I/II trial, afatinib may become a 
valuable choice in the treatment armamentarium of children suffering from 
recurrent/refractory tumours with ErbB deregulation. Although biomarkers of ErbB 
deregulation were successfully identified in the biomarker prevalence study, which was 
conducted outside of this clinical trial (c09990672-01), it still has to be established  if the 
observed degree of efficacy in paediatric patients suffering from certain tumour indications 
(HGG, DIPG, EM) and other solid tumours with ErbB pathway deregulation or proven 
genomic, transcriptomic or proteomic ErbB alterations, render afatinib a suitable agent for 
further clinical evaluation.
Finally, even if the hypothesis described above cannot be confirmed, the phase I dose finding 
part has established the maximum tolerated dose for afatinib in children and safety data in 
children will be available to the paediatric oncology community (c09990672-01). 
As this trial is a “first in child” trial with afatinib, a data monitoring committee (DMC) will 
continuously monitor the benefit /risk for all patients participating in the trial (for details, 
refer to section 3.1.1). For an early detection of rare but potential toxicities, the patients will 
also be assessed for the following:
-
Potential for drug-induced liver injury (DILI) is under constant surveillance by 
sponsors and regulators. Therefore, this study requires timely detection, evaluation, 
and follow-up of laboratory alterations of selected liver laboratory parameters to 
ensure patients´ safety. For details refer to Section 5.2.2.
-
Keratitis and ulcerative keratitis that have been reported following treatment with 
currently approved EGFR inhibitors for cancer. Although rarely observed with 
afatinib thus far, special safety precautions are provided in Section 4.2.1.
-
Left ventricular dysfunction that has been associated with HER2 inhibition in adults. 
Although stringent monitoring in adults did not demonstrate any impact of afatinib on 
cardiac function (c01802941), LVEF will continuously be monitored in this trial in 
children and precautions are given in Section 4.2.1.
-
Interstitial lung disease (ILD) is a rare and serious (potentially fatal) AE that has been 
reported with EGFR TKIs. Patients with known ILD are therefore excluded from trial 
participation. In case of suspected ILD on treatment please refer to Section 4.2.1.
Following the determination of a safe dose of afatinib in paediatrics, the goal of this study is 
to bring a new and efficacious treatment to paediatric patients who suffer from solid tumours 
with ErbB deregulation. Considering the (i) well established side effect profile in adult 
patients, (ii) the established concomitant treatment algorithms for afatinib related side effects, 
(iii) close safety monitoring by a DMC, (iv) participating paediatric phase I sites with 
experience in new drug development and (v) planned consultations with regulatory agencies 
at decision points (see figure in Appendix 10.1), the expected benefits from afatinib treatment 
for the paediatric patients will outweigh its risks.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a Phase I/II open-label, dose escalation study to determine the MTD of afatinib as 
single agent and to assess its anti-tumour activity in children with recurrent or refractory 
malignant neuroectodermal tumours, RMS and/or other solid tumours with ErbB pathway 
deregulations.
This phase I/II trial is connected to a translational biomarker prevalence study which is 
informative for the identification of possible biomarkers which are considered suitable for 
inclusion of patients in the MTD expansion cohorts/Phase II part. The biomarker prevalence 
study was conducted outside of this clinical trial. For details refer to Section 2.1 and Section 
5.6. Results of the biomarker prevalence study are partially reported (c09990672-01).
This clinical trial has 2 parts (see Figure 3.1:1):
1. A dose finding part
2. A biomarker specific MTD expansion cohorts/Phase II part
The trial will end when the last patient has completed the 28-30 day safety follow-up (FU) 
visit. For additional information on trial termination, see also Section 3.3.4.2 and Section 8.6.
Figure 3.1:1
Trial design
1. Dose finding part: Accounting for the low incidence of each paediatric tumour entity 
within the above group and the heterogeneity of ErbB pathway deregulations 
described, the dose finding part of the trial will be conducted in paediatric patients 
with recurrent/refractory neuroectodermal tumours, and RMS, for whom no further 
treatment option exist and who are likely to derive benefit from treatment as their
tumours are known to show ErbB deregulation in literature. In addition, patients with 
other solid tumours (regardless of histology) with known ErbB deregulations, 


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assessed by institutional standards, may be included into this part of the trial. All of 
these patients will be included to determine the MTD. A rolling-6 design will be used 
for patients’ assignment to dose cohorts (see Table 4.1.4.1:1). 
Patients in Phase I dose finding part will undergo retrospective testing for ErbB 
deregulation. 
This part was completed (c09990672-01).
2. MTD expansion cohorts/Phase II part: Once the MTD is determined, patients will 
be tested and recruited only if they fulfil at least two of the following biomarker
criteria (i) EGFR gene amplification (FISH) and/or (ii) HER2 gene amplification 
(DDISH) and/or (iii) EGFR protein expression (membrane staining): H-score > 150 
and/or (iv) HER2 protein expression (membrane staining): H-score > 0 (see section 
5.6). A minimum of 5 patients in each of the four following cohorts, i.e. HGG, DIPG, 
EM and a mixed histology agnostic cohort of patients with refractory tumours, will be 
accrued to confirm a safe recommended Phase II dose (RPIID) and to be assessed for 
response. An exploratory cohort of a maximum of 6 patients with proven genomic, 
transcriptomic or proteomic ErbB alterations which are not defined above will also be 
included. This part of the trial will allow the collection of further safety and PK data 
to limit failure due to dosing issues in further clinical development, but also give 
insight if the “targeted” patient selection increases the level of clinical efficacy. 
3.1.1
Administrative structure of the trial
The coordinating investigator is an expert in paediatric oncology with experience in new drug 
development. The coordinating investigator has been designated by Boehringer-Ingelheim 
and will sign the clinical trial report. Selected investigators from the network of “Innovative 
Treatments for Children with Cancer (ITCC)” and other participating investigators are 
likewise experts in the paediatric oncology with experience in this type of trial and 
investigations and in new drug development.
A steering committee including the coordinating investigator, selected ITCC investigators in 
different EU countries, non-ITCC in non-EU countries and BI representatives, will monitor 
the study on a regular basis (recruitment issues, data quality, decisions on dose escalation, 
etc.).
A data monitoring committee (DMC) will be appointed by BI. The DMC will consist of an 
independent, multidisciplinary group who have expertise in paediatric oncology and new 
drug development trials in children. A statistician must be part of this group. The DMC’s 
responsibility will be the continuous assessment of the trial data to ensure the overall 
benefit/risk of the patients treated and to monitor the quality of the trial. The DMC will 
advise BI and the steering committee about the conduct of the trial and the integrity of the 
data. Regular safety review and benefit/risk assessment will be performed by the DMC as 
described in the DMC charter. The latter defines but is not limited to e.g. a regular DMC 
meeting schedule, adhoc meetings in case of unexpected SAE, regular AE listings to be 
provided by the sponsor, etc.. The DMC will guide the sponsor throughout the trial. 


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Since the implementation of the Regulation (EC) No 1901/2006 of the European Parliament 
(R09-2583) numerous paediatric development programs on new oncology compounds started 
but Paediatric Investigation Plans (PIPs) were driven by adult indications, which were not 
waived for children, rather than by a paediatric unmet medical need (R13-1146). Where 
pursued, paediatric development is frequently hampered by an early focus on rare indications 
with lack of feasibility of patient recruitment. In contrast, trials set up too broadly provided 
scattered evidence of clinical activity but were neither evaluable for effect size per indication 
examined, nor for a biomarker enriched population, as biomarkers were frequently introduced 
retrospectively to help explaining an observed effect. Different compounds targeting similar 
pathways in relatively few paediatric cancer patients compete for patient accrual into clinical 
trials. If no clear working hypothesis/rationale for the assessment of a certain compound in a 
particular population is generated, it is difficult to convince cooperative groups and patients’ 
guardians to recruit into these trials. BI proposes to conduct a Phase I trial in patients with 
relapsed and or poor prognostic neuroectodermal tumours, which are embryologically and 
ontogenetically derived from the same germinal sheet, and for which therefore some rationale 
for ErbB deregulation in tumour genesis can be hypothesized and evidence in the literature 
exists. In addition, the dose finding part of this trial allowed to include patients with solid 
tumours (regardless of histology) with known ErbB pathway deregulations, assessed by 
institutional standards– this part is completed (c09990672-01). The above described 
paediatric patients don’t have further treatment options outside of clinical trials, but are likely 
to derive benefit from treatment with the ErbB family blocker afatinib as their tumours are 
known (i) to show ErbB deregulation per literature review , or (ii) demonstrated ErbB 
deregulation by institutional standards. Patients in the MTD expansion cohorts/Phase II part 
will be recruited based on ErbB pathway deregulations, defined in the biomarker prevalence 
study (c09990672-01), see also Section 5.6. With the proposed design, three questions can be 
addressed at the same time: (i) identifying the right dose during the dose finding, (ii) hitting 
the right target, and (iii) the impact of targeted patient selection on efficacy. The basket 
approach will address feasibility of patient recruitment and the biomarker driven patient 
selection will address unanswered questions on ErbB deregulation. For patients’ benefit refer 
to Section 2.3.
Dose finding Part: A rolling 6 design will be used to determine the MTD. The MTD will be 
assessed by DLT as described in Table 4.1.4.1:2. The MTD will be determined as the highest 
dose at which no more than 1/6 patients experienced DLT. The rolling 6 design was chosen 
to limit the waiting period for paediatric patients seeking treatment, as depicted below.
MTD expansion cohorts/Phase II part will recruit a minimum of 5 patients in each of the
four disease specific cohorts for HGG, DIPG, EM and other solid tumours fulfilling ErbB
biomarker selection criteria (see Section 3.3.2) and an exploratory cohort of patients with 
proven genomic, transcriptomic or proteomic ErbB alterations. Efficacy will be assessed by 
objective response (OR) and the OR rate must be considered meaningful by experts in the 
field of paediatric oncology and regulatory agencies to pursue further clinical development. 


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Tumour material from all patients entered into this clinical trial must be available for 
retrospective testing of an ErbB pathway deregulation (for DIPG in dose finding part, see 
section 3.3.2) or prospective patient screening into the MTD expansion cohorts/Phase II part.
Intra-patient dose escalation: No clear exposure-efficacy correlation for afatinib has been 
identified in adult cancer patients yet. Conventional dosing in oncology trials is based on the 
MTD, or a recommended Phase II dose close to the MTD, dependent on overall safety. 
Treatment at lower dose tiers may be hampered by a presumed lack of efficacy. Assessment 
of the MTD or the recommended Phase II dose in oncology trials is based on a frequency of 
patients with DLTs. Trial 1200.120 will allow intra-patient dose escalation. As soon as the 
next higher dose tier is considered safe by standard DLT incidences in course one, patients of 
the lower dose tier, who benefit from treatment may resume treatment at the next higher dose. 
Although these patients will not be counted into MTD dose cohorts – see rolling 6 design- the 
safety database at the MTD level/ higher dose tiers and hopefully patients’ benefit from 
participation in Phase I dose finding will be increased. 
This part has been completed (c09990672-01).
3.3
SELECTION OF TRIAL POPULATION
17 patients were treated in the dose finding part to determine the MTD according to a rolling 
6 design Skolnik et al (R12-4744). Once the MTD was determined, MTD expansion 
cohorts/Phase II part will include up to 38 additional patients who must be evaluable for OR. 
It is expected that up to 550 patients will need to be screened to treat 55 patients who will be 
evaluable for MTD/OR in the trial.
About 30 trial sites in EU/US/Canada are expected to recruit in this trial. The sites will have
experience in paediatric oncology and in new drug development. All sites are willing to 
deliver tissue samples from recruited patients.
A log of all patients included into the study will be maintained in the ISF at the 
investigational site irrespective of whether they commenced trial drug or not.
The MTD expansion cohorts/Phase II part will provide biomarker specific efficacy data to 
establish proof of concept of anti-tumour activity of afatinib in ErbB deregulated paediatric 
cancer patients.
3.3.1
Main diagnosis for study entry
The proposed Phase I/II trial will include paediatric patients with refractory or recurrent 
HGG, DIPG, lower grade astrocytoma, neuroblastoma, ependymoma, medulloblastoma and 
PNET, rhabdomyosarcoma (R13-0506, R12-3164), and/or other solid tumours with known 
ErbB pathway deregulation regardless of tumour histology. 


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3.3.2
Inclusion criteria
Phase I dose finding part
1. Patients with a histological diagnosis of high grade glioma (HGG), diffuse intrinsic 
pontine glioma (DIPG), low grade astrocytoma, medulloblastoma/PNET, 
ependymoma (EM), neuroblastoma, rhabdomyosarcoma and/or patients with other 
solid tumours (regardless of histology ) but with known ErbB pathway deregulation
2. Patients must have recurrent or refractory disease following at least one prior standard 
treatment regimen
3. Patients aged between ≥2 to < 18 years*
4. Patients must have recovered (to CTCAE grade 1 or baseline) from any acute toxicity
resulting from any prior anti-cancer treatment (except alopecia)
5. No effective conventional therapy exists
6. Patient assent and parent(s)/legal guardian(s)’ written informed consent that is 
consistent with local law and ICH-GCP guidelines
7. Archival and/or fresh tumour tissue available. For DIPG, if the latter is not available, 
biopsy data on tumour histology and tumour profiling (if applicable) must be made 
available
8. Performance status: Lansky ≥ 50% for patients ≤ 12 years of age or Karnofsky ≥ 50% 
for patients older than 12 years of age assessed within two weeks prior to enrolment
9. Patients with CNS malignancies must be neurologically stable for at least 7 days 
before inclusion into the trial as per investigator judgement
10. Patients, both males and females, with reproductive potential (girls post menarche and 
males after 1st ejaculation) and sexually active must agree to practice highly effective 
contraceptive measures for the duration of study drug therapy and for at least 28 days 
after completion of study drug therapy (see Section 4.2.3.3 for highly effective 
contraceptive measures)
11. Patients must be able and willing to swallow/take afatinib orally once daily (tablets or 
oral solution) as per investigator judgement
12. LVEF ≥50%
* In special cases where a patient / guardian(s) signed a pre-screening consent when the patient was 17 years old and 
the patient turns 18years before the trial consent was signed, the patient can be included in the trial. 
In any case, the rate of patients >18years at treatment start must not exceed 19% of the whole trial population
Inclusion criteria for MTD expansion cohorts/ Phase II part:
-
Inclusion Criterion 1: Patients with HGG, DIPG, EM and other solid tumours than 
aforementioned which fulfil at least two of the below criteria:


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o
EGFR gene amplification (FISH): Either EGFR/Cen7 ≥ 2.0 or ≥10% of cells 
with ≥15 copies or ≥40% of cells with ≥ 4 copies or gene cluster in ≥10% of 
cells and/or
o
HER2 gene amplification (DDISH): Her2/CEP17 ≥ 2.0 and/or
o
EGFR protein expression: H-score > 150 (membrane staining) and/or
o
HER2 protein expression: H-score > 0 (membrane staining)
Inclusion will be based on biomarker assessment prior to inclusion, as detected by 
central laboratory analysis of tumour biopsy material
-
Inclusion criterion #3: Patients aged between ≥1 to < 18 years
-
Inclusion criterion #7: Archival and/or fresh tumour tissue available. 
Inclusion criteria 2, 4, 5, 6, 8-12 apply as above
-
Inclusion criterion #13: Patients with proven genomic, transcriptomic or proteomic 
ErbB alterations which are not defined in the above inclusion criterion #1 regardless 
of tumour histology (See Section 5.6, tables 5.6:1 to 5.6:4).
-
Inclusion criterion#14: Patients must have at least one measurable lesion according to 
the institutional response criteria for the given tumour type.
3.3.3
Exclusion criteria
1. Chemotherapy within 3 weeks prior to the start of study treatment, biological 
therapy or investigational agents within 4 weeks prior to the start of study treatment 
or prior to passing 5 half-lives, i.e. systemic clearance, whatever comes first 
2. Radiotherapy within 2 weeks before starting study treatment
(palliative 
radiotherapy is allowed if not focused on a target lesion)
3. Surgery within 4 weeks before starting study treatment or planned surgery during 
the projected course of the study which compromises patient’s trial participation by 
investigator judgement
4. Known hypersensitivity to afatinib or its excipients 
5. History or presence of clinically relevant cardiovascular abnormalities as per 
investigator judgement
6. Female patients of childbearing potential, who are nursing or are pregnant 
7. Any history of or concomitant condition that, in the opinion of the investigator, 
would compromise the patient’s ability to comply with the study or interfere with 
the evaluation of the efficacy and safety of the test drug


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8. Requirement of treatment with a prohibited concomitant medication listed in the 
CTP that cannot be stopped for the duration of trial participation
9. Known pre-existing interstitial lung disease (ILD), or signs and symptoms 
indicative of the latter as per investigator judgement (see Section 4.2.1)
10. Any history or presence of poorly controlled gastrointestinal disorders that could 
affect the intake/absorption of the study drug (e.g. Crohn’s disease, ulcerative 
colitis, chronic diarrhoea, malabsorption) as per investigator judgement
11. Active hepatitis B infection (defined as presence of HepB sAg and/ or Hep B 
DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or 
known HIV carrier
12. Known keratitis
13. Inadequate liver function (AST/ALT>2.5xULN, Bilirubin>1.5xULN adjusted for 
age)
14. Inadequate kidney function, i.e. creatinine>1.5xULN adjusted for age and/or 
creatinine clearance <70 ml/min/1.73m² estimated by institutional standard formula 
for estimation of GFR in paediatric patients
15. Inadequate bone marrow function (ANC ≤1000/mm³, platelets ≤100000/mm³) 
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
The Investigator, patient and/or parent/legal guardian may stop study treatment at any time 
for safety or personal reasons.  
If a patient is entered in violation of inclusion/exclusion criteria, the sponsor, in discussion 
with the investigator and if needed DMC, will determine the medical benefit/risk on a 
patient-by-patient basis and can require such a patient be discontinued from the study 
treatment.
A patient is to discontinue study medication if:
1
The patient and/or parent/legal guardian withdraw assent/consent to continue 
therapy without the need to justify.
2
The patient is no longer receiving benefit from treatment, in the opinion of the 
investigator.
3
In the investigator’s medical judgment, further participation would not be in the 
best interest of the patient, or might be injurious to the health and well-being of 
the patient 
4
The patient is no longer able to participate for other medical reasons (e.g. surgery, 
adverse events, secondary malignancy, or other diseases)


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5
A female post-menarchal patient becomes pregnant (Section 5.2.2.3)
6
The patient is diagnosed with ILD, keratitis or heart failure (including clinically 
relevant LVEF reduction) (Section 4.2.1)
7
The patient needs further dose reductions considered necessary but not allowed 
according to the protocol (Section 4.1.4.3)
The sponsor may remove patients from the study after completion of the primary analysis and 
grant access to afatinib via an alternative source e.g. through an expanded-access program, 
named patient use program, or compassionate use protocol.
Patient discontinuation of study participation:
A patient, who has discontinued study medication, will complete a follow-up (FU) visit 28-30
days after the last intake of the trial drug. After this FU visit, no further study procedure will 
be performed and the patient will enter the observation period during which only data 
collection on (S)AE(s) considered relevant by investigator, vital status and further anti-cancer 
treatment will be requested.
For all patients, the reason for withdrawal (e.g. adverse events) must be recorded in the 
eCRF. These data will be included in the trial database and reported.
If the patient and/or parents and/or legal guardian withdraw assent/consent to continue further 
trial procedures and the follow-up visit activities, no additional study assessments will be 
completed. In this event patients and parents or legal guardians will be asked whether they 
agree to allow continued further data collection of associated clinical outcome parameters
during the observation period. If the patient/parents do not permit further contact/data 
collection this will be documented in the eCRF and in the source data.
Patients who withdraw from the trial after entering active treatment phase may be replaced if 
the primary endpoint of the respective trial phase is not achieved (see Section 5).
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the trial
3. Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing the 
appropriate conduct of the trial
4. The recommendation of the DMC that would require discontinuation of the trial due to an 
imbalance in benefit/risk
5. Discontinuation of the clinical development programme with afatinib in paediatrics.


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6. The primary analysis has been completed and all patients have either experienced 
progressive disease or are eligible to receive afatinib under the conditions indicated in 
Section 3.3.4.1
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
Patients will be treated with once daily oral dosing of afatinib.
Oral solid single-unit dosage forms represent stable and convenient formulation approaches 
and are therefore proposed for treatment of paediatric patients that are able to swallow them.
For younger children who cannot swallow the film-coated tablets, and for doses which cannot 
be achieved by the film-coated tablets, capsules and solvent for oral solution have been 
developed. This oral liquid formulation may also serve as alternative formulation for older 
paediatric patients who do not accept the film-coated tablets.
4.1.1
Identity of BI investigational product
Substance (INN)
Afatinib 
(Brand name):
(Giotrif®, Gilotrif®)
Pharmaceutical form:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
20, 30, 40 and 50 mg film-coated tablets (the dose of afatinib in 
the film-coated tablets is related to the free base equivalent to 
afatinib)
Route of administration:
Oral
Posology:
Once daily
Substance (INN)
Afatinib 
(Brand name):
Pharmaceutical form:
Capsules and Solvent for Oral Solution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
200 mg capsule to be dissolved in aqueous solvent (2 capsules 
per 100ml solvent), i.e. 4 mg/ml
Route of administration:
Oral
Posology:
Once daily


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4.1.2
Method of assigning patients to treatment groups
Patients who have given their informed assent/written consent and whose parent(s)/legal 
guardian(s) gave written consent will be enrolled sequentially. A screening form must be 
faxed or emailed to the sponsor as soon as written informed consent has been obtained. 
Recruitment will be competitive.
Patients who meet all eligibility criteria will be entered into the study. A registration form
will be faxed or emailed to the sponsor for patients who meet the eligibility criteria prior to 
starting study treatment.
The screening form and the registration form will be used by the sponsor for tracking 
purposes (overall recruitment, dose cohort assignment, tumour type information)
During the dose finding part, a rolling 6 statistical design will be used for dose escalation 
(R12-4744). Treatment slots are assigned by the sponsor in close collaboration with the 
recruiting sites according to Table 4.1.4.1:1. The sponsor will return the registration form for 
cohort confirmation.
The MTD expansion cohorts/Phase II part will recruit patients in a biomarker specific 
approach, see section 3.3.2. For cohorts 1 to 4, ErbB deregulation in each patient’s tumour 
sample must be confirmed centrally. For cohort 5, an analytical laboratory report to prove
genomic, transcriptomic or proteomic ErbB alterations (which are not defined in Tables 5.6:1 
- 5.6:4) must be provided prior to study entry. For the MTD expansion cohorts/Phase II part a 
high rate of screening failures is expected. Therefore a pre-screening informed consent may 
be used to allow collection of tumour tissue samples and minimum data for central 
assessment of ErbB deregulation (further details are explained in the pre-screening informed 
consent. Upon confirmation of positivity for selection biomarkers (see Section 3.3.2) and 
before to proceed with trial procedures, the informed consent/assent for trial entry must be 
signed.
Recruitment will be closely monitored by the sponsor and sites will be informed of global 
patient enrolment numbers on an ongoing basis. Recruitment will continue until confirmation 
is received that patients included are evaluable for MTD (dose finding part) and the minimum 
number of patients required for assessment of OR (MTD expansion cohorts/Phase II part) is 
reached (see Section 3.3).
Following registration, patients should begin protocol treatment within 7 days.
4.1.3
Selection of doses in the trial
The choice of afatinib dose levels for this trial follows current clinical development practice 
and regulation (P96-1356) taking into account the available strengths of the tablet 
formulation. Five dose levels are planned in this trial. They are based on the approved dose 
for adults of 40 mg and described in Table 4.1.3:1.
(http://www.ema.europa.eu/docs/en_GB/document_library/EPAR -_Product_Information/human/002280/WC500152392.pdf)
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/201292s010lbl.pdf )
A recently published comparative analysis of paediatric dose finding trials of molecularly 
targeted agents with adults’ dose finding trials by Paoletti et al (R13-4734) showed that the 


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recommended Phase II dose for paediatric patients ranged between 90% to 130% of the BSA-
adjusted adult dose for 70% of the trials. Due to conventional dose escalation, 63% of 
paediatric patients did not receive an optimal dose during Phase I. Toxicity profiles were very 
similar between children and adults. For EGFR targeted agents and dual HER2/EGFR 
inhibitors BSA adjusted paediatric MTDs ranged between 100% and 180% of RPIID or FDA 
approved dose (R13-4734). However, as afatinib has shown anti-tumour activity at doses 
between 20 – 50 mg in adults a starting dose at 80% level of the adult dose is chosen for 
safety reasons. Allometric scaling of the dose, based on BSA (R13-5168, R13-5170, R13-
5167, P13-15789), is proposed in the dose finding part to take allometric differences between 
children and adults into account. The dose escalation will start at 80% of the approved adult 
dose (estimated by allometric scaling) with escalation levels to 100%, 125% and 150%; in 
case 80% is exceeding the MTD, dose level -1 will allow dose de-escalation to 50%. For 
obese patients BSA may be derived based on ideal body weight per institutional standard.
Table 4.1.3:1
Target dose in child as a function of efficacious dose in adult and 
dose level
Dose 
level
Percentage of adult 
dose (%)
Equivalent 
pediatric dose 
mg/m²*
-1
50
12
0
80
18
1
100
23
2
125
29
3
150
35
* for actual dose, please refer to Table 4.1.4:1
The dose finding part has been completed and the MTD was determined at 80% of the 
approved adult dose (estimated by allometric scaling based on BSA) (c09990672-01).
4.1.4
Drug assignment and administration of doses for each patient
Patients will be administered a single oral dose of afatinib each day. Treatment will be 
applied continuously until the development of progressive disease or unacceptable adverse 
events.
The medication should be taken at the same time each day (± 2 hours) without food (at least 
one hour before or at least three hours after a meal). If above time intervals cannot be adhered 
to in patients ≥1year and <2 years, time and type of food consumed within the critical 
application window for afatinib has to be recorded in the patient diary.
Missed doses of afatinib can be made up during the same day as soon as the patient 
remembers.  However, if the next scheduled dose is due within 8 hours then the dose must be 
skipped and patients should take the next scheduled dose at the usual time. Patients with 
emesis must not take a replacement dose.


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Depending on age, BSA (see Appendix 10.7), dose strength and individual preference,
afatinib film-coated tablets or liquid formulation prepared from afatinib capsules and solvent 
for oral solution may be applied. 
Assuming comparable exposure for both formulations (see Section 1.2), the oral solution and 
the film-coated tablets may be used interchangeably when determining the MTD, in case of 
matching doses (deviation -/+ 10%) as specified in Table 4.1.4:1. However, individual
patients shall not switch between formulations as long as this is not necessitated by dose 
adaptations due to changing weight or BSA, or changes in the clinical health status or if 
patient adherence to treatment is otherwise endangered. In any case, it must be attempted 
to keep all patients on their starting formulation for their first treatment cycle. This will 
be crucial for MTD determination.
BSA has been recommended as the principal basis for drug dosage in the majority of 
chemotherapy regimens in adults and children (R13-1191; R13-1141; P13-03365).
For the current afatinib development in paediatric patients, allometric scaling was used to 
support estimation of a starting dose for different age groups based on the approved adult 
dose (40 mg).
Table 4.1.4: 1
Proposed afatinib dosing schedule for the Phase I/II
Dose levels
Level -1 (50%)
Level 0 (80%)
Level 1 (100%)
Level 2 (125 %)
Level 3 (150%)
BSA range 
(m2)
AOS 
(mL)
Tablet 
(mg)
AOS 
(mL)
Tablet 
(mg)
AOS
(mL)
Tablet 
(mg)
AOS
(mL)
Tablet 
(mg)
AOS
(mL)
Tablet 
(mg)
<0.40
1.0
-
2.0
-
2.5
-
3.0
-
3.5
-
[0.40 - 0.50[
1.5
-
2.5
-
3.0
-
3.5
-
4.5
-
[0.50 - 0.65[
1.5
-
2.5
-
3.5
-
4.0
-
5.0
-
[0.65 - 0.71[
2.0
-
3.0
-
3.5
-
4.5
-
5.5
-
[0.71 - 0.79[
2.0
-
3.5
-
4.0
-
5.0
-
6.0
-
[0.79 - 0.86[
2.5
-
3.5
-
4.5
-
5.5
-
7.0
-
[0.86 - 0.93[
2.5
-
4.0
-
5.0
-
6.0
-
7.5
-
[0.93 - 1[
2.5
-
4.5
-
5.5
20
6.5
-
8.0
30
[1 - 1.08[
3.0
-
4.5
20
5.5
-
7.0
30
8.5
-
[1.08 - 1.16[
3.0
-
5.0
20
6.0
-
7.5
30
9.5
40
[1.16 - 1.28[
3.5
-
5.5
20
6.5
-
8.5
-
10
40
[1.28 - 1.38[
3.5
-
6.0
-
7.5
30
9.0
40
11
-
[1.38 - 1.49[
4.0
-
6.5
-
8.0
30
10.0
40
12
50
[1.49 - 1.56[
4.5
-
7.0
30
8.5
-
10.5
40
13
50
≥1.56*
-
20
-
30
-
40
-
50
-
2 x 30
AOS: afatinib oral solution, 4 mg/mL
*Patients with a BSA ≥1.56, who are not able to swallow film coated tablets can also receive oral solution 
Study drug will be prescribed by the investigator and may be dispensed either by the 
investigator, site staff or affiliated pharmacy. Afatinib oral solution (capsules and solvent for 


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oral solution) will be prepared preferably at the investigational site. After preparation, 
afatinib oral solution is stable for 4 weeks. At each course, the dose level of the drug must be 
checked and the patient will be re-supplied with a new bottle of freshly prepared afatinib oral 
solution.
Feeding tubes made of PVC and PUR have successfully been tested with Afatinib oral 
solution, i.e. they showed no negative influence on the intended dose of afatinib. The oral 
syringe (see Section 4.1.6) must not be used for rinsing the feeding tube.
Afatinib film-coated tablets should be swallowed with a glass of water and should not be 
chewed or crushed.
4.1.4.1
Dose escalation of afatinib for MTD determination
The MTD will be determined as the highest dose at which no more than 1/6 patients 
experienced DLT. The MTD will be determined when the last patient included into the dose 
finding part completed his/her 1st treatment cycle and is evaluable for DLTs.
The dose finding part will use a rolling six design (R12-4744).The dose escalation and de-
escalation and the MTD determination will be performed as described in Table 4.1.4.1:1
Table 4.1.4.1:1
Dose escalation and de-escalation schedule and determination of 
MTD
DLT data among the enrolled 
patients
Enrolling dose level for the 
next patient
No. of 
enrolled 
patients per 
dose cohort
No. 
with 
DLT
No. 
without 
DLT
No. with 
DLT data 
pending
MTD not 
exceeded
MTD 
exceeded **
2
0 or 1
Any
Any
d
--
2
0
0
d – 1
--
3
0
3
0
d + 1
d
1
Any
Any
d
--
>=2
Any
Any
d – 1
--
4
0
4
0
d + 1
d
0
Other 
Other
d
d
1
Any
Any
d
d
>=2
Any
Any
d – 1
d – 1
5
0
5
0
d + 1
d
0
Other
Other
d
d
1
Any
Any
d
d
>=2
Any
Any
d – 1
d – 1
6
0
5, 6
1, 0
d + 1
MTD
0
Other
Other
Suspend***
Suspend
1
5
0
d + 1
MTD
1
Other
Other
Suspend
Suspend
>=2
Any
Any
d – 1
d – 1
Table adapted from Skolnik et al JCO 2008 Table 1 pp 191 (R12-4744.)
Note this table does not take into account unevaluable patients.
*
d is the current dose level; d + 1 and d – 1 represent dose escalation and de-
escalation, respectively.


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** 
MTD exceeded means that the ‘d + 1’ dose level has >=2 out of 3 to 6 patients with DLT (which is why 
there is no escalation in any of the listed scenarios).
*** 
‘Suspend’ means there is not enough information to determine the next patient’s dose level, one needs 
to wait until pending DLT data become available.
Note that the Rolling 6 design allows enrolling up to 6 patients on each dose cohort. The first 
cohort of patients will start with dose level 0 (i.e. 80% of adult dose) as listed in Table 
4.1.3:1. As soon as at least two patients are treated at dose level 0, the dose level for the third 
and subsequent patients will be determined based on the number of patients determined to 
have experienced DLT, those determined without DLT, and those with DLT data pending for 
the first treatment course, as illustrated in the first row of Table 4.1.4.1:1. For illustration 
purpose, an example (considering 4 patients treated on dose level 0) is given below: 
1) If DLT data of all 4 patients are available and none of them observed with DLT, 
the dose level may be escalated and the 5th patient will be enrolled to dose level 1 
2) If data is not yet available for one or more of the first 4 patients, or if one patient 
with DLT is observed, then the 5th patient will remain on dose level 0; the 
decision on further dose escalation or de-escalation will be made based on the 
rules illustrated for a 5-patient cohort
3) If more than 2 patients are observed with DLTs, the dose will be de-escalated and 
the 5th patient will be enrolled to dose level -1 
If scenario 1) occurs, dose level 1 becomes dose ‘d’ in Table 4.1.4.1:1. The process repeats 
after two patients are enrolled on dose level 1. 
If scenario 3) occurs, dose level 0 exceeds the MTD, and dose level -1 is the lowest dose 
level allowed in this trial. Up to six patients will then be treated on this level, if <=1/6 
patients with DLT, then dose level -1 will be the MTD; if >=2 patients with DLT, then there 
will be no MTD.
Similarly, suppose the trial has been escalated to higher dose levels, e.g. dose level 3, and 
>=2 patients had DLT, and if dose level 2 treated less than 6 patients previously, then the 
dose will be de-escalated to level 2 to fill up to 6 patients and the decision will be made 
according to the last column in Table 4.1.4.1:1.
As shown in Table 4.1.4.1:1, in order for a dose level to be the MTD, there must have been 6 
patients treated on the dose level (at most one patient can have DLT) and the next higher dose 
level exceeded MTD (>=2 patients with DLT). The exception to this rule is if none of the 4 
dose levels exceeds MTD, then dose level 3 will be MTD. 
If a patient experiences DLT (for definition refer to Table 4.1.4.1:2), therapy may be 
continued at a reduced dose (for dose reduction, refer to Table 4.1.4.3:1) after recovery of the 
respective adverse event(s) to pre-dose CTCAE grade(s). The investigator shall liaise with BI 
and ask for confirmation of the dose of the trial drug before a new treatment course is started 
for any patient. In questionable cases, the DMC might be involved in decision making. If a 
patient is not eligible for further therapy, the patient has to discontinue further treatment with 
the trial drug. 


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Table 4.1.4.1:2
Dose limiting toxicities
Dose limiting toxicity (DLT)
DLTs are defined as any of the following events that are considered related to afatinib:
1.
CTCAE grade 4 hematologic toxicity lasting for 7 days
2.
CTCAE Grade 3 or 4 non-hematologic toxicity (except fever grade 3). 
3.
CTCAE Grade 2 or higher decrease in cardiac left ventricular function
4.
CTCAE Grade 2 or higher worsening of renal function as measured by serum creatinine, newly 
developed proteinuria, or newly developed decrease in glomerular filtration rate
5.
CTCAE Grade 2 diarrhoea persisting for 7 or more days, despite supportive treatment (loperamide 
treatment or other effective anti-diarrhoeal medication)
6.
CTCAE Grade 2 nausea and/or vomiting persisting for 7 or more days despite antiemetic treatment
7.
CTCAE grade 5 events
4.1.4.2
Intra-patient dose escalation of afatinib
For the patients included in the dose finding part, retreatment and intra-patient dose 
escalation to the next dose tier may be allowed when this dose tier was considered safe (for 
dose tiers, refer to Table 4.1.3:1; for dosing, refer to Table 4.1.4:1). This will allow all 
patients remaining on treatment to maximize their benefit from treatment, and prevent under-
dosing patients in the initial dose cohorts (Section 3.2).
The decision on when to consider the next higher dose tier safe will be based on a thorough 
assessment by the steering committee and, if required, by the DMC. Intra-patient dose 
escalation still needs to be confirmed with the sponsor.
4.1.4.3
Dose reduction of afatinib
Treatment related toxicities will be managed by treatment interruptions and subsequent dose 
reductions of afatinib according to the schedule described in Table 4.1.4.3: 1. Dose 
reductions will apply to individual patients only. Once the treatment 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 
4.2. 


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Table 4.1.4.3:1
Dose reduction scheme for afatinib
AE type and CTCAE Grade
Action
Dose reduction scheme
Events related to study drug:
Diarrhoea Grade 2 persisting for 7 or 
more consecutive days 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 
schedule opposite.
If patient has not recovered 
to Grade ≤1 or baseline1
within 
14 
days,
study 
treatment 
must 
be 
permanently discontinued2.
If patient was treated at dose 
level 3, resume treatment at 
dose level 2
If patient was treated at dose 
level 2, resume treatment at 
dose level 1
If patient was treated at dose 
level 1, resume treatment at 
dose level 0
If patient was treated at dose 
level 0, resume treatment at 
dose level -1
If patient was treated at dose
level -1, discontinue afatinib.
Acute onset and/or unexplained 
worsening of pulmonary symptoms
(dyspnoea requiring supplementation of 
oxygen with cough and/or 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 ILD is confirmed, 
discontinue afatinib.
Acute onset of symptoms indicative of 
keratitis
Pause afatinib while clinical 
assessment of keratitis is 
ongoing.
If a diagnosis of ulcerative 
keratitis is confirmed, treatment 
with afatinib should be 
discontinued. Unless the 
treatment benefit for the patient 
outweighs the risks of 
worsening keratitis (blindness) 
in the opinion of the 
investigator.
Acute onset of symptoms indicative of 
cardiac failure and/or CTCAE Grade ≥2 
LVEF decrease and/or ≥20% decrease of 
LVEF from baseline
Pause afatinib while clinical 
assessment is ongoing and 
until patient recovers to 
Grade≤1 or baseline1
If patient has not recovered 
despite appropriate treatment to 
Grade ≤1 or baseline1 within 14 
days, study treatment must be 
permanently discontinued2
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 the sponsor and the investigator.
In the event of any unrelated adverse events, the investigator may choose to interrupt the 
medication for up to 14 days, but no dose reduction should occur once treatment is resumed.  


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If the medication is interrupted for more than 14 days, the decision to continue with afatinib 
will be made by the BI clinical monitor in agreement with the investigator.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Not applicable
4.1.5.2
Procedures for emergency unblinding
Not applicable.
4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the ISF.
Trial drug packages will have unique medication numbers which will be used for tracking 
purposes only. The medication numbers will not be linked to randomisation numbers.
Afatinib will be supplied:

As film-coated tablets with available dosage strengths of 20 mg, 30 mg, 40 mg and 50 
mg in child resistant plastic bottles. Each bottle containing 30 tablets.

As capsules and solvent for oral solution. Afatinib solution will be prepared at site: 
two 200mg capsules must be dissolved in the co-supplied bottle of 100mL of solvent
resulting in a concentration of 4mg/mL. See details in reconstitution instruction 
provided in the ISF.  Dosing and administration is planned to be performed by the 
parents/caregivers with a co-supplied oral syringe suitable for the intended volume. 
The syringe can be connected to the bottle via an adapter plug. See details in handling 
instruction (illustration of administration procedure) provided in the ISF (also to be 
provided to parents/caregivers). The oral solution is stored in child resistant solvent 
bottles.
4.1.7
Storage conditions
Trial medication, which will be provided by the sponsor and/or a CRO appointed by the 
sponsor, must be kept in a secure, limited access storage area under the storage conditions 
defined below until supplied/administered to patient. Temperature logs must be maintained to 
make certain that the drug supplies are stored at the correct temperature. In case temperature 
would be out of range, this has to be reported in the ISF and the sponsor be notified.
Afatinib tablets:
Afatinib must be stored in the original package in order to protect from light. Film-coated 
tablets are humidity-sensitive; therefore, bottles must be kept tightly closed to protect from 
moisture. Tablets must be stored according to label instructions.


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Afatinib capsules and solvent:
Afatinib capsules must be stored in the original container in order to protect from moisture.
Solvent for Oral Solution must be stored according to label instructions.
After preparation, the solution is stable for 4 weeks at 25°C (date of preparing the oral 
solution has to be reported on the bottle label). The solution must be stored in the original 
solvent container/ amber glass bottle.
4.1.8
Drug accountability
Drug supplies, which will be provided by the sponsor or a CRO appointed by the sponsor, 
must be kept in a secure, limited access storage area under the storage conditions defined by 
the sponsor. Where necessary, a temperature log must be maintained to make certain that the 
drug supplies are stored at the correct temperature.
The investigator or delegate (e.g. pharmacist or study drug storage manager) will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

approval of the study protocol by the IRB / ethics committee,

availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre,

approval/notification of the regulatory authority, e.g. competent authority,

availability of the curriculum vitae of the principal investigator,

availability of a signed and dated clinical trial protocol or immediately imminent 
signing of the clinical trial protocol, 

where applicable, availability of the proof of a medical licence for the principal 
investigator, 

for USA, availability of the Form 1572.
The investigator or delegate must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or alternative 
disposition of unused product(s). 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product(s) and trial patients. The 
investigator or delegate will maintain records that document adequately that the patients were 
provided the doses specified by the CTP and reconcile all investigational product(s) received 
from the sponsor. At the time of destruction at site or return (if applicable) to the sponsor 
and/or appointed CRO, the investigator or delegate must verify that all unused or partially 
used drug supplies have been returned by the clinical trial patient and that no remaining 
unused supplies are in the investigator’s possession.


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4.1.9
Drug acceptability
Acceptability of the drug formulations in children per EMA/CHMP/QWP/805880/2012 Rev2 
will be assessed using drug acceptability questionnaires for patients, parents/caregivers and
investigator/site staff. Drug acceptability will be assessed after completion of the first course 
of treatment with the given formulation.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
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. In cases of suspected overdose, afatinib should be withheld and supportive 
care initiated. If indicated, elimination of unabsorbed afatinib may be achieved by emesis or 
gastric lavage. 
Common adverse events of afatinib treatment observed in adults with specified management 
recommendations and/or requirements include diarrhoea, mucositis 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.
Concomitant treatments
Concomitant medications or therapy to provide adequate supportive care may be given as 
clinically necessary. 
After study enrolment, 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 must not be used for 
tumour response assessment. During palliative radiotherapy, study treatment should be 
paused and 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 
the BI clinical monitor in agreement with the investigator. Continuous interruption of >28 
days due to palliative radiotherapy will not be allowed.
All concomitant therapies, including anaesthetic agents (except pre-planned anaesthetic 
agents e.g. related to imaging exams), 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 for trial participation, and ending at 
the EOT visit. After the EOT visit, only concomitant therapy indicated for treatment of an AE 
has to be reported. 
In case of major surgery (as judged by the investigator), it is recommended to stop treatment 
with afatinib around one week prior to the surgery, and to restart treatment after complete 


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wound healing. If afatinib is interrupted for more than 14 days, the decision to continue will 
be made by the BI Clinical Monitor in agreement with the investigator.
Emergency procedures
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnoea, cough, fever and demand for oxygen supplementation) 
should be performed to exclude interstitial lung disease (ILD). Study drug should be 
interrupted pending investigation of these symptoms. If interstitial lung disease is diagnosed, 
study 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.
In case the patient develops acute onset of symptoms indicative of cardiac failure and/or 
CTCAE Grade ≥2 LVEF decrease and/or ≥20% decrease of LVEF from baseline, study drug 
should be interrupted pending investigation of symptoms. The patient should be monitored 
closely for recovery. If patient has not recovered despite appropriate treatment to Grade ≤1 or 
baseline within 14 days study treatment must be permanently discontinued.
4.2.2
Management of expected adverse events
At occurrence of a drug related AE:
-
Pause the drug if applicable, refer to Table 4.1.4.3:1
-
Treat the side effect
-
Dose reduce at reintroduction if applicable
Dermatologic adverse events and diarrhoea are the most common side-effects associated 
with treatment with afatinib in the adult population. Treatment of these side-effects 
should be proactive and should be started as early as possible after onset of symptoms.
4.2.2.1 Management of diarrhoea and hydration status following treatment with afatinib
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 4.2.2.1:1). 
At the time of initiation of treatment with afatinib, patients/ parents/legal guardian should be 
given a supply of loperamide (if applicable) to keep with them at all times or access to 
loperamide (if applicable) should be confirmed; and patients/ parents/legal guardian(s) should 
be counselled on the appropriate use. In cases where loperamide is not available or approved 


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for the age group institutional standards for treatment of “chemotherapy-associated 
diarrhoea” must be followed.
Maintaining fluid balance in children developing diarrhoea is crucial at all times to avoid 
dehydration and renal insufficiency. Investigators need to assure that parents are alerted to 
this and must describe early signs and symptoms of dehydration (dry mucosal membranes, 
crying without tears, fever, decrease in urine output) clearly to caregivers/patients. Also 
assure that caregivers understand diarrhoea is an afatinib associated side effect which requires 
treatment. Caregivers/patients must seek medical advice on occurrence of initial signs and 
symptoms of diarrhoea and complications thereof.
To maintain fluid balance, the patient’s fluid deficit must be assessed according to clinical 
standards. In addition daily fluid requirements may be estimated as 1.8L/m2/day, or more 
precisely 100 mL/kg/day can be calculated for the first 10 kg (1-10 kg). 50 mL/kg/day will be 
added for each kg body weight from 11-20 kg and 25 mL/kg/day can be calculated for each 
kg body weight from 20-30 kg. In addition estimated fluid deficits should be replaced within 
36 hours, replacing the initial third of estimated fluid loss within 8-10 hours. CAVE: special 
rules apply for hypertonic dehydration (R14-2337).
Table 4.2.2.1: 1 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 if any. Oral 
rehydration can be attempted, 
but i.v. fluid replacement 
should start quickly if oral 
rehydration is not effective. For 
oral rehydration, advice the 
patient/caregiver to assure fluid 
consumption of at least 
1.8L/m² electrolyte balanced 
fluids per day; in addition
loperamide and racecadotril are 
preferred drugs for the 
treatment of diarrhoea. 
Treatment is to be started 
immediately according to the 
age-specific label instructions,
i.e. for loperamide 0.4-0.8 
mg/kg/24 h po should be 
applied at dose intervals of 6-
12 hours until diarrhoea 
resolves; for chronic diarrhoea 


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Table 4.2.2.1: 1 Grade specific treatment recommendations for afatinib related diarrhoea-(cont’d)
0.5-1.5 mg/kg/24h po, given at
dose interval of 6-12 hours,  for 
maintenance reduce to 0.25-1 
mg/kg/24 h po given at dose 
interval of 6-12 hours (R14-
2354, R14-2355)
For racecadotril, where 
available, a dose of 1.5 mg/kg 
3 times per day** proved very 
effective in stopping chronic 
diarrhoea (P13-10876, P14-
08260)
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 ≥ 7 days in which 
case treatment must be 
interrupted until 
recovered to ≤Grade 1 
followed by dose 
reduction
Continue loperamide/
racecadotril as described 
above; 
assess degree of dehydration 
and electrolyte imbalance and
consider i.v. fluid and 
electrolyte replacement early;
an infectious process should be 
ruled out with stool cultures
Severe (Grade 3) 
Increase of ≥7 stools per 
day over baseline; 
incontinence; IV fluids > 
24 hours; hospitalization; 
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 aggressive 
i.v. fluid replacement until 
fluid balance is restored; 
hospitalization 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 the sponsor and the investigator.
** Recommended for children of >3 months
4.2.2.2
Management recommendations for dermatological AEs following treatment with 
afatinib
Dermatologic AEs of afatinib include rash, acne, dermatitis acneiform and dry skin. General 
recommendations for prophylaxis are summarized in Table 4.2.2.2: 1 and treatment 
recommendations specified by CTCAE grade are summarized in Table 4.2.2.2: 2. For dose 
adjustment of afatinib refer to Table 4.1.4.1:2.  
Specific interventions should be reassessed at each visit 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. (Adapted from R11-
0826)


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Table 4.2.2.2: 1 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 (if applicable) 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, sunglasses and wearing a hat should be 
recommended.
Moisturizer treatment
It is important to moisturize the skin as soon as anti-ErbB therapy with afatinib 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 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 4.2.2.2: 2 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 referral to dermatologist.
Consider topical antibiotics, e.g. 
clindamycin 2% or topical erythromycin 1% 
cream or metronidazole 0.75% or topical 
nadifloxacin 1% as available, applicable 
and appropriately dosed  for respective age 
group;
Isolated scattered lesion: cream preferred
Multiple scattered areas: lotion preferred
Moderate (Grade 2)
Macular or papular eruptions with 
pruritus or other associated 
symptoms; localized desquamation 
or other lesions covering <50% of 
Consider referral to dermatologist.
Topical treatment as for Grade 1 as 
available and applicable per age group
plus short term topical steroids, e.g. 


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Table 4.2.2.2: 2 Grade specific treatment recommendations of skin reactions to afatinib-
(cont’d)
BSA
prednicarbate cream 0.02% plus
an oral antibiotic (for at least 2 weeks) e.g. 
erythromycin, clindamycin, minocycline 
hydrochloride as available, applicable and 
appropriately dosed for respective age 
group.
Severe (Grade 3)
Severe, generalized erythroderma or 
macular, popular or vesicular 
eruption; desquamation covering ≥ 
50% of BSA; associated with pain, 
disfigurement, ulceration or 
desquamation
Consult a dermatologist.
Topical and systemic treatment as for   
Grade 2.
Consider systemic steroids appropriately 
dosed  for respective age groups.
Assess fluid loss and replace fluid.
Life threatening 
(Grade 4)
Generalized exfoliative, ulcerative, 
or bullous dermatitis
Consult a dermatologist, hospitalize the 
patient, see also Grade 3 above.
Systemic steroids are recommended
appropriately dosed  for respective age 
group.
Assess fluid loss and replace fluid.
EARLY AND LATE XEROTIC SKIN REACTIONS – PRURITUS
Mild (Grade 1)
Mild or localized
Consider referral to dermatologist
Topical polidocanol cream.
Consider oral antihistamines, e.g. 
diphenhydramine, dimethindene, cetirizine, 
levocetirizine, desloratidine, fexofenadine 
or clemastine) as available, applicable and 
appropriately dosed  for respective age 
groups
Moderate (Grade 2)
Intense or widespread
Consider referral to dermatologist
See Grade 1 plus oral antihistamines;
Consider topical steroids, e.g. topical 
hydrocortisone as available, applicable and 
appropriately dosed  for respective age 
group
Severe (Grade 3)
Intense or widespread and interfering 
with activities of daily living (ADL)
See Grade 2.
XEROSIS (DRY SKIN)
Mild (Grade 1)
Asymptomatic
Consider referral to dermatologist
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 as available, 


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Table 4.2.2.2: 2 Grade specific treatment recommendations of skin reactions to afatinib-
(cont’d)
applicable and appropriately dosed  for 
respective age group
FISSURES
Mild (Grade 1)
Asymptomatic
Consider referral to dermatologist.
Consider topical treatment as available, 
applicable and appropriately dosed for 
respective age group: e.g. 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 as available, 
applicable and appropriately dosed for 
respective age group.
Severe (Grade 3)
Symptomatic,
Interfering with ADL
See Grade 2.
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 4.1.4.3:1
4.2.2.3
Management of mucositis/stomatitis 
General and grade specific recommendations are described in Table 4.2.2.3:1. For dose 
adjustment refer to Section 4.1.4 and for restrictions on concomitant therapies refer to 
Sections 4.2.3, 10.5 and 10.6.
Mucositis and associated pain may lead to fluid loss and hypo-alimentation. Therefore 
maintaining fluid balance and appropriate pain control are crucial. Please assure that parents 
are alerted to this and describe early signs and symptoms of mucositis and fluid loss clearly to 
caregivers/patients. Caregivers/patients should quickly seek medical advice on occurrence of 
initial signs and symptoms. In addition below measures may be useful.
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/sorbet as tolerated, 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 


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support may be needed. Examples of some of the agents suggested in Table 4.2.2.3:1 include: 
topical analgesics –viscous lidocaine 2%; mucosal coating agents - topical kaolin/pectin; oral 
antacids, maltodextrin, sucralfate; topical antifungals – nystatin suspension. (Adapted from 
P11-09424)
Table 4.2.2.3: 1
Grade specific treatment recommendations of study-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 Section 4.1.4.
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 Section 4.1.4
*Also consider Rugo et al. (R17-1688)
4.2.3
Restrictions
4.2.3.1
Restrictions regarding concomitant treatment
Concomitant medications, or therapy to provide adequate supportive care, may be given as 
clinically necessary.
Palliative radiotherapy may be given as described in Section 4.2.1.
Additional experimental anti-cancer treatment and/or standard chemo-, immunotherapy, 
hormone treatment, or radiotherapy (other than palliative radiotherapy for symptom control) 
is not allowed concomitantly with the administration of study treatment. 
Afatinib is a substrate of the P-gp transporter. Caution should be exercised when combining 
afatinib with strong P-gp modulators including, but not limited to strong P-gp inhibitors
ritanovir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, 
tacrolimus, nelfinavir, saquinavir, and amiodarone. Conversely, strong P-gp inducers such as 
rifampicin, carbamazepine, phenytoin, phenobarbital or St. John’s Wort may decrease the 
plasma concentrations of afatinib. Co-administration of P-gp modulators must be avoided 


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during course 1 of Phase I dose finding. In addition P-gp modulators should be avoided 
within 14 days or at least 5 half-lives of the drug (whichever is longer) prior to the first dose 
of afatinib. For use of strong P-gp inhibitors after course 1 of the dose finding part and during 
the MTD expansion cohort, staggered dosing must be considered. For use of strong P-gp 
inducers after course 1 of the dose finding part and during the MTD expansion cohorts/Phase
II part, afatinib daily dose should be increased based on tolerability and discussion with the 
sponsor. For a list of potent P-gp inhibitors and inducers see Appendix 10.4.
4.2.3.2
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 4.2.2.2.
4.2.3.3
Boys and girls with reproductive potential – contraception and pregnancy
prevention
Patients who are not of reproductive potential (i.e. pre-pubertal) do not need to use 
contraception to be eligible for the trial.
All other patients are considered to have childbearing potential (had 1st menarche or 1st
ejaculation) and must use adequate contraception throughout the trial if sexually active (from 
screening until 28 days after last dose of trial medication). Highly effective methods of birth 
control per ICH M3 (R2) are methods that result in a low failure rate of less than 1% per year 
when used consistently and correctly (R09-1400). These include hormonal contraception 
associated with inhibition of ovulation, IUD, intrauterine hormone-releasing system, bilateral 
tubal occlusion, partner vasectomy (if vasectomized partner is sole sexual partner) (R16-
0373). When using hormonal contraceptives, or with partners using hormonal contraceptives, 
patients must also be using an additional approved barrier method of contraception, i.e. 
condom or occlusive cap with spermicide, or vasectomised partner.
A method of contraception which is not considered highly effective (> 1% failure rate) is the 
double barrier method. Double barrier method of contraception is defined as two barrier 
methods used simultaneously each time the patient has intercourse. Use of male and female 
condom together, partner vasectomy (if different sexual partners), natural "rhythm" and 
spermicidal jelly/cream are not acceptable methods of contraception.
Female patient who become pregnant while participating in the study must discontinue study 
medication immediately.  The pregnancy must be reported following procedures detailed in 
Section 5.2.2.3.
4.3
TREATMENT COMPLIANCE
The appropriate number of afatinib tablets/ afatinib liquid formulation for 4-weeks of 
treatment will be provided to the patients to be self-administered at home. An appropriate 
number of syringes will be co-supplied with afatinib oral liquid formulation. The patient will 
be requested to maintain a medication diary of each dose of medication. The medication diary 


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will be returned to clinic staff at the end of each course. During the first treatment course, 
compliance may also be verified by pharmacokinetic assessment.
Patients will be asked to bring the remaining trial medication at the end of each 4-week 
period to the investigational site for a compliance check. The remaining film-coated tablets 
will be counted by the investigator/site staff and the remaining volume of afatinib oral liquid 
formulation will be estimated as well (for details refer to ISF) and recorded at the 
investigational site. Discrepancies between the number of tablets/amount of liquid 
formulation remaining and the calculated amount of medication the patients should have 
taken must be documented and explained. An early compliance check at course 1 day 8 will 
be done by the investigator/site for ensuring that the medication is being taken correctly. At 
the end of each 4-week period, any remaining medication will be collected. If the patient is 
eligible for further treatment, new bottle(s) of study medication must be dispensed. 
The investigator and/or the sponsor should discuss patient’s withdrawal from the study in the 
event of serious and persistent non-compliance which jeopardizes the patient’s safety or 
renders study results for this patient unacceptable. Patients who do not attend a minimum of 
75% of scheduled study visits, unless due to exceptional circumstances, should be discussed 
with the BI trial monitor and be evaluated for compliance. For afatinib, a maximum of 25% 
of the dispensed afatinib doses may be missed for other reasons than drug-related AEs. For 
details, see section 7.3. Patients who miss afatinib treatment more frequently are considered 
non-compliant.  
During the first course of the dose finding part, patients should not miss more than 25% of 
afatinib doses (regardless of the reason of missed doses) to render patients evaluable for 
MTD. For details, see section 7.3.


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5.
VARIABLES AND THEIR ASSESSMENT
For details on time points of evaluation and specific assessments, refer to the following 
Sections 5.1, 5.2 and 5.5.1.
The endpoints are categorised as follows and explained in more detail in the sections below:
Primary Endpoint 
-
In dose finding part
o
DLT measured during the first course of treatment
o
Pharmacokinetics (AUCτ,ss, Cmax,ss)
-
In MTD expansion cohorts/Phase II part
o
Objective Response by investigator assessment according to the 
institutional response evaluation criteria for the given tumour type, 
assessed every 8 weeks until progression of disease. 
Secondary Endpoints
-
In dose finding part
o
Objective Response by investigator assessment according to the 
institutional response evaluation criteria for the given tumour type, 
assessed every 8 weeks until progression of disease. 
o
Pharmacokinetics (AUC0-24, Cmax, tmax(,ss) and accumulation (or effective) 
half-life)
-
In MTD expansion cohorts/Phase II part
o
Progression free survival (PFS)
o
Duration of objective response (DoR)
o
Pharmacokinetics (AUCτ(,ss), Cmax(,ss), tmax(,ss) and accumulation (or 
effective) half-life)


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5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoint(s) of efficacy
5.1.1.1    Primary endpoint
For the dose finding part, a primary endpoint of efficacy is not applicable. The primary 
endpoint for safety is described in Section 5.2.1.
In the MTD expansion cohorts/Phase II part, the primary endpoint will be objective response 
by investigator assessment according to the institutional response evaluation criteria for the 
given tumour type, assessed every 8 weeks until progression of disease.
5.1.1.2   Secondary endpoints
In the dose finding part of this trial, the objective tumour response (OR) assessed by 
investigator assessment according to the institutional response evaluation criteria for the 
given tumour type will represent a secondary endpoint. 
In the MTD expansion cohorts/Phase II part, progression free survival (PFS) and duration of 
objective response (DoR) will be secondary endpoints for efficacy. PFS is defined as the 
duration of time from the date of first treatment until the date of the first documented 
progression or death due to any cause. If a patient has not had an event, PFS will be censored 
at the date of last adequate tumour assessment. Duration of overall objective response (DoR) 
is defined only for those patients with a response (CR or PR) as the interval between the date 
of randomization and the earliest date of disease progression.
5.1.2
Assessment of efficacy
Response and progression will be evaluated in this study by investigator assessment 
according to the institutional response evaluation criteria for the given tumour type. 
Each tumour type should be assessed using appropriate techniques. The method used at 
baseline must be continuously used throughout all consecutive tumour assessments.
In addition, all image data will be sent to a central imaging unit for digitization, quality 
control and archiving. If deemed necessary, a retrospective independent review of 
radiographic images may be performed. All procedures will be done according to the 
specifications provided in the investigator site file.
5.2
SAFETY
5.2.1
Endpoint(s) of safety
Primary endpoint: DLT 


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The primary objective of the dose finding part is to determine the MTD as defined by patients
with DLT in a paediatric population. It will be reported as primary endpoint of safety in this 
part of the trial.
For the purpose of dose escalation, patients with DLT events that occur during the first 
treatment course will be considered. Decisions on dose escalation/dose de-escalation will be 
made only after discussion between the sponsor and the investigators/steering committee, and 
in consideration of all the available toxicity and pharmacokinetic data. For details on the 
determination of MTD and definition of DLT, please refer to sections 4.1.4.1 and 7.3.1.
Once the MTD will be obtained, the MTD expansion cohorts/Phase II part will allow further 
collection of safety data and efficacy data. DLT will be monitored throughout the whole trial
and all safety data will be collected in order to confirm the safety of the recommended Phase 
II dose. 
Other safety endpoints will include:
-
The overall incidence and CTCAE grade of adverse events, as well as relatedness of 
adverse events to treatment
-
Events leading to dose reduction
-
Events leading to permanent treatment discontinuation
-
AESI
-
Causes of death
The safety of afatinib will be assessed by a descriptive analysis of incidence and intensity of 
adverse events graded according to US NCI CTCAE Version 3.0 (R04-0474). 
5.2.2
Assessment of adverse events
Safety assessments will consist of monitoring and recording all adverse events (AEs) and 
serious adverse events (SAEs) and include periodic physical examinations, measurement of
vital signs, assessment of performance status, monitoring of laboratory tests (i.e. 
haematology, chemistry, coagulation, urine analysis), assessment of cardiac function with 
periodic ECGs and echocardiograms, pregnancy test(s) as outlined in the Schedule of 
Procedures/Assessments (Section 6.2.1).
If the investigator becomes aware of an SAE or AESI after the FU visit (28-30 days after the 
last dose of study drug), it should be reported by the investigator to the sponsor if considered 
relevant by the investigator.
A diagram of the Adverse Event/Serious Adverse Event reporting requirements is provided in
Table 5.2.2.2:1
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 


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pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 
judgement which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions.
Cancers with new histology are always considered serious.
The following hospitalizations are not considered to be serious adverse events (SAEs) 
because there is no “adverse event” (i.e., there is no untoward medical occurrence) associated 
with the hospitalization:
Hospitalizations for respite care 
Planned hospitalizations required by the protocol (including anaesthesia for imaging 
exams)
Hospitalization planned prior to informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration)
Hospitalization for administration of study drug 
Intensity of adverse event
The intensity of the AE should be judged based on the following:
-
The intensity of adverse events should be classified and recorded according to the 
Common Terminology Criteria for Adverse Events (CTCAE) v3.0 in the (e)CRF.
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE. 


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The reason for the decision on causal relationship needs to be provided in the eCRF and on 
the SAE form (if applicable).
Worsening of the underlying disease or other pre-existing conditions
Worsening of pre-existing conditions other than underlying disease will be recorded as an 
(S)AE in the (e)CRF.
Exemptions to SAE Reporting
Disease Progression is a study endpoint for analysis of efficacy. Disease progression is 
exempted from reporting as a (S)AE. Progression of the patient's underlying malignancy,
including death due to progression of the underlying malignancy, will be recorded in the 
appropriate pages of the (e)CRF as part of efficacy data collection.
Examples of exempted events of PD are:
•         Progression of underlying malignancy (Progressive disease PD): if PD is clearly 
consistent with the suspected progression of the underlying malignancy as defined by 
the respective response criteria. 
•         Hospitalization/Procedures due solely to the progression of underlying malignancy 
(PD)
•         Clinical symptoms and/or signs of progression (with or without confirmation by 
objective criteria e.g. imaging, clinical measurement): if the symptom can exclusively 
be determined to be due to the progression of the underlying malignancy and does 
meet the expected pattern of progression for the disease under study.
However, when there is evidence suggesting a causal relationship between the drug and the 
progression of the underlying disease, the event must be reported as (S)AE in the eCRF and 
on the SAE Form.
Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the (e)CRF , if they are judged clinically relevant by the investigator.
Adverse Events of special interest (AESIs)
Protocol-specified AESIs
The following are considered as Protocol-specified AESIs:
Hepatic injury defined by the following alterations of liver parameters: 
1.
For patients with normal liver function (ALT, AST and bilirubin within 
normal limits) at baseline an elevation of AST and/or ALT >3 fold ULN 
combined with an elevation of bilirubin >2 fold ULN measured in the same 
blood draw sample and/or a marked peak aminotransferase (ALT, and/or AST) 


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elevations ≥ 10 fold ULN. Patients showing these lab abnormalities need to be 
followed up according to APPENDIX 10.2 of this clinical trial protocol and 
according to the "DILI checklist" provided in the ISF
2.
For patients with abnormal liver function at baseline an elevation of AST 
and/or ALT >5 fold ULN combined with an elevation of bilirubin >2 fold 
ULN measured in the same blood draw sample. Patients showing these lab 
abnormalities need to be followed up according to APPENDIX 10.2 of this 
clinical trial protocol and according to the "DILI checklist" provided in the 
ISF.     
Although rare, drug-induced liver injury is under constant surveillance by sponsors 
and regulators and is considered a protocol-specified AESI.  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.  

Dose limiting toxicity. The definition of DLT is given in Section 4.1.4.1
Protocol-specified AESIs need to be reported to the Sponsor’s Pharmacovigilance 
Department within the same timeframe that applies to SAE, see Section 5.2.2.2.
If the investigator determines any protocol-specific AESI is related to study drug, the 
administration of the study drug must be managed according to Section 4.1.4.3 of the 
protocol.
Expected Adverse Events
For expected (listed) AEs of afatinib, see the current version of the IB (c01802941).
5.2.2.2
Adverse event and serious adverse event reporting
The residual effect period (REP) for afatinib is 28 days after last intake of afatinib.
All adverse events, serious and non-serious, occurring from signing of the informed 
consent/patient assent for trial participation onwards until the FU visit i.e.28-30 days after 
last administration of study medication, regardless of relatedness and listedness, will be 
collected, documented and reported to the sponsor by the investigator.
SAEs and AESIs occurring after the FU visit (28-30 days after last administration of study 
medication) will be reported in case they are considered relevant by the investigator. 
All AEs, including those persisting after end of study medication must be followed up until 
they have resolved or have been sufficiently characterised, unless the sponsor and the 
investigator agree not to pursue them further. Reporting will be done according to the specific 
definitions and instructions detailed in the adverse event reporting section of the ISF. A 
summary of the AE reporting requirements is given in Table 5.2.2.2:1.


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Table 5.2.2.2:1 AE/SAE reporting requirements
Time period
Reporting requirements
From signing of informed consent for trial 
participation* to the FU visit (≤28-30 days 
after last trial drug administration)
*Does not apply to pre-screening consent
Report all AEs and SAEs regardless of 
relatedness or whether the trial drug was 
administered. This includes all deaths.
Post-treatment: after the FU visit (>28-30
days after last trial drug administration)
Report only SAEs which are considered 
relevant by the investigator
The investigator must report the following events via fax using the SAE form immediately 
(within 24 hours) to the sponsor:
• SAEs
• non-serious AEs which are relevant for the reported SAE/AESI
• protocol-specified AESIs
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, a query will be 
raised if a non-serious AE is identified to be serious per BI definition. The investigator must 
verify the description and seriousness of the event.  If the event description is correct, the 
item “serious” needs to be ticked and an SAE has to be reported in expedited fashion 
following the same procedure as above.
The list of these adverse events can be found via the RDC-system and in the ISF.
SAEs occurring in patients after having discontinued in the trial due to screening failures. i.e. 
after the screening period and who did not receive any trial medications, are to be reported if 
the investigator considered the SAE related to the screening procedure. SAEs which occurred 
during the screening period are to be reported according to standard procedure.
5.2.2.3
Pregnancy reporting
In very rare cases, pregnancy might occur in paediatric clinical trials. Once a female patient 
has been enrolled into the clinical trial, after having taken study medication, the investigator 
must report immediately any drug exposure during pregnancy to the sponsor. Drug exposure 
during pregnancy has to be reported immediately (within 24 hours) to the defined unique 
entry point for SAE forms of the respective BI OPU (country-specific contact details will be 
provided in the Investigator Site File). The outcome of the pregnancy associated with the 
drug exposure during pregnancy must be followed up. In the absence of an (S)AE, only the 
Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be completed. The 
ISF will contain the Pregnancy Monitoring Form for Clinical Trials (consists of Part A and 
Part B).


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5.2.3
Assessment of safety laboratory parameters
Safety laboratory samples will be analyzed at the investigator’s local laboratory. Safety 
laboratory examinations will include hematology, biochemistry and urine examinations. 
Table 5.2.3: 1 presents the laboratory tests to be performed at screening, Day1 of each course 
and/or EOT whatever applies.
Table 5.2.3:1
Clinical Laboratory Tests
Category
Parameters 
Haematology
Haemoglobin (Hb), platelet count, white blood 
cell count ( WBC), with differential (neutrophils, 
lymphocytes, monocytes)
Coagulation
International Normalized Ratio (INR), activated 
Partial Thromboplastin Time (aPTT)
Chemistry
Electrolytes
sodium, potassium, calcium, magnesium, 
chloride, bicarbonate (HCO3)
Liver function tests
alkaline phosphatase, aspartate 
aminotransferase (AST), alanine 
aminotransferase (ALT), γ-
glutamyltransferase (GGT), total  bilirubin
Renal function 
parameters
Blood urea/blood urea nitrogen (BUN), 
creatinine; Creatinine clearance estimate by
institutional standard formula for estimation 
of GFR in paediatric patients.
Category
Parameters 
Other
glucose, albumin, phosphorus, lactate 
dehydrogenase (LDH), total protein, uric acid, 
creatine phosphokinase (CK); in case of 
pathological CPK further evaluation (e.g by 
determination of isoenzymes, troponin assays, 
ECG exam) should be performed as clinically 
indicated, CRP
Urinalysis
pH, protein, glucose, erythrocytes, leucocytes,
nitrite and, if clinically indicated ketones, 
urobilinogen, specific gravity; in case of 
pathological finding(s) further evaluation should 
be performed and results of the latter must be 
documented 
Pregnancy test
β-HCG testing in urine or serum in girls of 
childbearing potential (WOCBP)


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Limited lab tests (Hb, WBC, ANC, thrombocytes) will be required at intermediary visits
The investigator should complete additional evaluations of laboratory tests as clinically 
indicated.  Any abnormal findings from these investigations need to be reported as an 
Adverse Event. For confirmation of laboratory findings indicative for drug induced liver 
injury (DILI), local laboratories will be used
5.2.4
Electrocardiogram
12-lead ECG will be taken at the time points specified in the Flow Chart.  The investigator 
will review the ECG recording, comment on any clinical significance and if applicable record 
any ECG abnormality that meets AE criteria.
5.2.5
Assessment of other safety parameters
5.2.5.1
Physical examination, vital signs, height and weight, performance score
A full physical exam must include: vital sign measurements blood pressure [systolic blood 
pressure, diastolic blood pressure], pulse rate, temperature, cardiopulmonary examination, 
examination of the regional lymph nodes, and examination of the abdomen and an assessment 
of the mental and neurological status. Additional symptoms which have not been reported 
during a previous examination must be clarified. Wherever possible the same investigator 
should perform this examination.
A complete physical examination will be done at Screening, Day 1, every visit on study, and 
at the End-of-Treatment visit. 
Measurement of height (in cm), body weight (in kg) and the evaluation of the performance 
score (Lansky for patients ≤ 12 years or Karnofsky for patients older than 12 years at the time 
of informed consent) will be conducted at the times specified in the Flow Chart.
5.2.5.2
Left ventricular function
LVEF will be assessed by echocardiography (ECHO) at time points specified in the Flow 
Chart. 
5.2.5.3
Ophthalmologic examination
Standard ophthalmological examination to exclude keratitis will be conducted at time points 
specified in the Flow Chart.
5.2.5.4
Pulmonary examination
Pulmonary examination must include transdermal O2 saturation at time points specified in 
the Flow Chart and may be supplemented by a chest X-ray if clinically indicated.


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5.3
OTHER
5.3.2
Other assessment(s)
5.3.3
Pharmacogenomic evaluation
Not applicable
5.4
APPROPRIATENESS OF MEASUREMENTS
The US NCI CTCAE criteria 
version 3.0 (R04-0474) are used in the assessment of adverse events in cancer patients.


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5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.5.1
Pharmacokinetic endpoint(s)
Pharmacokinetics will be a primary endpoint for the dose escalation part and a secondary 
endpoint for the biomarker specific MTD expansion cohorts/Phase II part. Extensive plasma 
PK sampling is therefore crucial in this trial. Whenever possible, a full plasma PK profile will 
be taken after first dose and at steady state (e.g. after 8 days of treatment with afatinib). An 
additional trough sample will be taken on day 15 to confirm steady state exposure to afatinib. 
In exceptional cases and only if paediatric patients are by no means able to undergo extensive 
plasma PK sampling a limited sampling approach should be applied.
In addition, in patients carrying a Rickham- or Ommaya reservoir, or undergoing lumbar 
puncture for clinical reasons not related to the trial, trough CSF sampling may be performed 
on day 8 or later to investigate CNS exposure to afatinib. This procedure is optional. The 
trough CSF PK sample must be accompanied by a trough plasma PK sample taken at the 
same time-point.
In any case, it must be attempted to keep all patients on their starting formulation for the first 
treatment course. This will be crucial for the MTD determination and PK assessment during 
first course.
In case patients’ switch from tablet to liquid formulation or vice versa becomes necessary 
during treatment or if for any other reason (e.g. AE) plasma PK sampling cannot be 
performed as planned, plasma PK profiles may be obtained within treatment course 1 as 
deemed appropriate by the investigator and after consultation with the sponsor.
All details with respect to sampling procedures and time points are described in Section 5.5.2
and tabulated in Appendix 10.3.
Pharmacokinetics (PK) will be evaluated as follows:

Non-compartmental analysis: PK parameters will include AUC, Cmax, tmax and 
accumulation (or effective) half-life will be performed for all patients with extensive 
PK sampling

Model-based analysis will be performed for all patients with sparse as well as 
extensive PK sampling
For further details regarding the PK analysis, please refer to Section 7.3.5.


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5.5.2
Methods of sample collection
For quantification of afatinib plasma concentrations, 1 mL of venous blood will be taken in a 
K-EDTA (potassium ethylendiamine tetraacetic acid)-anticoagulant blood drawing tube at the 
blood sampling times indicated in Appendix 10.3.
Determination of afatinib CSF concentrations will be performed from optional 1 mL samples 
taken via puncture of a Rickham- or Ommaya reservoir, or lumbar puncture conducted for 
clinical reasons not related to the trial, at the time-points specified in Appendix 10.3. The 
type of the respective reservoir or lumbar puncture will be recorded in the eCRF.
Blood will be processed to plasma and all samples (plasma and CSF) further handled as 
described in the laboratory manual. This document gives all details about sample collection, 
preparation, storage and shipment.
All PK samples will be uniquely labelled with study number, subject number, visit number, 
and protocol (planned) time according to the time schedule in Appendix 10.3. Would a 
patient discontinue treatment at the time of a PK sampling, the sample(s) taken at this visit 
may need to be renamed for the EOT visit.
Pharmacokinetic samples will only be used for the analyses as described in the Clinical Trial 
Protocol. The plasma and CSF samples will be discarded at the latest when the CTR has been 
signed.
Correct sample handling as well as correct and complete documentation of drug 
administration and blood/CSF sampling is mandatory to obtain data of adequate quality for 
the pharmacokinetic analysis.
Date and time of pharmacokinetic sampling should be recorded on the eCRF. In addition, the 
dose, date and time of afatinib administration and time of food intake before and after 
medication for the four (4) days prior to pharmacokinetic sampling should be recorded in the 
eCRF.
5.5.3
Analytical determinations
Plasma and CSF concentrations of afatinib will be determined by validated HPLC-MS/MS 
assays (high performance liquid chromatography, tandem mass spectrometry) at an 
appropriate bioanalytical laboratory e.g.
 
. If necessary individual patient plasma samples may be analyzed on an „ad hoc” 
basis.
5.6


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5.6.1
Endpoints based on biomarker(s)
The objective response level obtained from the biomarker selected MTD expansion 
cohorts/Phase II part must be considered meaningful by experts in the field of paediatric 
oncology. For further details refer to Section 7.6.
5.6.2
Methods of sample collection
Sample analyses and logistics will be performed by 
 a 
certified central laboratory, after validation of assay procedures. 
Tissue sample from archived tumour blocks is preferred. Alternatively, a minimum of 15 up 
to 20 slides of 4 µm thickness should be provided. Further details are provided in the ISF.
Data transfer agreements, data storage and analysis will be handled by BI. 
5.6.3
Analytical determinations
Refer to section 5.6.1
5.7
PHARMACODYNAMICS
Not applicable
5.7.1
Pharmacodynamic endpoints
Not applicable
5.7.2 
Methods of sample collection
Not applicable
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
Correlation between drug concentration and response may be made if appropriate data are 
available. In addition, exploratory correlation will also be made between drug concentration 
and AEs. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
After the screening visit, patients will have to come to the investigational site on the days 
provided in the Flow Chart. More visits can be performed if deemed necessary by patient, 
caregivers and/or investigator. As soon as the treatment with afatinib will be permanently 
discontinued, the patient has to undergo the end of treatment visit (i.e within 7 days of last 
afatinib administration). A last visit will be performed at the end of the residual period (i.e. 
28-30 days after the last afatinib administration) for safety follow-up. This last safety follow-
up visit will represent the end of trial visit for the patient. Thereafter, regular contacts (every 
12 weeks) after the end of trial visit will be done either via phone/correspondence to collect 
information whether the patient is still alive.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
The screening period may be as long as 28 days between signing informed consent and first 
administration of the trial drug. The screening period may be longer in case of administrative 
issues and/or if the patient would have to recover from an intercurrent disease. 
During the screening period, the following actions will be performed:
Before screening period
Applies only to MTD expansion cohorts/Phase II part: Where requested, a pre-
screening informed consent may be used allowing only for collection and 
testing of tumour tissue for ErbB deregulation (see Section 4.1.2). If tested
positive for ErbB selection biomarkers, parents /legal guardian have to sign an 
informed consent –and patients have to assent in order to be entered into this 
trial and proceed with trial procedures (see below).
Informed consent
An informed consent has to be given by the parents /legal guardian and assent by 
the patient by using a suitable informed consent for the respective age group.
Demographics
Medical and oncological 
history
For details refer to Section 5.2.5
Vital signs and physical 
examination
Preferably be done by the same person throughout the trial for a respective 
patient if feasible
Ophthalmological
examination
To exclude keratitis
Pulmonary examination
To exclude ILD
Height and weight
Height in cm and weight in kg
Performance score
To be assessed using Lansky score for the patients aged ≤12 years and the 
Karnofsky score for the patients aged >12 years at time of informed consent
Planned hospital stay
Any stays in hospital that are planned to be performed during the trial shall be 
reported
Check of inclusion and 
exclusion criteria
To assess eligibility of the patient
Pregnancy test
To be performed in post-menarchal female patients who are of childbearing 
potential and within 7 days prior to first treatment.
Cardiac assessment

LVEF echocardiography shall be performed and the results must be 


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documented in source data and eCRF

12 lead-ECG as detailed in Section 5.2.4
Blood sampling for safety 
lab 
Blood collection for assessment of the parameters as described in Section 5.2.3. 
In case the safety lab parameters as outlined in Section 5.2.3 have been collected 
within the past 7 days prior signing informed consent, the data may be reported 
in the eCRF and no new blood needs to be collected during screening
Assessment of the tumour 
disease
Depending on the tumour type, an assessment of the tumour disease has to be 
reported in the eCRF based on:
o
imaging findings 
o
tumour markers in blood or urine if indicated
o
bone marrow if indicated
Tumour assessment does not need to be repeated at the screening visit if there 
are valid results available from assessments which were performed as part of 
routine clinical practice within the allowed time window (within 28 days prior to 
start of treatment).
Tumour tissue
-Dose finding part: confirm tumour tissue availability for retrospective
biomarker testing or provide evidence of ErbB pathway deregulation
-MTD expansion cohort: provide tumour tissue for prospective biomarker testing 
of ErbB pathway deregulation – see Section 5.6
Concomitant therapies 
See Section 4.2.1
Adverse events
All AEs occurring since the signature of the informed consent - See Section 
5.2.2
Dose assessment
Confirmation of dose according to dose level and BSA
6.2.2
Treatment period(s)
COURSE 1
Visit 1 (day 1)
The very first intake of afatinib will take place on day 1 of course 1. Patients may stay in 
hospital for the day 2 assessments such as blood sampling for safety laboratory and 
pharmacokinetics if applicable and if considered necessary by the investigator. 
Before the first intake of afatinib, the following assessments shall be done:
Vital signs and physical 
examination
Preferably be done by the same person throughout the trial for a respective 
patient if feasible
Weight
Performance score
Lansky for patients ≤ 12 years or Karnofsky for patients older than 12 years at 
time of informed consent
Quality of life questionnaire
For MTD expansion cohorts/Phase II part only
Blood sampling for safety 
lab
Not to be older than 48 hours before the trial drug intake
Blood for the baseline 
pharmacokinetic
Pre-dose sample to be collected about 5 minutes before afatinib intake, see 
Appendix 10.3
Concomitant therapies 
Update if applicable
Adverse events
Update if applicable
Dispense trial drug
The allocated treatment kit(s) should be dispensed to the 
patient/parent(s)/caregiver for the first drug intake at site followed by the daily 
intake along this treatment course.


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After first drug intake:
Blood for pharmacokinetics 
post dose
To be collected on day 1 at 1, 2, 3, 4, 5, 6, 8 hours after afatinib intake as 
described in Section 5.5.2 and at the time points tabulated in Appendix 10.3. It is 
of utmost importance to report the exact clock time of the first trial drug intake 
and the actual sampling date and time for blood samples in the eCRF. In 
exceptional cases and only if patients are by no means able to undergo extensive 
PK sampling, a limited sampling approach should be applied with blood 
sampling before, 1h and 3 h after afatinib administration. For further details see 
Section 5.5.2 and Appendix 10.3.
Visit 1 (day 2)
Repeated procedures
Physical examination and vital signs; update on concomitant therapies and 
adverse events
Blood for pharmacokinetic
For extensive PK sampling, samples to be collected 24 hours after afatinib 
intake. Patients (or parents and/or legal guardian) should be instructed not to take 
the trial medication prior to the 24h blood sample. The trial medication must be 
taken after the last PK blood sample has been drawn
Drug intake
Intake of the trial drug should take place at the same time as previous day
Patient diary
Check for completion
Visit 2 (day 8)
Repeated procedures
Physical examination and vital signs; weight; blood sampling for safety lab
(limited); update on concomitant therapies and adverse events
Cardiac assessment
12 lead-ECG as detailed in Section 5.2.4
Blood for pharmacokinetics 
pre-dose at steady state
Pre-dose sample to be collected about  5 minutes before afatinib intake, see 
Appendix 10.3
Drug intake
blood for pharmacokinetic 
post dose at steady state
Extensive PK sampling: blood has to be collected at 1,2,3,4,5,6,8 and 24 hours 
after afatinib intake (refer to Appendix 10.3). Patients (or parents and/or legal 
guardian) should be instructed not to take the trial medication prior to the 24h 
blood sample (day 9). The trial medication must be taken after the last PK blood 
sample has been drawn. 
In exceptional cases and only if patients are by no means able to undergo 
extensive PK sampling, a limited sampling approach should be applied with 
blood sampling before, 1h and 3 h after afatinib administration. For further 
details see Section 5.5.2 and Appendix 10.3.
Patient diary
Check for completion
Compliance check
Check on trial drug compliance
Visit 3 (day 15)
Repeated procedures
Physical examination and vital signs; weight; blood sampling for limited safety 
lab; update on concomitant therapies and adverse events
Blood for pharmacokinetics 
pre-dose to confirm steady 
state
Pre-dose sample to be collected about  5 minutes before afatinib intake, see 
Appendix 10.3


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Patient diary
Check for completion
Visit 4 (day 22)
Repeated procedures
Physical examination and vital signs; weight; blood sampling for limited safety 
lab; update on concomitant therapies and adverse events
Patient diary
Check for completion
COURSE 2 
Visit 1 (day 1)
This visit should take place at day 29 from start of treatment and should serve for confirming 
patient’s eligibility for treatment continuation

Depending on the patient status, the investigator has to perform a disease assessment 
on patient’s eligibility for the next treatment course. This might include but is not 
limited to:
o
Imaging findings (requested only every 2 courses: course 3 visit1, C5V1, 
C7V1…)
o
Tumour markers in blood or urine if indicated
o
Bone marrow if indicated
In case treatment discontinuation is required at this visit, please complete the EOT visit 
instead of this visit.
For patients included in the dose escalation part, a DLTs evaluation should be provided 
before to start a new course of treatment.
C2V1 visit should include:
Patient acceptability 
Completion of acceptability questionnaires by patients, parents/caregiver and 
investigator/site staff
Special note: at any time, if the patient switches from his/her initial formulation 
to the other, the questionnaires should be completed again after 28 days of intake 
of the new formulation.
Quality of life questionnaire
For MTD expansion cohorts/Phase II part only
Repeated procedures
Physical examination and vital signs; weight; blood sampling for safety lab;
update on concomitant therapies and adverse events
Performance score
Lansky for patients ≤ 12 years or Karnofsky for patients older than 12 years at 
time of informed consent
Cardiac assessment
LVEF echocardiography shall be performed and the results must be documented 
in source data and eCRF for DLT evaluation
Patient diary
Check for completion
Compliance check
Check on trial drug compliance
Eligibility for treatment 
continuation
Confirm eligibility for further treatment
If the patient eligibility for further treatment is confirmed:
Dose assessment
Assess appropriateness of the afatinib dose 
Dispense trial drug
New afatinib kit(s) must be dispensed to the patient/parent(s)/legal guardian 


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(recalculate BSA for allocation of dose) for a daily drug intake along this 
treatment course
Visit 2 (day 15) 
Repeated procedures
Physical examination and vital signs; weight; blood sampling for limited safety 
lab; update on concomitant therapies and adverse events
Dose assessment
Assess appropriateness of the afatinib dose
COURSE 3 AND ONWARDS
Visit 1 (day 1)
Repeated procedures
Physical examination and vital signs; weight; height (every other course); blood 
sampling for safety lab; update on concomitant therapies and adverse events
Quality of life questionnaire
For MTD expansion cohorts/Phase II part only
Performance score
Lansky for patients ≤ 12 years or Karnofsky for patients older than 12 years at 
time of informed consent
Cardiac assessment (every 
3rd course)

LVEF echocardiography 

12 lead-ECG as detailed in Section 5.2.4
Patient diary
Check for completion
Compliance check
Check on trial drug compliance
Tumour assessment 
Imaging assessment every 8 weeks, tumour markers where indicated
Eligibility for treatment 
continuation
Confirm eligibility for further treatment
If the patient eligibility for further treatment is confirmed:
Height measurement
Every 2 courses
Dose assessment
Assess appropriateness of the afatinib dose 
Dispense trial drug
New afatinib kit(s) must be dispensed to the patient/parent(s)/legal guardian 
(recalculate BSA for allocation of dose) for a daily drug intake along this 
treatment course
6.2.3
End of treatment and follow-up period
End Of Treatment visit
This visit will take place as soon as a decision is made to permanently discontinue trial
treatment. 
The EOT visit will include the following actions:
Repeated procedures
Physical examination and vital signs; blood sampling for safety lab; update on 
concomitant therapies and adverse events


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Ophthalmological
examination
To exclude keratitis
Pulmonary examination
To exclude ILD
Pregnancy test
To be performed in post-menarchal female patients who are of childbearing 
potential
Performance score
Lansky for patients ≤ 12 years or Karnofsky for patients older than 12 years at 
time of informed consent
Cardiac assessment

LVEF echocardiography 

12 lead-ECG as detailed in Section 5.2.4
Assessment of the tumour 
disease
Depending on the tumour type, an assessment of the tumour disease has to be 
reported in the eCRF based on:
o
imaging findings 
o
tumour markers in blood or urine if indicated
o
clinical findings
o
bone marrow if indicated
Patient diary
Check for completion
Compliance check
Check on trial drug compliance
Conclusion of treatment
To confirm permanent treatment discontinuation
Follow-up visit for safety (28-30 days after last afatinib intake)
Safety update
Update on concomitant therapies and adverse events
Conclusion of patient 
participation
Confirmation of trial discontinuation for the patient
6.2.4
Observational period
The observational period is a post-trial period for data collection on vital status. The site will 
contact patients/parent(s)/legal guardian or patients’ health care providers to collect patients’ 
vital status every 12 weeks. Death information from public sources, e.g. death registry, 
obituary listing, etc. can also be used when it is available and verifiable.
The data should be documented in the patient’s chart.
Adverse events/serious AEs should still be reported in this period if they are considered 
relevant by the investigator.
The whole trial will end when the last patient has completed the 28-30 day FU visit.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a Phase I/II, open-label trial (including a Phase I dose finding and a Phase I MTD 
expansion cohorts/Phase II part) to explore the safety and possibly early signs of efficacy of 
afatinib in paediatric patients with neuroectodermal tumours, rhabdomyosarcoma and/or 
other solid tumours with known ErbB pathway deregulation regardless of tumour histology.

The dose finding part will use a rolling 6 design and recruit up to 30 patients who are 
evaluable for DLT to determine the MTD.
In the MTD expansion cohorts/Phase II part, a minimum of 5 patients in each of the 
following cohorts, i.e. HGG, DIPG, EM and a mixed histology agnostic cohort of 
patients with refractory tumours, will be accrued. All patients must fulfil two of the 
biomarker screening criteria, i.e. EGFR FISH positive and/or EGFR H-score >150 
and/or HER2-DDISH positive and/or HER2 H-score > (see Section 3.3.2). An 
exploratory cohort will recruit patients with proven genomic, transcriptomic or 
proteomic alterations which are not defined above. All patients must be evaluable for 
OR/efficacy. Further safety data will be collected.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No formal hypothesis testing is planned in this trial. All analyses will be descriptive and 
exploratory in nature.  
7.3
PLANNED ANALYSES
All patients who receive at least one dose of afatinib will be included in the analysis for 
safety and efficacy and they are defined as treated set. 
7.3.1
Primary analyses
Dose finding part: 
In order to determine the MTD, the number of patients with DLT deemed to be related to 
administration of afatinib will be assessed based upon the patients in dose finding part of the 
trial. (See Table 4.1.4.1:2). The advanced disease of the patients in this trial makes it possible 
that significant adverse events, including events that would qualify as DLT, will occur, but 
will not be caused by afatinib.  The MTD will be determined as the highest dose at which no 
more than 1/6 patients experienced DLT considered related to afatinib. (See Table 4.1.4.1:1)


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Pharmacokinetics is a primary endpoint for the dose finding part. For details see Section 7.3.5
MTD expansion cohorts/Phase II part: 
OR will be assessed when the last patient enrolled in the MTD expansion cohorts/Phase II
part will be evaluable for efficacy. 
Each patient will be assigned to one of the following categories based on investigator’s 
assessment according to the institutional response evaluation criteria for the given tumour 
type, irrespective of protocol violation or missing data:

CR (complete response)

PR (partial response)

SD (stable disease)

PD (progressive disease)

Not evaluable (not assessable, insufficient data)
Objective response is defined as CR and PR. 
If the International Criteria for Neuroblastoma Response Criteria (INRC) (R14-2418) is used, 
each patient will be assigned to one of the following categories:

CR (complete response)

VGPR (very good partial response)

PR (partial response)

MxR (mixed response)

NoR (no response)

PD (progressive disease)
The objective response is then defined as CR, VGPR, PR or MxR. 
OR will be tabulated and provided with the proportion and the exact 95% confidence interval
based on all treated patients in the MTD expansion cohorts/Phase II part. 
7.3.2
Secondary analyses
In dose finding part, number of patients with OR will be described per dose level.


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In the MTD expansion cohorts/Phase II part, the PFS and DoR will be secondary endpoints. 
PFS is defined as the time from the date of first administration of treatment to the date of 
disease progression, or to the date of death, whichever comes first.  The Kaplan-Meier 
estimates of PFS rate and 95% confidence intervals will be calculated at the time of each 
planned assessment. DoR is defined only for those patients with a response (CR or PR) as the 
interval between the date of randomization and the earliest date of disease progression. The 
Kaplan-Meier estimates of DoR and 95% confidence intervals will be calculated at the time 
of each planned assessment.
Pharmacokinetics is a secondary endpoint for the MTD expansion cohorts/Phase II part. For 
details see Section 7.3.5.
7.3.3
Safety analyses
DLTs will be tabulated for each dose cohort in the Phase I dose finding part. The tabulation 
will be done in two ways: (1) DLTs with onset in the first treatment course; (2) all DLTs 
regardless of treatment course at onset. The definition of DLT is defined in Table 4.1.4.1:2. 
Events that started within the course of treatment, starting after the first administration of the 
treatment and until 28 days after the last administration of treatment will be considered as 
having occurred on treatment. In general later events will be attributed to the post-study 
period and will be presented separately. However post-study events will be examined to 
determine whether they need to be combined with on-treatment events in an additional table. 
Adverse events will be graded according to CTCAE v3.0 and reported according to BI 
standards. Serious adverse events will be tabulated. In addition, events leading to dose 
reduction or treatment discontinuation will be examined, but may not be reported as 
individual tables, depending upon the extent of overlap. 
Descriptive statistics will be used to describe changes in laboratory parameters over time. In 
additional, all abnormalities of potential clinical significance will be reported. In general, 
potential clinical significance is defined as at least CTCAE Grade 2 and an increase in 


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CTCAE classification from baseline. The incidence and intensity of adverse events will be 
correlated descriptively with pharmacokinetic data if possible.
7.3.4
Interim analyses
No formal interim analysis is planned.
Results of the dose finding part and PK may need to be summarized and documented.
7.3.5
Pharmacokinetic analyses
Extensive plasma sampling:
Pharmacokinetic profiles of afatinib will be taken on Day 1 (after single dose) and Day 8 (at 
steady state) of Course1. An additional trough sample will be taken on day 15 to confirm 
steady state exposure to afatinib. If data allow, the following pharmacokinetic parameters will 
be evaluated:

area under the plasma concentration-time curve
-
over the dosing interval (24 h) and after uniform intervals , following the first dose 
and at steady state (AUC0-24 and AUCτ,ss)
-
over the time interval from zero to the time of the last quantifiable drug concentration 
(AUC0-tz and AUC0-tz,ss) within the dosing interval 

maximum measured plasma concentration following the first dose and at steady state 
after uniform intervals (Cmax and Cmax,ss) 

time from dosing to the maximum plasma concentration following the first dose and at
steady state after uniform intervals (tmax and tmax,ss)

accumulation ratio (RA,Cmax and RA,AUC)

accumulation (or effective) half-life
Other parameters may be calculated as deemed appropriate.
The derivation of the PK parameters will be performed in line with BI internal procedures 
(MCS-36-472, current version). The accumulation (or effective) half-life can be calculated 
according to the formula t1/2=τ·ln2 / ln(RA,AUC/(RA,AUC -1) (P09-09363).
The following descriptive statistics will be calculated for all PK parameters: N, arithmetic 
mean, standard deviation, minimum, median, maximum, arithmetic coefficient of variation, 
geometric mean, and geometric coefficient of variation. The descriptive statistics of PK 
parameters will be calculated using the individual values with the number of decimal places 
as provided by the evaluation program. Then the individual values as well as the descriptive 
statistics will be reported with three significant digits in the clinical trial report.


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Sparse plasma sampling:
In the clinical trial report, afatinib plasma concentrations from patients who were not able to 
undergo extensive sampling, and for whom sparse sampling was performed, will be 
summarised by time point by descriptive statistics and, if feasible, graphically inspected. 
Model based analysis
A model-based analysis over all available PK data (extensive and sparse sampling) will be 
performed.
Structure of the available population PK model
Based on existing afatinib PK models in adult patients having various solid tumours (studies 
1200.1; .2; .3; .4 and 20 (U12-1393) and 1200.28; .32 and .33 (U12-1394)), a model will be 
developed based on 1200.120 data in paediatric population.
Model development
A non-linear mixed effect modelling approach will be taken to conduct the analysis. The 
parameters of the model are defined by fixed effects, so called θs and potential random 
effects (Inter (η) or intra-individual variabilities (κ)). These random effects are normally 
distributed around zero with a variance ω2. The combination of the fixed effects and random 
effects allow the estimation of individual parameters (Pi) as described in the following 
example equation:
Pi = θ * exp(ηi)
In addition, a residual variability, ε, adjusts the prediction of the model to the observed 
measurement. This residual variability is normally distributed with a variance σ2 and can be 
described according to the following equation:
Yi,j = IPREDi,j + εi,j
where Yi,j is the jth observation for ith individual, IPREDi,j is the individual prediction of the 
model for the jth observation of the ith individual, εj,i s the residual variability for the jth
observation of the ith individual. In the current situation Y is the plasma concentration of 
afatinib. If possible First Order Conditional Estimation with Interaction (FOCE / INT) will be 
used for the complete model development. The data from all dose groups of this study will be 
used for model development. 
Effect on Body weight on clearance and on volume of distribution will be evaluated, and the 
respective parameters (CL, V) will be scaled based on body weight.
Handling of missing data: Samples marked as no sample available (NOS) or non-valid result 
(NOR) will not be included in the dataset. Handling of missing PK data will be performed 
according to BI standards as stated in Section 7.4 (MCS-36-472, current version).


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The objective function value as well as the following criteria will be used to evaluate a 
model:

A “successful minimization” statement by the NONMEM program at the end of the 
estimation step.

The final parameter estimates have a number of significant digits ≥3.

Estimates of θ’s not close to a boundary.

Correlation of the uncertainty of the estimates of fixed effect parameters < 0.95 and > 
-0.95

No significant trends in the basic goodness-of-fit plots (predictions (PRED), 
individual predictions (IPRED) vs. dependent variable (DV))

Residuals (weighted and un-weighted) scatter randomly and uniformly around zero 
when plotted against PRED, IPRED and TIME.

Symmetric distributions of individual ηs.
Results
The following outcomes of the modeling based analysis will be reported:

Structure and parameter estimates of the final PK model including the potential 
covariate submodel.

Steady state concentrations for appropriate age range will be simulated. Cmax,ss and 
AUCτ,ss as well as apparent clearance (CL/F) and volume of distribution (Vd/F) will 
be calculated from these predictions.
Further details will be described in the TSAP.
PK data (plasma and CSF) may additionally be used to evaluate the penetration of afatinib 
into the brain, applying non-compartmental methods and pharmacokinetic modelling 
techniques as appropriate.
7.3.6
Pharmacodynamic analyses
No formal pharmacodynamics analysis is planned. 
7.3.7
Pharmacogenomic analyses
No pharmacogenomic analyses are planned.
7.3.8
Biomarker Analyses
The prevalence of biomarkers will be determined during the biomarker prevalence study
taking place outside of the clinical trial but being informative for the latter.
7.4
HANDLING OF MISSING DATA
In general, missing data will not be imputed. 


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-
Missing or incomplete AE onset and end dates are imputed according to BI standards 
(001-MCG-156_RD-01) 
-
For pharmacokinetics:
Handling of missing PK data will be performed according to BI standards (MCS-36-
472, current version). For the non-compartmental analysis, concentration data identified 
with NOS, NOR or NOA will generally not be considered. Concentration values in the 
lag phase identified as BLQ or NOP will be set to zero. All other BLQ/NOP values of 
the profile will be ignored. The lag phase is defined as the period between time zero and 
the first time point with a concentration above the quantification limit.
7.5
RANDOMISATION
No randomisation will be performed. 
7.6
DETERMINATION OF SAMPLE SIZE
In order to complete the dose finding part, which uses a rolling 6 design (see Table 4.1.4.1:1 ) 
an estimated 24 evaluable patients will be needed given the number of dose levels to be tested 
in this trial. To further account for early drop-out of patients or patients not evaluable for 
DLT during the first course of treatment, an estimated 30 patients were planned to be 
recruited to achieve this. 17 patients were needed to determine the MTD (c09990672-01).
Once the MTD is determined, a minimum of 5 patients in each of the four following cohorts, 
i.e. HGG, DIPG, EM and a mixed histology agnostic cohort of patients with refractory 
tumours, (see Section 3.3.2) will be accrued into an MTD expansion cohorts/Phase II part
(Table 7.6:1) to confirm a safe recommended Phase II dose (RPIID) and to be assessed for 
response. An exploratory cohort of patients with proven genomic, transcriptomic or 
proteomic alterations which are not defined in Tables 5.6:1-5.6:4 will also be included.
Table 7.6:1 shows the probability of observing more than one responder given the total 
number of patients assuming the true response rate being 20% and 30% respectively. 
Table 7.6:1
Probability of observing more than one responder for different 
response rates
Sample size per cohort
P(no response)*
P(1 or more response)**
P(2 or more response)***
ORR = 20%
5
32.8%
67.2%
26.2%
ORR = 30%
5
16.8%
83.2%
47.1%
ORR = 20%
6
26.2%
73.8%
34.4%
ORR = 30%
6
11.8%
88.3%
60%
ORR = 20%
10
10.7%
89.2%
62.4%
ORR = 30%
10
2.8%
97.2%
85.1%
*P(no response) = Chances of observing no response given the assumed response rate
**P(1 or more response) = Chances of observing one or more than one response given the assumed response 
rate
***P(2 or more response) = Chances of observing two or more than one response given the assumed response 
rate


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Table 7.6:2 summarizes for different prevalences the adjusted number of patients needed to 
be screened to ensure for a certain number N of biomarker positive patients with a probability 
of 90%.
Table 7.6:2
Number of patients to be screened to have with 90% probability at 
least N biomarker positive patients
Number N of
biomarker
positive patients
Prevalence of biomarker positive patients (%)
5
10
15
20
25
30
35
40
20
529
263
174
130
103
85
72
63
30
754
375
249
185
147
122
104
90
40
975
485
322
240
191
158
135
117
50
1193
594
394
294
234
194
166
144
60
1410
702
466
348
277
230
196
171
70
1626
810
538
402
320
266
227
198
80
1840
917
609
455
363
301
257
224
90
2054
1023
680
508
405
336
287
250
100
2266
1130
751
561
447
372
317
277
200
4370
2180
1450
1085
866
720
615
537
Considering that up to 55 patients will be included into this trial and of these up to 38 will be 
selected by biomarkers as described earlier (See Section 5.6) into the MTD expansion/Phase 
II part and assuming a biomarker prevalence of 10-15%, between 322 - 485 patients will need 
to be screened for that biomarker.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The protocol has been written in compliance with the recommendations given by the ICH E
11 Guidance for Industry (Clinical Investigation of Medicinal Products in the Paediatric 
Population, R10-4556) and Ethical considerations for clinical trials on medicinal products 
conducted with the paediatric population (R10-4959).
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF (Investigator Site File).
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from 
patient's parent(s) (both or one based on national regulation) or the legal guardian, as well as 
an informed assent of the minor patient according to ICH GCP and to the regulatory and legal 
requirements of the participating country. Each signature must be personally dated by each 
signatory and the informed consent and any additional patient-information form retained by 
the investigator as part of the trial records. A signed copy of the informed consent and any 
additional patient information must be given to each patient or the patient’s legally accepted 
representative.
If only mother or father (or one legal guardian) has sole legal custody, this needs to be 
confirmed with signature and date on the informed consent by the person with legal custody.
For the process of informed assenting, a separate patient information suitable for the
respective age group will be provided to the patients. In the younger age group, children may
not be capable of reading a text alone; in this case the parent(s) or legal guardian and/or site
personnel need to read out the document.
Both documents (consent and assent) outline the participant’s rights to decline to participate
or to withdraw from the study at any time. Consenting/assenting is a dynamic and continuous 
process that should be maintained during the trial. At each new treatment course the site staff


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should briefly discuss with parents and patients the main aspects of the trial, focusing in
particular on any new information that might affect their willingness to continue the
participation in the trial. The site staff is recommended to document this process in the
medical records. 
The patient (where appropriate) and the patient’s parent(s) or legal guardian must be 
informed that his/her personal trial-related data will be used by Boehringer Ingelheim in 
accordance with the local data protection law. The level of disclosure must also be explained 
to the patient and his/her parent(s) or legal guardian.
The patient (where appropriate) and the patient’s parent(s) or legal guardian must be 
informed that his / her medical records may be examined by authorised monitors 
(CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer Ingelheim, by 
appropriate IRB / IEC members, and by inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
The trial will be conducted according to the principles of GCP and the company's SOPs.
Sites and investigators are selected for participation in this trial basing on the fact that they 
have experience in treating patients in the trial indication and/or being member of the 
respective network group. An investigators' meeting including training sessions and a clinical 
monitor/CRA meeting will be organised prior to the initiation of the trial to ensure 
standardization of procedures and techniques across multiple sites and countries. In case an 
investigator meeting would not be feasible each investigator and his/her staff will be trained 
during the initiation visit at the latest. Training will be provided to all investigators, 
coordinators and CRAs to ensure consistency and accuracy of the entered data. Each site will 
receive an ISF including all information needed to conduct the trial.
Periodic on Site Visits will be performed by the CRAs to ensure trial conduct according to 
the protocol and documents referred to above. Details for on-site monitoring and the extent of 
source data verification are described in the trial monitoring manual and respective BI SOPs.
An external DMC will be tasked to assess the safety and quality of the data during the trial. 
The DMC will also recommend the dose escalation and/or de-escalation steps. The tasks of 
the DMC are described in detail in the DMC charter which is filed in the sponsor's CTMF.
Adverse events and diagnoses will be coded using the MedDRA coding system. Concomitant
therapies will be coded using the WHO drug dictionary.
The data management procedures to ensure the quality of the data are described in detail in
the trial data management and analysis plan (TDMAP) available in the CTMF.
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.


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8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via remote 
data capture. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs all data must be derived from source documents:

Patient identification (gender, date of birth)

Patient participation in the trial (substance, trial number, patient number, date patient 
was informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if 
available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results (in validated electronic format, if available)

Imaging results if performed

Bone marrow assessment if performed

ECG recording

LVEF results

Conclusion of Patient’s Participation in the trial
8.3.2
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all eCRFs, and written informed 
consents. The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.


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8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not.
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For afatinib this is the current version of the Investigator’s Brochure (c01802941). The 
current version of this reference document is to be provided in the ISF. No AEs are classified 
as listed for the study design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.6
COMPLETION OF TRIAL
The whole trial will end when the last patient has completed the 28-30 day FU visit.
For EU member states:
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last patient out) or early termination of the trial. 


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R04-0474
Common terminology criteria for adverse events Version 3.0 (CTCAE) 
(Publish Date: 12 December 2003).
R09-1400
European Medicines Agency (EMEA). MCH topic M3 (R2): Non-
Clinical Safety Studies for the Conduct of Human Clinical Trials and 
Marketing Authorization for Pharmaceuticals – step4: Note for 
guidance on non-clinical safety studies for conduct of human clinical 
trials and marketing authorization for pharmaceuticals (June 
2009,!"#"$%!&$'()$*+, -- .//0$111234352367805236 9'::*,
R09-2583
Regulation (EC) no. 1901/2006 of the European Parliament and of the 
Council of 12 December 2006 on medicinal products for paediatric use 
and amending regulation (EEC) no. 1768/92, directive 2001/20/EC, 
directive 2001/83/EC and regulation (EC) no. 726/2004 (text with EEA 
relevance). Off J Eur Union 2006;49(L378):1-19.
R10-4556
European Medicines Agency (EMEA). ICH topic E 11: clinical 
investigation of medicinal products in the paediatric population: step 5: 
note for guidance on clinical investigation of medicinal products in the 
paediatric population (January 2001, CPMP/ICH/2711/99). 
www.emea.eu.int 2006.
R10-4917
Geoerger B, Hargrave D, Thomas F, Andreiuolo F, Varlet P, Frappaz 
D, Doz F, Riccardi R, Jaspan T, Vassal G, European Innovative 
Therapies for Children with Cancer (ITCC) Consortium. 
Pharmacokinetic and biological study of erlotinib in children as 
monotherapy for refractory brain tumors or with radiation for newly 
diagnosed brain stem gliomas. 45th Ann Mtg of the American Society 
of Clinical Oncology (ASCO), Orlando, 29 May - 2 Jun 2009; 2009. p. 
524S.
R10-4920
Jakacki RI, Hamilton M, Gilbertson RJ, Blaney SM, Tersak J, Krailo 
MD, Ingle AM, Voss SD, Dancey JE, Adamson PC. Paediatric Phase I 
and pharmacokinetic study of erlotinib followed by the combination of 
erlotinib and temozolomide: a Children's Oncology Group Phase I 
consortium study. 42nd Ann Mtg of the American Society of Clinical 
Oncology (ASCO), Atlanta, 2 - 6 Jun 2006. J Clin Oncol 2008;26(30): 
4921-4927.
R10-4921
National Cancer Institute. Phase I study of erlotinib and temozolomide 
in children with recurrent or refractory solid tumors (last modified: 
9/22/2008, first published: 1/23/2004) (registered in ClinicalTrials.gov: 
NCT00077454). www.cancer.gov; 2008.


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R10-4924 
Broniscer A, Baker SJ, Stewart CF, Merchant TE, Laningham FH, 
Schaiquevich P, Kocak M, Morris EB, Endersby R, Ellison DW, Gajjar 
A. Phase I and pharmacokinetic studies of erlotinib administered 
concurrently with radiotherapy for children, adolescents, and young 
adults with high-grade glioma. Clin Cancer Res 2009;15(2):701-707.
R10-4926
Daw NC, Furman WL, Stewart CF, Iacono LC, Krailo M, Bernstein 
ML, Dancey JE, Speights RA, Blaney SM, Croop JM, Reaman GH, 
Adamson PC. Phase I and pharmacokinetic study of gefitinib in 
children with refractory solid tumors: a Children's Oncology Group 
study. J Clin Oncol 2005; 23(25):6172-6180.
R10-4959
European Commission. Ethical considerations for clinical trials on 
medicinal products conducted with the paediatric population: 
recommendations of the ad hoc group for the development of 
implementing guidelines for Directive 2001/20/EC relating to good 
clinical practice in the conduct of clinical trials on medicinal products 
for human use (final 2008). 
http://ec.europa.eu/health/files/eudralex/vol-
10/ethical_considerations_en.pdf (access date 19.08.2010) 2008.
R10-4960
Geyer JR, Boyett J, Douglas J, Phillips P, Young-Poussaint T, Packer 
R, Friedman H, Prados M, Kieran M, Blaney S, Pollack I, Kun L. 
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newly diagnosed with brain stem tumors or incompletely resected 
supratentorial malignant gliomas. 46th Ann Mtg of the American 
Society for Therapeutic Radiology and Oncology (ASTRO), Atlanta, 3 
- 7 Oct 2004. Int J Radiat Oncol Biol Phys 2004;60(1):S251.
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Potthoff K, Hoffheinz R, Hassel JC, Volkenandt M, Lordick F, 
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2011;22(3):524-535.
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Schaiquevich P, Panetta JC, Throm S, Daw NC, Geyer JR, Furman 
WL, Stewart CF. Population pharmacokinetic (PK) analysis of gefitinib 
in pediatric cancer patients. 44th Ann Mtg of the American Society of 
Clinical Oncology (ASCO), Chicago, 30 May - 3 Jun 2008. J Clin 
Oncol 2008;26(15S)(Suppl).
R11-4988
Widemann BC, Fox E, Adamson PC, Baruchel S, Kim A, Ingle AM, 
Bender JG, Stempak D, Balis FM, Blaney SM. Phase I study of 
sorafenib in children with refractory solid tumors: a Children's 
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American Society of Clinical Oncology (ASCO), Orlando, 29 May - 2 
Jun 2009. J Clin Oncol 2009;27(15S)(Suppl).


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R11-4989
Fouladi M, Stewart CF, Blaney SM, Onar-Thomas A, Schaiquevich P, 
Packer RJ, Gajjar A, Kun LE, Boyett JM, Gilbertson RJ. Phase I trial 
of lapatinib in children with refractory CNS malignancies: a Pediatric 
Brain Tumor Consortium study. J Clin Oncol 2010;28(27):4221 -4227.
R11-5021
Lapatinib in treating young patients with recurrent or refractory CNS 
tumors (this study has been completed) (sponsor: Pediatric Brain 
Tumor Consortium, collaborator: National Cancer Institute (NCI), 
information provided by: Pediatric Brain Tumor Consortium, Clinical 
Trials. gov identifier: NCT00095940) (last updated on November 9, 
2010). 2011.
R11-5022
Geoerger B, Hargrave D, Thomas F, Ndiaye A, Frappaz D, Andreiuolo 
F, Varlet P, Aerts I, Riccardi R, Jaspan T, Chatelut E, Deley MC le, 
Paoletti X, Saint-Rose C, Leblond P, Morland B, Gentet JC, Meresse 
V, Vassal G, ITTC (Innovative Therapies for Children with Cancer) 
European Consortium. Innovative therapies for children with cancer 
pediatric phase I study of erlotinib in brainstem glioma and 
relapsing/refractory brain tumors. Neuro-oncology 2011;13(1):109-
118.
R11-5046
Pollack IF, Stewart CF, Kocak M, Poussaint TY, Broniscer A, Banerjee 
A, Douglas JG, Kun LE, Boyett JM, Geyer JR. A phase II study of 
gefitinib and irradiation in children with newly diagnosed brainstem 
gliomas: a report from the Pediatric Brain Tumor Consortium. Neuro-
oncology 2011;13(3):290-297.
R12-1159
Perilongo G, Massimino M, Sotti G, Belfontali T, Masiero L, 
Rigobello L, Garre L, Carli M, Lombardi F, Solero C, Sainati L, 
Canale V, Brach del Prever A, Giangaspero F, Andreussi L, Mazza C, 
Madon E, Italian Pediatric Neuro-Oncology Group (IPNG). Analyses 
of prognostic factors in a retrospective review of 92 children with 
ependymoma: Italian Pediatric Neuro-Oncology Group. 26th Ann Conf 
of the International Society of Pediatric Oncology (SIOP), Paris, 20 -
24 Sep1994 Med Pediatr Oncol 1997;29:79-85.
R12-1172
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Proposal_r acecadotril.pdf (access date: 28 May 2014) 2007.


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P96-1356
Smith TL, Lee JJ, Kantarjian HM, Legha SS, Raber MN. Design and 
results of phase I cancer clinical trials: three-year experience at 
M.D.Anderson Cancer Center. J Clin Oncol 1996;14(1):287-295.
9.2
UNPUBLISHED REFERENCES
c01802941
Investigator’s Brochure. Afatinib. Oral treatment of cancer. Current 
version 
U09-2233
 Relative bioavailability 
of a single dose of 20 mg BIBW 2992 administered as tablet (final 
formulation) compared to BIBW 2992 drinking solution and BIBW 
2992 tablet (trial formulation II) following oral administration to 
healthy male volunteers (an open-label, randomized, single-dose, three-
way crossover phase I study).1200.35. 22 October 2009.
U12-1393
Clinical Report Population Pharmacokinetic Analysis: 
Characterisation of the nonlinear pharmacokinetic behaviour of afatinib 
in a combined study of Phase I trials in patients with advanced solid 
tumors. Version 1, 11-Jul-2012.
U12-1394
 Clinical Report Population Pharmacokinetic 
Analysis: Combined population pharmacokinetic analysis of afatinib 
monotherapy in patients suffering from various cancer types. Version 
1, 06-Jul-2012.
U13-2281-01
 Scientific Advice Afatinib (BIBW 2992). 27-Jun-2013.
c09990672-01
. Synoptic interim report: 
Phase I open label, dose escalation trial to determine the MTD, safety, 
pharmacokinetics and efficacy of afatinib monotherapy in children 
aged 2 years to <18 years with recurrent/refractory neuroectodermal 
tumours, rhabdomyosarcoma and/or other solid tumours with known 
ErbB pathway deregulation regardless of tumour histology. 21-Jun-
2016
ra00592318
Type B pre-IND 118981 FDA meeting minutes – November 27, 2013
ra00865826
Written Request referring to the "7808;3< "3<=5/7=> 
?/6<@ A3B63;/
submitted to CDE ':F'*' 
G87 5G5/=H=I 
- December 6, 2016


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10.
APPENDICES


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10.2
CLINICAL EVALUATION OF LIVER INJURY
10.2.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (Protocol-Specified 
AESIs, are to be further evaluated using the following procedures: 
10.2.2
Procedures
Any elevation of ALT/AST and bilirubin qualifying as laboratory alert should be confirmed 
using the initial sample if possible.
If the alert is confirmed on initial sample, or it is not possible to repeat testing using initial 
sample, the following must be completed:
1) Evaluate the patient within 48 hours and, 
2) Perform the following laboratory tests:
3) Repeat  of AST, ALT, bilirubin (with fractionation to total and direct) 
1. Haptoglobin
2. Complete blood count and cell morphology
3. Reticulocyte count
4. CK
5. LDH
6. Alkaline Phosphatase
The results of these laboratory tests must be reported to BI as soon as possible.
Use clinical judgement when performing all of the required examinations. Use a staggered 
approach based on clinical judgement to complete all examinations. If needed, a hepatologist 
should be consulted for advice. To be considered when proceeding: the patient’s disease, 
clinical situation, exposure, suspected co-medications, past viral infections, vaccination 
status, social circumstances of life. Sparse blood drawing should be used and diagnostic 
procedures should be refined accordingly.
If the initial alert values (i.e. AST,ALT, and bilirubin) are confirmed on the second sample 
described as above, then an abdominal ultrasound or clinically appropriate alternate imaging  
(to rule out biliary tract, pancreatic or intrahepatic pathology, e.g. bile duct stones or 
neoplasm) must be completed within 48 hours 
The findings from the hepatic imaging (including comparison to prior imaging if available) 
must be made available as soon as possible as part of the adverse event reporting process.  In 
the event the aetiology of the abnormal liver tests results is not identified based on the 
imaging (e.g. biliary tract, pancreatic or intrahepatic pathology), then the “DILI checklist” 
must be completed.  Details of the “DILI checklist” are provided in the ISF.  The following 
assessments need to be performed in order to complete the “DILI checklist” and results will 
be reported via the eCRF:


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o
obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “DILI checklist” provided in the ISF;
o
obtain history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets 
according to the “DILI checklist” provided in the ISF;
o
obtain a history of exposure to environmental chemical agents (consider home and work 
place exposure) according to the “DILI checklist” provided in the ISF;
o
complete the following laboratory tests as detailed in the DILI checklist provided in the 
ISF:

Clinical chemistry
alkaline phosphatase, cholinesterase (serum)*, albumin, PT or INR, CK, 
CK-MB, α-1 antitrypsin*, transferrin*, amylase, lipase, glucose, 
cholesterol, triglycerides

Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), 
Hepatitis C (Anti-HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-
IgM, Anti-IgG), Hepatitis E (Anti-HEV, Anti-HEV IgM, RNA if Anti-
HEV IgM positive), Epstein Barr Virus (VCA IgG, VCA IgM), 
cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, IgM)*, varicella 
(IgG, IgM)*, parvovirus (IgG, IgM)*
Consider virus reactivation due to patient’s immune-compromised clinical 
status; consider assessment of viral load by PCR testing instead of 
serology (especially in transfused patients)

Hormones, tumour-marker
Thyroid-stimulating hormone(TSH)*

Haematology
Thrombocytes, eosinophils

Diagnostics for auto-immune hepatitis, Morbus Wilson and 
haemochromatosis can be completed at the very end of all assessments. 
These examinations are not going to change within a short time period but 
rather proof of a long persisting chronic condition, i.e. Anti-Smooth 
Muscle antibody (titre), Anti-nuclear antibody (titre), Anti-LKM (liver-
kidney microsomes) Antibody, anti-mitochondrial antibody, 
coeruloplamin*
*If clinically indicated (e.g. immunocompromised patients)
-
Long term follow-up
Use clinical judgement when performing examinations for long term follow up and report 
these via the eCRF. Always use a staggered approach based on clinical judgement to 


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complete all examinations and consider consulting a hepatologist for advice. Sparse blood 
drawing should be used and diagnostic procedures should be refined accordingly.
o Initiate close observation of subjects by repeat testing of ALT, AST, and 
bilirubin (with fractionation to total and direct) at least weekly until the 
laboratory ALT and or AST abnormalities stabilize or return to normal, then 
according to the protocol. Depending on further laboratory changes, additional 
parameters identified e.g. by reflex testing will be followed up based on 
medical judgement and Good Clinical Practices (GCP).


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10.3
FLOW CHART (PK SAMPLING)
Visit
Time Point [hh:min]
Extensive samplinga
Sparse samplingb
CRF Time 
/PTMc
Event
CRF Time 
/PTMc
Event
1 (Day 1)
Five minutes before study 
drug administration
-0:05
PK Blood
-0:05
PK Blood
0:00
0:00
Drug admin.
0:00
Drug admin.
1:00
1:00
PK Blood
1:00
PK Blood
2:00
2:00
PK Blood
3:00
3:00
PK Blood
3:00
PK Blood
4:00
4:00
PK Blood
5:00
5:00
PK Blood
6:00
6:00
PK Blood
8:00
8:00
PK Blood
24.0
24.0
PK Blood
2 (Day 8)
or 
3 (Day 15)
or 
4 (Day 22)d
Five minutes before study 
drug administration
-0:05
PK Blood
-0:05
PK Blood
0:00
0:00
Drug admin.
0:00
Drug admin.
1:00
1:00
PK Blood
1:00
PK Blood
2:00
2:00
PK Blood
3:00
3:00
PK Blood
3:00
PK Blood
4:00
4:00
PK Blood
5:00
5:00
PK Blood
6:00
6:00
PK Blood
8:00
8:00
PK Blood
24.0
24.0
PK Blood
3 (Day 15)
or 
4 (Day 22)d
Five minutes before study 
drug administration
-0:05
PK Blood
-0:05
PK Blood
0:00
0:00
Drug admin.
0:00
Drug admin.
a
Whenever possible a full PK profile should be taken after first dose and at steady state. An additional trough 
sample will be taken on day 15 to confirm steady state exposure to afatinib.
b
For paediatric patients who are not able to undergo extensive PK sampling, a limited sampling approach should be 
applied
c
All samples should be taken as close as possible to the given time points
d
In case patients’ switch from tablet to liquid formulation or vice versa becomes necessary during treatment or if for 
any other reason (e.g. AE) PK sampling cannot be performed as planned, additional PK profiles may be obtained 
within treatment course 1 as deemed appropriate by the investigator and after consultation with the sponsor.
In addition, in patients carrying a Rickham- or Ommaya reservoir, or undergoing lumbar 
puncture for clinical reasons not related to the trial, trough CSF sampling may be performed 


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on day 8 or later to investigate CNS exposure to afatinib. This procedure is optional. The 
trough CSF PK sample always must to be accompanied by a trough plasma PK sample taken 
at the same time-point


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10.4
P-GLYCOPROTEIN INHIBITORS AND INDUCERS
Examples of P-gp modulators that can be considered as potent inhibitors and/or potent 
inducers of the P-gp (P-gp is also known as MDR1) are listed below in Table 10.4: 1.
Table 10.4: 1   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
As the information on potent inhibitors and inducers of P-gp may evolve, it is important for 
the investigator to assess such status on concomitant therapies. Of note, co-administration of 
P-gp modulators must be avoided during course 1 of Phase I dose finding.
In addition P-gp modulators should be avoided within 14 days or at least 5 half-lives of the 
drug (whichever is longer) prior to the first dose of afatinib. For use of strong P-gp inhibitors
after course 1 of the dose finding part and during the MTD expansion cohort, staggered 
dosing must be considered. For use of strong P-gp inducers after course 1 of the dose finding 
part and during the MTD expansion cohort, afatinib daily dose should be increased based on 
tolerability and discussion with the sponsor.
In case of questions the sponsor/sponsor representative should be contacted.


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10.5
TUMOUR DIAGNOSIS AND TREATMENT OF PAEDIATRIC TUMOURS 
The below table summarizes the different tumour types to be considered in the dose finding part of this trial
Table 10.5:1
Standard methods for diagnosis and treatment of paediatric tumours 
Tumour 
diagnosis
Standard methods for diagnosis
Standard treatment at diagnosis
1.
HGG
Clinical presentation: variable and nonspecific, depending on the location of the 
lesion. Frequently symptoms suggestive of increased intracranial pressure are observed 
e.g. headache, nausea, and vomiting, neurological symptoms: Ataxia, cranial nerve 
palsies, meningisms, changes in consciousness, visual and verbal disturbances, 
endocrine disorders, pareses, urine and stool incontinence, mood and personality 
changes, school difficulties, seizures, obstructive hydrocephalus with severe lethargy. 
Increased head circumference or bulging fontanel, failure to thrive can occur in infants. 
Imaging and other diagnostics measures include: Neurological exam, 
ophthalmological exam, cerebral MRI, cerebral CT with contrast to discover 
calcifications; histopathological diagnosis is made from tumour tissue, sometimes 
additional IHC exams like glial fibrillary acidic protein (GFAP), synaptophysin or 
neurofilament protein staining may be needed
In case of recurrent/refractory or metastatic disease cMRI with and without 
gadolinium and CSF puncture are indicated
multimodality therapy consisting of surgery, 
radiotherapy and chemotherapy; chemotherapy: 
vincristine and carboplatin combinations; 
lomustine, topotecan, temozolomide, iproplatin, 
actinomycin D, ifosfamide, cyclophosphomide 
2. DIPG
see HGG
no effective therapy; hyperfractionated 
radiotherapy, pre-irradiation chemotherapy, 
adjuvant chemotherapy (for standard 
chemotherapy agents used, please refer to HGG), 
high dose chemotherapy, concurrent chemo-
radiotherapy and radiosensitizers


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Table 10.5:1
Standard methods for diagnosis and treatment of paediatric tumours (cont’d)
3. Lower 
grade 
astrocyto
mas
see HGG
Resection; extent of resection strongly correlates 
with survival; chemotherapy at recurrence: 
carboplatin and vincristine, cisplatin, etoposide, 
lenalidomide, TMZ 
4. Neuro-
blastoma
Clinical symptoms largely depend on the location of the tumour. Nerve palsy, 
paralyses, renal symptoms and obstructions (tracheal and genitourinary) are frequently 
observed. Neurological symptoms include the Horner-syndrome, fever, and periorbital 
ecchymosis may be present.
Laboratory exams include urine and serum HVA/VMA assessment, NSE, LDH, 
ferritin, molecular markers (nmyc, chromosome 1p changes) are also included.
Bone marrow biopsies reveal typical Homer Wright rosettes and material can be used 
for RT-PCR
Imaging exams include but are not limited to Xray, CT, MRI and ultrasound; MIBG 
scans and scan using somatostatin receptor analogues;
chemotherapy combinations of alkylating agents, 
anthracyclines, topoisomerase inhibitors, 
platinum compounds and vinca alkaloids (i.e. 
combination therapies including agents like 
ifosfamide, cyclophosphamide, dacarbazin, 
melphalan, adriamycin, etoposide, topotecan, 
cisplatin, carboplatin, vincristine and vinblastin), 
radiotherapy, MIBG treatment, high dose 
chemotherapy with bone marrow rescue, 
immunotherapy with anti-GD2 antibodies
5. Ependymo
ma
see HGG
As most of the ependymomas (60%-70%) are located in the posterior fossa, typically, 
there is a relatively short (few weeks to few months) history of the symptoms described 
above. Supratentorial ependymomas can cause lobar syndromes, mood and personality 
changes with un-explained school difficulties, headaches, nausea and vomiting, and 
less commonly seizures. Due to the young age at diagnosis symptoms as described for 
infants above, occur more frequently. 
high frequency of chemotherapy and radiation 
resistance surgery with the at most curative 
intent, mostly chemotherapy combinations of 
cisplatin or carboplatin and vincristine, also 
and/or etoposide, cyclophosphamide 


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Table 10.5:1
Standard methods for diagnosis and treatment of paediatric tumours (cont’d)
6. Medullo-
blastomas 
and 
PNETs
see HGG
Many patients already demonstrate symptoms of systemic metastases at diagnosis and 
clinical may be dominated by symptoms of metastases (loss of function, pain); 
Histopathology Homer Wright rosettes or at least two of the below mentioned markers 
must be present: translocation t(11;22)(q24;q12) (1), t(21;22)(q22;q12) or 
t(7;22)(p22;q12); NSE, S100 synaptosin, chromogranin, vimentin, cytokeratin, actin 
und LCA stains are performed
Usually patients show elevated levels of LDH and ferritin in their blood labs; 
Imaging exams include but are not limited to Xray, Ct, MRI and ultrasound; in case of 
metastatic disease FDG-PET is used. 
Tumour biopsies are mandated to confirm the initial diagnosis.
surgery, radiation and chemotherapy; 
combination chemotherapy for medulloblastoma: 
vincristine, carbo-/cisplatin, cyclophosphamide 
and/or lomustine, etoposide, TMZ; Chemotherapy 
for PNETs, like those for neuroblastoma: 
combinations of agents like alkylating agents 
(ifosfamide, cyclophosphamide), 
anthracyclines(adriamycin), etoposide, 
actinomycin D and vincristine
7. RMS
Clinical symptoms largely depend on the location of the tumour
Imaging exams include but are not limited to Xray, CT, MRI and ultrasound; in case 
of metastatic disease FDG-PET is used.
Tumour biopsies are mandated to confirm the initial diagnosis, and should be 
performed as open surgical intervention to assure that sufficient material is obtained 
for histopathology, IHC and cyto-, and molecular genetical exams. Myogenin, 
MyoD1, desmin, vimentin, myoglobin, actin, NSE, S-100, MIC2 stains are done. 
Furthermore e.g. in alveolar RMS - t(2;13)(q35;q14)) exams are done.
Treatment options for high- risk limited; 
conventional treatment with chemotherapy, 
surgery and radiotherapy; chemotherapy: 
dactinomycin, vincristine, alkylating agents 
(ifosfamide, cyclophosphamide), anthracyclines 
(doxorubicin and epidoxorubicin), etoposide, and 
platinum compounds.


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10.6 
DATA OF THE RELATIVE BIO-EQUIVALENCE STUDY 1200.35 
The statistical evaluation of the relative BA results is summarized in Table 10.6: 1 below.
Table 10.6:1 
Summary of results from the relative bioavailability trial 1200.35 
20 mg film-coated tablet versus drinking solution
Test
Reference
Parameter
Geometric
mean ratio
(%)
Lower
90% CI
(%)
Upper
90% CI
(%)
Intra-
individual 
gCV (%)
20 mg film-
coated 
tablet
(FF tablet)
Drinking 
solution 
20 mg per 
bottle
Cmax
[ng/mL]
85.31
68.75
105.88
42.3
AUC0-∞
[ng∙h/mL]
92.24
76.30
111.51
36.7
Source data: Trial 1200.35 (U09-2233, Table 11.5.2.1.3: 1)
It should be noted that the trial was not intended to show bioequivalence between the 
formulations (N=22 healthy volunteers were treated in a cross-over design; considering the 
variability in PK observed in this trial, N=84 healthy volunteers would have been required to 
have a targeted power of 90% to show bioequivalence assuming a ratio of 0.95 for both 
formulations).


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10.7
BODY SURFACE AREA CALCULATION
The target dose of Afatinib has been calculated based on BSA derived from the Dubois and 
Dubois formula. 
BSA = (W 0.425 x H 0.725) x 0.007184
Whereas:
W is the weight is in kilograms 
H is the height is in centimetres.
The paediatric dose was calculated as follows:
Dose child = Dose adult x (BSA child / BSA adult)   considering BSA = 1.75 m2 for adult


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10.8 
EXAMPLE FOR FORMULA APPROPRIATE FOR GFR ESTIMATION IN 
CHILDREN
Please use the modified Schwartz-formula below or your institutional standard formula 
appropriate for GFR estimation in paediatric patients. In case GFR measurements are 
available, these may replace GFR estimation.
eGFR = k x L/Scr
whereas:
eGFR is estimated GFR in millilitres per minute per 1.73m²
L is height in centimeters
Scr is serum creatinine in milligrams per decilitre
k is 0.45 for term infants throughout the first year of life, 0.55 for children and adolescent 
girls and 0.7 for adolescent boys
Note that the Cockroft-Gault formula is not suitable to estimate GFR in paediatric 
patients


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
04 May 2015
EudraCT number
2014-002123-10
BI Trial number
1200.120
BI Investigational Product(s)
Giotrif®, Gilotrif®, Afatinib Capsules and Solvent for 
Oral Solution
Title of protocol
Phase I open label, dose escalation trial to determine 
the MTD, safety, PK and efficacy of afatinib 
monotherapy in children aged 2 years to <18 years 
with recurrent/refractory neuroectodermal tumours, 
rhabdomyosarcoma and/or other solid tumours with 
known ErbB pathway deregulation regardless of 
tumour histology
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
applies to optional CSF PK sampling
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
applies to clarification for P-gp modulators
Section to be changed
1. Flow-Chart
2. Abbreviations
3. Section 1.2
4. Section 4.2.3.1
5. Section 5.5
6. Section 7.3.5
7. Appendix 10.3
8. Appendix 10.4
Description of change
1. Add optional CSF PK sampling
2. Add CSF
3. Additional details on handling of strong P-


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Number of global amendment
1
gp inhibitors/inducers provided
4. Same as change 3
5. Same as change 1
6. Same as change 1
7. Same as change 1
8. Same as change 3
Rationale for change
Changes 1, 2, 5, 6, 7 : 
To assess afatinib penetration into the CSF
Changes 3, 4, 8:
Clarification that the use of strong P-gp 
inhibitors/inducers is prohibited during course 1 
of dose finding to assure that MTD definition is 
not affected by potential co-administration of 
strong P-gp inhibitors/inducers. Additional details
are given on how to use strong P-gp 
inhibitors/inducers with afatinib if their use
cannot be avoided after course 1 of the dose 
finding part and how to handle them during MTD 
expansion cohort.
Number of global amendment
2
Date of CTP revision
18 Aug 2016
EudraCT number
2014-002123-10
BI Trial number
1200.120
BI Investigational Product(s)
Giotrif®, Gilotrif®, Afatinib Capsules and Solvent for 
Oral Solution
Title of protocol
Phase I open label, dose escalation trial to determine 
the MTD, safety, PK and efficacy of afatinib 
monotherapy in children aged 2 years to <18 years 
with recurrent/refractory neuroectodermal tumours, 
rhabdomyosarcoma and/or other solid tumours with 
known ErbB pathway deregulation regardless of 
tumour histology
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 


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Number of global amendment
2
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Flow-Chart, Section 4.1.2, 4.2.1, 5.2.2, 
6.2.1 and 6.2.2
2. Section 6.2.1
3. Section 6.2.2
4. Section 1.2, 2.3, 5.2.2.1, 8.4.1 and 9.2
Description of change
1. Clarification on the possible use of a pre-
screening informed consent for the 
collection and testing of tumour tissue 
sample
2. Clarification on how to manage collection
of tumour images during the screening 
period
3. Alignment of the section with Flow Chart 
4. Deletion of IB version reference 
Rationale for change
1. Clarification
2. Clarification
3. Clarification - correction of typo and 
omission
4. Clarification to always refer to the most 
recent IB version
Number of global amendment
3
Date of CTP revision
02 June 2017
EudraCT number
2014-002123-10
BI Trial number
1200.120
BI Investigational Product(s)
Giotrif®, Gilotrif®, Afatinib Capsules and Solvent for 
Oral Solution
Title of protocol
Phase I/II open label, dose escalation trial to determine 
the MTD, safety, PK and efficacy of afatinib 
monotherapy in children aged ≥1 years to <18 years 
with recurrent/refractory neuroectodermal tumours, 
rhabdomyosarcoma and/or other solid tumours with 
known ErbB pathway deregulation regardless of 
tumour histology
To be implemented only after 
approval of the 


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Number of global amendment
3
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Synopsis
2. Flow Chart
3. Section 1 (1.1 and 1.2)
4. Section 2 (2.1, 2.2, 2.3)
5. Section 3 (3.1, 3.2, 3.3)
6. Section 4 (4.1.2, 4.1.3, 4.1.4, 4.2.2.3, 4.2.3)
7. Section 5 (5.1, 5.2.1, 5.3.1, 5.4, 5.5.1, 5.5.3, 
5.6-5.6.1)
8. Section 6 (6.2.1, 6.2.2, 6.2.3)
9. Section 7 (7.1, 7.3.1, 7.3.2, 7.3.5, 7.6)
10. Section 9 (9.1, 9.2)
11. Section 10 (10.1, 10.3)
Description of change
1. Multiple changes for adaptive Phase I/II 
design
2. Same as 1
3. Same as 1 and literature update
4. Same as 1
5. Same as 1
6. Same as 1, literature update and update on 
contraception methods
7. Same as 1
8. Clarification on pre-screening informed 
consent use/editorial changes
9. Same as 1
10. Addition of literature references
11. Same as 1 and clarification on alternative PK 
samplings
Rationale for change
Changes 1 to 7, 9, 11: 
to reflect changes necessary to comply with the
Written Request received from FDA


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Number of global amendment
3
Additional change 6: 
to follow the contraception guidance per ICH M3 
(R2) and HMA CTFG
Change 8 and 11: 
clarifications and correction of typos
Additional changes 3, 6 and change10: 
to consider latest updates from literature


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02332639
5.0
clinical-trial-protocol-version-04
Phase I/II open label, dose escalation trial to determine the MTD, safety, PK and
efficacy of afatinib monotherapy in children aged ≥1 year to <18 years with
recurrent/refractory neuroectodermal tumours, rhabdomyosarcoma and/or other solid
tumours with known ErbB pathway deregulation regardless of tumour histology
Author-Clinical Monitor
02 Jun 2017 15:30 CEST
Approval-Therapeutic Area 
02 Jun 2017 15:44 CEST
Author-Trial Statistician
02 Jun 2017 15:51 CEST
Approval-Team Member Medicine
03 Jun 2017 01:29 CEST
Author-Clinical Pharmacokineticist
06 Jun 2017 10:17 CEST
Author-Clinical Monitor
06 Jun 2017 10:20 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02332639
5.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c20741038-03
BI Trial No.:
1200.120
Title:
Phase I/II open label, dose escalation trial to determine the MTD, 
safety, PK and efficacy of afatinib monotherapy in children aged 
≥1 year to <18 years with recurrent/refractory neuroectodermal 
tumours, rhabdomyosarcoma and/or other solid tumours with 
known ErbB pathway deregulation regardless of tumour histology
Including Protocol Amendment 1 (c02332639-03), 2 (c02332639-     
04) and 3 (c02332639-05)
Investigational
Product(s):
Giotrif®, Gilotrif®, Afatinib Capsules and Solvent for Oral 
Solution
Responsible trial 
statistician(s):
 
Phone: 
Fax: 
Date of statistical 
analysis plan:
31 JUL 2020 REVISED 
Version:
Revised
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINT(S).......................................................................................................9
5.1
PRIMARY ENDPOINT(S) ..................................................................................9
5.2
SECONDARY ENDPOINT(S) ............................................................................9
5.2.1
Key secondary endpoint(s)...................................................................................9
5.2.2
Secondary endpoint(s) ..........................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................13
6.1
TREATMENT(S)................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
PATIENT SETS ANALYSED...........................................................................15
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................17
7.
PLANNED ANALYSIS......................................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.3
TREATMENT COMPLIANCE........................................................................18
7.4
PRIMARY ENDPOINT(S) ................................................................................18
7.4.1
Dose Finding Part: ..............................................................................................18
7.4.2
MTD expansion cohort part: .............................................................................18
7.5
SECONDARY ENDPOINT(S) ..........................................................................19
7.5.1
Key secondary endpoint(s).................................................................................19
7.5.2
(Other) Secondary endpoint(s) ..........................................................................20
7.7
EXTENT OF EXPOSURE.................................................................................20
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse events.....................................................................................................21
7.8.2
Laboratory data ..................................................................................................22
7.8.3
Vital signs.............................................................................................................24
7.8.4
ECG......................................................................................................................24
7.8.5
Others...................................................................................................................24
8.
REFERENCES....................................................................................................25


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10.
HISTORY TABLE..............................................................................................27


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LIST OF TABLES
Table 5.2.2: 1 Censoring rules and determination of date of event or censoring for PFS.......10
Table 6.1: 1
Definition of analysing treatment periods ........................................................13
Table 6.2: 1
Important protocol deviations...........................................................................14
Table 7.4.2: 1 Confirmation rule for best overall response .....................................................19
Table 7.8.2: 1 Primary laboratory parameters .........................................................................23
Table 7.8.2: 2 Secondary laboratory parameters .....................................................................24
Table 10: 1
History table .....................................................................................................27


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AUC
Area Under Curve
BMI
Body mass index
BRPM
Blinded report planning meeting
BSA
Body surface area
BUN
Blood urea nitrogen
Cmax
Maximum Concentration
CR
Complete Response
CTC
Common Terminology Criteria  
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DLT
Dose Limiting Toxicity
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DoR
Duration of objective response
DRA
Drug Regulatory Affairs
EMA
European Medicines Agency
FAS
Full analysis set
FDA
Food and Drug Administration
ICH
International Conference on Harmonisation
INRC
International Criteria for Neuroblastoma Response Criteria
IPD
Important protocol deviation
LVEF
Left ventricular ejection function
MedDRA
Medical Dictionary for Regulatory Activities
MQRM
Medical Quality Review Meeting
MTD
Maximum Tolerated Dose
MxR
Mixed response
NOR
Not-valid results
NOS
No sample available
NR
No response
O*C
Oracle Clinical
OR
Objective Response


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Term
Definition / description
PD
Progressive Disease
PFS
Progression free survival
PK
Pharmacokinetics
PopPK
Population Pharmacokinetic(s)
PPS
Per protocol set
PPSR
Proposed pediatric study request
PR
Partial Response
PSTAT
Project Statistician
PT
Preferred term
Q1
Lower quartile
Q3
Upper quartile
SAS
Statistical Analysis System
s.d.
Standard deviation
SD
Stable Disease
SMQ
Standardised MedDRA query
SOC
System Organ Class
tmax
Time to reach maximum concentration
TCM
Trial Clinical Monitor
TMW
Trial Medical Writer
TOC
Table of contents
TSAP
Trial Statistical Analysis Plan
TSTAT
Trial Statistician
VGPR
Very good partial response


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol and its
amendments, and to include detailed procedures for executing the statistical analysis of the 
primary and secondary variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomization.
SAS® Version 9.4 will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The clinical trial protocol (CTP) v3 was amended based on the feedback received from the 
FDA during a PPSR request. The MTD expansion cohorts will now recruit up to 38 patients 
evaluable for OR based on biomarker selection criteria as well as specific tumour indications. 
The definition of duration of objective response was misspecified in the  CTP as the interval 
between the date of randomization and the earliest date of disease progression. The correct 
definition is clarified in Section 5.2.2 of this TSAP as the time from first documented 
response of CR, VGPR, PR, or MxR until the earliest of disease progression or death among 
patients with objective response.


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5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT(S)
Dose finding part:

The primary endpoint is the dose limiting toxicity (DLT) measured during the first 
course of treatment. DLTs are defined in Table 4.1.4.1.2 of the CTP. 

Pharmacokinetics (AUCτ,ss, Cmax,ss)
The primary objective of the dose finding part is to determine the maximum tolerated dose 
(MTD) of the study drug as defined by patients with DLT in a paediatric population. The 
MTD will be determined as the highest dose at which no more than 1/6 patients experienced 
DLT. The MTD evaluation period is defined as the initial 28 days of study treatment. Patients 
who developed DLT at any time during the initial 28 treatment days and patients who have 
completed the MTD evaluation period without missing more than 25% of the afatinib doses 
regardless of the reason will be referred to as patients evaluable for DLT.
MTD expansion cohort part:

Objective response (OR) by investigator assessment according to the institutional 
response evaluation criteria for the given tumour type, assessed every 8 weeks until 
progression of disease.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
There were no key secondary endpoints for this study.
5.2.2
Secondary endpoint(s)
Dose finding part:

Objective response (OR) assessed by investigator according to the institutional 
response evaluation criteria for the given tumour type, assessed every 8 weeks until 
progression of disease

Pharmacokinetics (AUC0-24, Cmax, tmax(,ss) and accumulation (or effective) half-life)
MTD expansion cohort part:

Progression free survival (PFS) is defined as the duration of time from the date of 
first drug administration to the date of the first documented disease progression 
evaluated according to institutional response criteria or to the date of death from any 
cause, whichever occurs first. Censoring rules and dates of outcome for PFS under 
difference scenarios are specified in Table 5.2.2: 1.

Duration of objective response (DoR) is defined as the time from first documented 
response of CR, VGPR, PR, or MxR until the earliest of disease progression or death 
among patients with objective response. Censoring rules and dates of outcomes follow 
the same specifications as for PFS in Table 5.2.2: 1 for applicable scenarios.

Pharmacokinetics (AUCτ(,ss), Cmax(,ss), tmax(,ss) and accumulation (or effective) half-life)


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Table 5.2.2: 1
Censoring rules and determination of date of event or censoring for 
PFS
Situation
Outcome 
(event or 
censored)
Date of outcome
No baseline radiological assessment (no 
death before second scheduled 
radiological assessment)
censored
Date of first treatment administration
Death without progression. At most one 
missed radiological assessments, i.e. at 
most 112 days between death and last 
assessment (or treatment start date if no 
post-baseline assessments).
event
Date of death
Death without progression. Two or 
more missed radiological assessments, 
i.e. longer than 112 days between death 
and last assessment (or treatment start 
date if no post-baseline assessments).
censored
Date of last radiological assessment / 
Date of first treatment administration 
if no post-baseline assessments
No radiological assessment performed 
post-baseline, vital status is unknown or 
patient is known to be alive
censored
Date of first treatment administration
Progressed according to radiological 
assessment. At most one missed 
radiological assessments, i.e. at most 
112 days between progression and last 
assessment before progression.
event
Date of radiological assessment of 
progression
Progressed according to radiological 
assessment, i.e. longer than 112 days 
between progression and last 
assessment before progression.
censored
Date of last radiological assessment 
before progression
Alive and not progressed (irrespective 
of missed radiological assessments)
censored
Date of last radiological assessment
Initiation of subsequent anti-cancer therapy
Subsequent anti-cancer therapy started 
before progression or death
censored
Date of last radiological assessment 
before subsequent anti-cancer therapy
No baseline and/or post-baseline 
imaging and subsequent anti-cancer 
therapy started prior to a death
censored
Date of first treatment administration
For further details on endpoints, please see CTP Section 5.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
Daily single oral doses of afatinib will be investigated in this study for paediatric patients. 
Dose escalation starts at 80% of the adult MTD by m2 BSA and allometric scaling (Level 0) 
and can be escalated to 100% (level 1), 125% (level 2) and 150% (level 3) of the adult dose if 
required.  In case level 0 exceeds the MTD, a dose level -1 will allow de-escalation to 50% of 
the adult MTD dose by m2 BSA and allometric scaling. Oral solution is available for younger 
children and patients who cannot swallow afatinib film coated tablets. 
Analysing treatment periods are defined in Table 6.1: 1 for reporting of treatment emergent 
AEs and safety laboratory data. An adverse event will be assigned to the analysing period 
where start date ≤ onset date of AE < stop date.
Table 6.1: 1
Definition of analysing treatment periods
Analysing 
treatment period
Start date (including)
Stop date (excluding)
Screening
Date of informed consent
Date of first intake of study drug
Course 1
Date of first intake of study drug
Start date of Course 2, or date of 
first intake of study drug + 28 days 
if the patient did not start Course 2
On-treatment
Date of first intake of study drug
Date of last intake of study drug + 
29 days
Residual effect 
period (REP)
Date of last intake of study drug 
+ 1 day
Date of last intake of study drug + 
29 day
Off-treatment
Date of last intake of study drug 
+ 29 day
Date of last follow up visit + 1 day 
or date of death + 1 day whichever 
occurred first
The residual effect period (REP) for afatinib is 28 days after last intake of afatinib. Data 
recorded between the first study drug intake until up to 28 days after the last study drug intake 
will be considered as on-treatment.
6.2
IMPORTANT PROTOCOL DEVIATIONS
A protocol deviation is important if it affects the rights or safety of the study patients, or if it 
can potentially influence the primary outcome measurements in a non-negligible way. 
Patients with important protocol deviations (IPDs) that could potentially impact the 
evaluation of the primary endpoint(s) will be excluded.


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The different categories of IPDs are defined in Table 6.2: 1. IPDs will be reviewed at Medical 
Quality Review Meetings (MQRMs) conducted periodically during the trial. A list of protocol 
deviations will be discussed at the report planning meetings (RPMs). If the data show other 
IPDs, this table will be supplemented accordingly at MQRMs or RPMs or through team 
review of the protocol deviation log. The decision whether a patient will be excluded from the 
analysis will be made at the final RPM prior to DBL.
Table 6.2: 1
Important protocol deviations
Category/
Code
Description
Comment/Example
Excluded 
from
Manual/
Automatic
A
Inclusion/Exclusion Criteria
A1
A1.1
Laboratories measurements
Exclusion 
criteria13,14,15
None
Automatic
A1.2
Forbidden concomitant diagnoses
Exclusion criteria 
4,5,7,9,10,11,12
None
Automatic
A1.3
Female patients who are pregnant or doing 
breast feeding at baseline
Exclusion criteria 6
None
Automatic
A1.4
Prohibited concomitant medications, 
radiotherapy and surgery
Exclusion criteria 
1,2,3, 8
None
Automatic
A2
Automatic
A2.1
Patient does not have trial diagnosis
Inclusion criteria 1 
None
Automatic
A2.2
Patient did not recover (to CTCAE grade 1 
or baseline) from any acute toxicity 
resulting from prior anti-cancer treatment 
(except alopecia)
Inclusion criteria 4
None
Automatic
A2.3
Patient did not have Lansky/Karnofsky 
(depending on age) scores >=50% 
assessed within 2 weeks prior to 
enrolment.
Inclusion criteria 8
None
Automatic
A2.4
Patient has LVEF <50%
Inclusion criteria 12
None
Automatic
A2.5
Required ErbB pathway deregulation 
absent 
MTD Expansion 
Cohort: Inclusion 
criteria 1or 13
None
Automatic
A2.6
Patient age at study start not between >=2 
to <18 years
Patient age at study start not between >=1
to <18 years
Dose finding cohort:
Inclusion criteria 3
MTD expansion 
cohort: Inclusion 
criteria 3 
None
Automatic
A2. 7
No tumour tissue available (exception of 
DIPG)
MTD Expansion 
Cohort: Inclusion 
criteria 7
None
Automatic
A2.8
Patient do not have at least one measurable 
lesion according to
the institutional response criteria for the 
given tumour type.
Inclusion criteria 14
None
Automatic


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Table 6.2: 1
Important protocol deviations (cont.)
Category/
Code
Description
Comment/Example
Excluded 
from
Manual/
Automatic
B
Informed Consent
Automatic
B1
Informed consent not given
Inclusion criterion 6
All
Automatic
B2
Informed consent after administration of 
trial medication
Inclusion criterion 6
None
Automatic
B3
Informed consent not in accordance with 
regulations
None
Manual
C
Trial Medication
C1
Dose change of afatinib not according to 
protocol
None
Manual
C2
Non-compliance
Afatinib not taken 
according to 
protocol
None
Manual
C3
Dose reduction/paused/discontinuation not 
according to protocol following an 
AE/DLT
Refer to Table 
4.1.2.3:1 and Table 
4.2.2.1:1 in the CTP
None
Manual
D
Concomitant Treatment
D1
Any other chemotherapy, immunotherapy 
or radiotherapy during the trial except for 
palliative radiation
Refer to Section 4.2 
of the CTP
None
Manual
D2
During palliative radiation, treatment was 
not paused until the patient recovered from 
any radiation associated toxicity
Refer to Section 4.2 
of the CTP
None
Manual
D3
Continuous interruption of >28 days due 
to palliative radiotherapy
Refer to Section 4.2 
of the CTP
None
Manual
E
Critical study procedure 
E1
Critical study procedure not followed
None
Manual
F
Privacy / data protection 
F1
Privacy and/or data protection violated
None
Manual
6.3
PATIENT SETS ANALYSED
Treated set (TS): 
This patient set includes all patients enrolled in the trial who were documented to have taken 
at least one dose of study medication. 
Dose finding cohort treated set:
This patient set includes all patients enrolled in dose finding cohort of the trial who were 
documented to have taken at least one dose of study medication.


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MTD Expansion cohort treated set:
This patient set includes all patients enrolled in expansion cohort who must satisfy the 
following criterion: 

Patients’ tumour must be tested for positivity on 2 of the following tests: EGFR 
IHC>150 and/or HER2 IHC>0 and/or EGFR FISH positive and/or HER2 DDISH 
positive.
or

Patient will have proven genomic, transcriptomic or proteomic alterations which are 
not defined above.
and

Patients who were documented to have taken at least one dose of study medication.
PK analysis set (PKS):
This set includes all patients in the treated set (TS) who provided at least one PK endpoint 
that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to 
PK non-evaluability. Thus, a patient will be included in the PKS, even if he/she contributes 
only one PK parameter value for one period to the statistical assessment. Descriptive and 
model based analyses of PK parameters will be based on the PKS.
6.5
POOLING OF CENTRES
This section is not applicable.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing or incomplete AE dates are imputed according to BI standards (3). Missing efficacy 
data, including vital status, tumour imaging data, will not be imputed in general. All 
reasonable efforts have been undertaken during the study to obtain such data.
Missing or incomplete drug stop dates are imputed as follows: 

If month and year known for drug stop date but day missing, then use date of death if 
within the month; otherwise use last day of month.

If both month and day unknown, then use the first available date in this order: date of 
death, date of last contact, last day of the month of last visit.
Missing data and outliers of PK data are handled according to (2). Samples marked as no 
sample available (NOS) or non-valid result (NOR) will not be included in the analysis. Please 
refer to Sections 7.3.5 and 7.4 of the CTP for more details.


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Study days and visits will be labelled according to the flow chart of the CTP.
Unless otherwise specified, baseline is defined as the latest time point before the very first 
administration of any study medication. If this criterion is not fulfilled, then no baseline will 
be derived. Note that for some trial procedures (for example performance score, body weight, 
vital signs, laboratory tests) this may be the value measured on the same day when trial 
medication was started. In these cases it will be assumed that the measurements were taken 
prior to the intake of any study medication. For laboratory values where not only the 
examination date but also time are recorded, examination time has to be taken into account 
when defining baseline. That is, a laboratory value on the same date as the first study drug 
administration is considered as baseline value if and only if the time of laboratory value is 
before or the same as the time of first study drug administration. If any of these times are 
missing and the date of laboratory value is equal to the date of first study drug administration, 
then the laboratory assessment will be considered as according to protocol, i.e. as prior to first 
study medication.


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Q1 
(lower quartile) / Median / Q3 (upper quartile) / Max.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient set 
whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
7.4
PRIMARY ENDPOINT(S)
7.4.1
Dose Finding Part:
One of the primary objectives is to assess the MTD based on the number of patients 
presenting DLTs during the MTD evaluation period. Therefore, an overall summary of DLTs 
(see CTP Section 4, Table 4.1.4.1.2 for the definition of DLTs) which occurred during the 
MTD evaluation period will be provided for each dose cohort from the dose finding cohort 
treated set. Patients who were replaced within the MTD evaluation period will be excluded 
from the determination of the MTD but will be considered for all other safety evaluations.
A summary of the number of patients with DLTs overall in any course will be also given by 
initial treatment and displayed in a similar format to the summary of DLTs occurring in the 
MTD evaluation period.
The determination of the MTD is based on a Rolling 6 design as illustrated in Section 4, Table 
4.1.4.1:1 of the CTP. The MTD is defined as the highest dose at which no more than 1/6 
patients experienced DLT considered related to afatinib during the MTD evaluation period. 
Refer to CTP 7.3.1 for further details on MTD evaluation. 
Analysis of the standard PK endpoints is performed according to (2) and (8) as outlined in 
Section 7.3.5 of the CTP.
7.4.2
MTD expansion cohort part:
Objective response (OR) is defined as a best overall response of complete response (CR) or  
partial response (PR) based on investigator’s assessment according to the institutional 


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response evaluation criteria for the given tumour type. If the International Criteria for 
Neuroblastoma Response Criteria (INRC) is used, OR is defined as complete response (CR), 
very good partial response (VGPR), partial response (PR) and mixed response (MxR). For 
further details on OR, please refer to CTP Section 7.3.1. The objective response rate will be 
calculated and reported as proportion of responders with 95% Clopper-Pearson CIs based on 
all treated patients. Objective response will be summarized regardless of confirmation.  
Additional summary or listing may be provided for confirmed response. If only few patients 
(fewer than 5) achieved objective response, a detailed listing will be reported. 
For objective responses, evaluated by institutional response evaluation criteria other than 
INRC, below confirmation rule for best overall response will be considered. 

If CR or PR: look at all subsequent visits, if there is another CR or PR >=28 days then 
the patient has a confirmed response. If there is not another CR or PR >=28 days then 
the patient can be SD. Please note that once patient achieve CR any response other 
than CR will be considered as PD. 
Detailed specifications are listed in Table 7.4.2: 1.
Table 7.4.2: 1
Confirmation rule for best overall response
Overall response 
(time point 1) 
Overall response 
(subsequent time point)
Unconfirmed best 
overall response 
Confirmed best overall 
response 
CR 
CR (>=28 days from 1)
CR
CR 
CR 
CR (< 28 days from 1)
CR
SD
CR 
PR1
CR
SD
CR 
SD 
CR
SD 
CR 
PD 
CR
SD 
CR 
NE/Missing 
CR
SD 
PR 
CR (>=28 days from 1)
CR
PR 
PR 
CR (< 28 days from 1)
CR
SD
PR 
PR (>=28 days from 1)
PR
PR 
PR 
PR (< 28 days from 1)
PR
SD
PR 
SD 
PR
SD 
PR 
PD 
PR
SD 
PR
NE/Missing 
PR
SD 
1= If truly a CR at first response, any subsequent disease (even a PR relative to baseline) makes the disease PD. Could 
only be a PR if initial CR is changed to PR (i.e. not a true CR).
For INRC, a similar derivation of confirmed response will apply. That is, a subsequent 
assessment with the same or a better overall response on or after 28 days is required for the 
confirmation of an objective response, in the order from best to worst of  CR > VGPR > PR >
MxR. Otherwise, a SD will be considered as the confirmed best overall response. 
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.


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7.5.2
(Other) Secondary endpoint(s)
For progression free survival (PFS), objective response (OR) and duration of objective 
response (DoR), a descriptive and graphical summary of the endpoint will be provided. The 
Kaplan-Meier estimates of PFS and DoR (if applicable) and 95% confidence intervals will be 
calculated at the time of each planned assessment. For the dose finding part, the number of 
patients with OR will be summarized by dose level. If fewer than 5 patients achieved OR, 
then DoR will only be listed; Kaplan-Meier estimates will not be calculated and no summary
table or graph will be provided. 
To evaluate the potential influence of age on pharmacokinetic parameters like Cmax and AUC, 
an exploratory subgroup analysis will be performed for different age groups. For this, binning 
of age into groups will be performed to ensure that groups have reasonable patient numbers. If 
feasible, a correlation of age and PK parameters may be performed. 
7.7
EXTENT OF EXPOSURE
Treatment exposure will be primarily summarized by the total on-treatment time and has been 
defined in Section 5.4 of this TSAP. 
Treatment interruptions before permanent discontinuation will not be excluded. Summary 
statistics for treatment time by each dose level of afatinib over time will also be provided.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
7.8.1
Adverse events
The analyses of adverse events (AE) will be descriptive in nature. All analyses of AEs will be 
based on the number of patients with AEs and not on the number of AEs. For analysis of 
duration, severity etc. of multiple AE occurrences, data on the case report form (CRF) will be 
collapsed into AE episodes provided that all of the following applies:

The same MedDRA lowest level term was reported for the occurrences.

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence).

Treatment did not change between the onset of the occurrences or treatment changed 
between the onsets of the occurrences, but no deterioration was observed for the later 
occurrence.
For further details on summarization of AE data, please refer to the BI guideline (4).
The analyses of adverse events will be based on the concept of treatment-emergent adverse 
events. That means that all adverse events occurring between first drug intake and 28 days 
after last drug intake or death, whichever occurs first, will be assigned to the on-treatment 
period. All adverse events occurring before any study drug intake will be assigned to 
‘screening’ and all adverse events occurring after last study drug intake + 28 days will be 
assigned to ‘Off-treatment’ (for listings only). For details on the treatment definition, see 
Section 6.1.
An overall summary of adverse events will be presented. The frequency of patients with 
adverse events will be summarised by highest CTC grade (grades 1, 2, 3, 4, 5 and all grades), 
treatment, primary system organ class and preferred term for each of the following AE tables
as well as relatedness of AEs to treatment and seriousness:

DLTs (1st course and all courses)

All AEs

Drug-related AEs

AEs leading to dose reduction

AEs leading to treatment discontinuation

Drug-related AEs leading to dose reduction

Drug-related AEs leading to treatment discontinuation

AEs leading to death

Serious AEs

Drug related serious AEs

Other significant AEs, defined as AEs leading to dose reduction or permanent 
discontinuation of study medication

Non-serious AEs with higher than 5% occurrence rate for disclosure on 
ClinicalTrials.gov


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Please refer to CTP Section 5.2.2.1 for definitions of the adverse events. All tables will be 
sorted by system organ classes (SOC) according to the standard sort order specified by the 
European Medicines Agency (EMA). Preferred terms (PTs) will be sorted by frequency 
(within SOC).
The table for all AEs will be repeated with the project defined grouping of AE terms (acute 
renal failure associated with severe diarrhoea, acne, rash, stomatitis, conjunctivitis, 
paronychia, severe cutaneous adverse reactions, interstitial lung disease, keratitis, hepatic 
impairment, pancreatitis, heart failure, gastrointestinal perforation, hypersensitivity reactions, 
nail disorders and fatigue). Details of the project defined groupings will be defined in the 
technical TSAP. In these tables the grouped AEs will replace the original PTs for all AEs that 
are included within the grouped term. The grouped AE categories will then be tabulated along 
with all remaining MedDRA PTs, sorted by descending frequency.
A reference table presenting the entire project defined groupings and MedDRA PTs within 
each grouping will also be produced.
Additional AE tables will be produced for AEs of special interest (hepatic injury as defined in 
CTP Section 5.2.2.1 and dose limiting toxicities as defined by CTP Section 4, table 4.1.4.2). 
Listings providing further details on highest CTC grade, action taken with study drug and 
time to first onset of AE will be produced.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards
(5). The same on-treatment period as considered for the analysis of AEs will be applied for 
laboratory values. CTC grade for applicable lab parameters will be calculated according to 
CTCAE v3.0 (7).
For a list of laboratory parameters considered for this trial, please refer to CTP Section 5.2.3, 
Table 5.2.3:1. Descriptive statistics of all normalized laboratory values by visit will be 
provided including changes from baseline. Transition tables of CTCAE grade from baseline to 
worst value and last value on treatment, and frequency tables of possible clinically significant 
abnormalities will be produced. For those parameters that have CTC grading possible 
clinically significant abnormalities are defined as those laboratory values with a CTC grade ≥ 
2 that have had an increase of ≥ 1 grade from baseline. For those parameters for which no 
CTC grade has been defined standard BI project definitions will be used to decide on clinical 
significance. See Tables 7.8.2: 1 and 7.8.2: 2 for the potential clinical significance rules.
Analyses of descriptive statistics will use normalized lab values (variables ULN, LABN).
Analyses of frequencies of patients with potential clinical significance, analyses of shift, and
liver function categories tables will use converted values (ULC, LABSTD).
Summaries will be produced of laboratory data recorded on-treatment. Listings will be 
provided for data recorded prior to treatment, on-treatment and post-treatment. For details on 
the treatment definition, see Section 6.1.
For the primary laboratory parameters listed in Table 7.8.2: 1, full analysis of descriptive 
statistics, transition tables and possible clinical significant abnormalities will be conducted. 


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Analysis of secondary laboratory parameters listed in Table 7.8.2: 2 will be limited to 
frequency tables of possible clinically significant abnormalities. Listings of converted and 
normalized values for all laboratory parameters considered for this trial will be provided in 
Appendix 16.2 of the CTR.
Table 7.8.2: 1
Primary laboratory parameters
Label
Lab test name
Direction 
of interest
Potential clinical 
significance rule
ALKP
Alkaline phosphatase
High
A1
APTT
APTT (Activated partial thrombopl. time)
High
A1
CRE
Creatinine
High
A1
CRECL
GFR/Creatinine clearance
Low
A1, 2
HGB
Haemoglobin
Low
A1
INR
PT-INR
High
A1
K
Potassium
Low
A1
LYMPH
Lymphocytes
Low
A1
NA
Sodium
Low
A1
NEUT
Neutrophils
Low
A1
SGOT
AST/GOT, SGOT
High
A1
SGPT
ALT/GPT, SGPT
High
A1
TBILI
Bilirubin, total
High
A1
WBC
White blood cell ct.
Low
A1
1A = CTCAE grade 2 or greater with an increase of at least one CTCAE grade from baseline.
2Values less than 0.25xLLN will be assigned CTCAE grade 3.


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Table 7.8.2: 2
Secondary laboratory parameters
Label
Lab test name
Direction of 
interest
Potential clinical 
significance rule
BUN
Blood urea nitrogen
High
> 10
CA
Calcium
Low & High
A1
CK
Creatine kinase
High
A1
GLUB
Glucose
Low & High
A1
LDH
LDH
High
≥ 3xULN
TPRO
Protein, total
Low & High
< 45, > 100
UREA
Urea
High
> 1.5xULN
URIC
Uric acid
High
A1, 3
1A = CTCAE grade 2 or greater with an increase of at least one CTCAE grade from baseline.
3Values >ULN – 10 mg/dL or ≤0.59 mmol/L will be assigned CTCAE grade 1.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
ECG data will be collected as described in CTP Section 5.2.4. Clinically significant findings 
in ECG data will be reported under “Adverse events” if applicable and will be analysed 
accordingly. 
7.8.5
Others
Left ventricular ejection function:
Left ventricular ejection function (LVEF) will be assessed by echocardiography (ECHO) as 
specified in the CTP Section 5.2.5.2.
Attainment of steady-state:
Attainment of steady-state will be assessed graphically.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; KMED
3
BI-KMED-BDS-HTG-0035: "Handling of Missing and Incomplete AE Dates", current 
version; KMED
4
BI-KMED-BDS-HTG-0066: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials”, current version; KMED
5
BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; KMED
6
BI-KMED-BDS-QRG-0011: “BI Lab Standards”, current version; KMED
7
Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0, published: 
August 9, 2006; U.S. Department of Health and Human Services, National Institutes of 
Health, National Cancer Institute.
8
BI Position Paper 3.8: Statistical Methods for PK, current version.


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10.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP.
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
17-JAN-18
None
This is the final TSAP without any 
modification
Revised
14-JUL-20
All
 
dded 
disease control as additional secondary 
endpoint.
Section 5: Aligned endpoint definitions 
with protocol. Added censoring rules for 
PFS. 
 
 
Section 6: Clarified definitions of 
analysis treatment periods. Updated 
definitions of important protocol 
deviation. Updated definition of PK 
analysis set. 
Section 7: Added confirmation rule for 
best overall response. Clarified analysis 
of DoR when number of patients with 
OR is low. 
 
 Updated analysis plan 
for adverse events and safety laboratory 
data. Added attainment of steady state 
analysis.
Section 8: Updated references to current 
company guidelines.
Revised
31-JUL-20
Sections 
4 and
5.2.2
The definition of “Duration of objective 
response”, a secondary endpoint, was 
incorrect in the CTP. A clarification is 
added in Section 4. The correct 
definition is provided in Section 5.2.2.