Conditions: Glioblastoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

Brief summary:
This study is a phase I, open label trial to determine the Maximum Tolerated Dose (MTD), safety, pharmacokinetics, and efficacy of BIBW 2992 (an epidermal growth factor receptor(EGFR)inhibitor) to be used in combination with:

* radiotherapy alone (in patients with an unmethylated (functioning) MGMT gene regulator) or
* radiotherapy and Temozolomide (in patients with a methylated (silenced) O6-methylguanine-DNA methyltransferase gene (MGMT) to treat newly diagnosed patients with Grade IV Glioblastoma (primary brain cancer).

Detailed description:

Arms:
arm 1: BIBW2992 + Radiotherapy arm 2: BIBW2992 + Temozolomide + Radiotherapy

Interventions: intervention 1: Temozolomide intervention 2: Radiotherapy intervention 3: BIBW2992 intervention 4: Radiotherapy intervention 5: BIBW2992
Intervention descriptions: intervention 1: During RT: 75 mg/m2 daily , 4 weeks after RT: given days 1 to 5 of 28 day cycles (150 mg/m2 in cycle 1, 200 mg/m2 in cycle 2 up to cycle 6) intervention 2: Day 1 to day 42 intervention 3: Escalating dose cohorts during Radiotherapy(RT) period, fixed dose after RT intervention 4: Day 1 to day 42 intervention 5: Escalating dose cohorts during Radiotherapy(RT) period , fixed dose after RT

Protocol document:
Prot_000.pdf: 
 
CLINICAL TRIAL PROTOCOL REVISION E 
(Including Amendment No. 1, 2, 3, 4 and 5 
Doc. No.: 
<c17151786>01 
 
EudraCT No.: 
BI Trial No.: 
2008-007284-17 
1200.38 Including Amendment No. 1, 2, 3, 4 and 5 
Page 1 of 91 
Investigational 
Product(s): 
 BIBW 2992 
Title: 
Phase I, open label trial to explore safety of combining BIBW 2992 and 
Radiotherapy with or without Temozolomide in newly diagnosed GBM 
Clinical Phase: 
I 
Trial Clinical 
Monitor: 
 
 
 
 
Tel: 
 
Fax: 
 
Co-ordinating 
Investigator: 
 
 
 
 
 
Tel: 
 
Fax: 
 
 
Status, Version, and 
Date of Protocol: 
Original: FINAL, 3 April 2009  
Revision A: 30Mar2010 (including Protocol Amendment1, 20Jan2010) 
Revision B: 02Jul2010 (including Protocol Amendment 2, 06May2010) 
Revision C: 04Apr2011 (including Protocol Amendment 3, 07Feb2011) 
Revision D: 02Apr2014 (including Protocol Amendment 4, 21Mar2014) 
Revision E: 24May2017 (including Protocol Amendment 5, 10May2017) 
Planned Dates of 
Trial: 
July 2009 to June 2015 
Proprietary confidential information.  
 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 
 


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TABLE OF CONTENTS 
 
TITLE PAGE.............................................................................................................................. 1 
TABLE OF CONTENTS .......................................................................................................... 2 
CLINICAL TRIAL PROTOCOL REVISION PAGE ........................................................... 7 
CLINICAL TRIAL PROTOCOL SYNOPSIS ....................................................................... 8 
FLOW CHART –REGIMEN U: UNMETHYLATED MGMT PROMOTER ................. 10 
FLOW CHART –REGIMEN M: METHYLATED OR UNMETHYLATED* MGMT 
PROMOTER ........................................................................................................... 12 
ABBREVIATIONS .................................................................................................................. 14 
1. 
INTRODUCTION .................................................................................................. 17 
1.1 
MEDICAL BACKGROUND ......................................................................................... 17 
1.2 
DRUG PROFILE ............................................................................................................ 18 
1.2.1 
BIBW 2992 ..................................................................................................... 18 
1.2.2 
Temozolomide ................................................................................................ 22 
1.2.3 
Radiotherapy ................................................................................................. 23 
1.3 
RATIONALE FOR PERFORMING THE TRIAL ..................................................... 24 
1.4 
BENEFIT - RISK ASSESSMENT ................................................................................ 24 
2. 
TRIAL OBJECTIVES ........................................................................................... 26 
2.1 
GENERAL AIM - OBJECTIVES ................................................................................. 26 
2.2 
PRIMARY ENDPOINTS ............................................................................................... 26 
2.3 
SECONDARY ENDPOINTS ......................................................................................... 26 
3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION ............................. 27 
3.1 
OVERALL TRIAL DESIGN AND PLAN – DESCRIPTION ................................... 27 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL 
GROUP ............................................................................................................................ 28 
3.3 
SELECTION OF TRIAL POPULATION ................................................................... 28 
3.3.1 
Inclusion criteria (Regimen U and Regimen M)......................................... 29 
3.3.2 
Exclusion criteria (Regimen U and Regimen M) ........................................ 29 
4. 
TREATMENTS ...................................................................................................... 31 
4.1 
TREATMENTS TO BE ADMINISTERED ................................................................. 31 


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4.1.1 
Identity of investigational products ............................................................. 31 
4.1.2 
Method of assigning patients to treatment groups ..................................... 32 
4.1.3 
Selection of doses in the trial ........................................................................ 32 
4.1.4 
Selection and timing of doses for each patient ............................................ 34 
4.1.4.1 BIBW2992 (Regimen  M and U) ............................................................... 34 
4.1.4.1.1 Dose escalation scheme for BIBW ............................................................. 34 
4.1.4.1.2 Dose reduction scheme for BIBW: Regimen U and M .............................. 36 
4.1.4.2 Temozolomide (TMZ): Regimen M ........................................................... 37 
4.1.5 
Blinding .......................................................................................................... 38 
4.1.6 
Packaging, labelling, and re-supply ............................................................. 38 
4.1.7 
Storage conditions ......................................................................................... 39 
4.2 
CONCOMITANT THERAPY ...................................................................................... 39 
4.2.1 
Rescue medication and additional treatment ............................................. 40 
4.2.2 
Restrictions..................................................................................................... 40 
4.2.3 
Management of expected adverse events..................................................... 40 
4.3 
TREATMENT COMPLIANCE .................................................................................... 43 
5. 
OBSERVATIONS ................................................................................................... 44 
5.1 
EFFICACY - CLINICAL PHARMACOLOGY OR PHARMACODYNAMICS .... 44 
5.1.1 
Primary endpoints ......................................................................................... 44 
5.1.2 
Secondary endpoints ..................................................................................... 44 
5.1.3 
Tumour assessment ....................................................................................... 44 
5.2 
SAFETY ........................................................................................................................... 45 
5.2.1 
Adverse events ............................................................................................... 45 
5.2.2 
Worsening of pre-existing conditions .......................................................... 46 
5.2.3 
Dose-limiting Toxicity (DLT) ....................................................................... 47 
5.2.4 
Maximum Tolerated Dose (MTD) ............................................................... 47 
5.2.5 
Significant Adverse Events ........................................................................... 48 
5.2.6 
Safety laboratory investigations ................................................................... 48 
5.2.7 
Physical examination, performance score ................................................... 49 
5.2.8 
Mini Mental State Examination (MMSE) ................................................... 49 
5.2.9 
ECG ................................................................................................................ 49 


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5.2.10 
Left ventricular function............................................................................... 49 
5.2.11 
Vital signs ....................................................................................................... 50 
5.3 
OTHER ............................................................................................................................ 50 
5.3.1 
Demographics and history ............................................................................ 50 
5.3.2 
Concomitant therapies and diagnoses ......................................................... 50 
5.4 
APPROPRIATENESS OF MEASUREMENTS .......................................................... 50 
5.5 
DRUG CONCENTRATION MEASUREMENTS - PHARMACOKINETICS ....... 50 
5.5.1 
Methods and timing of sample collection .................................................... 51 
5.5.2 
Analytical determinations ............................................................................. 51 
5.6 
BIOMARKER - PHARMACODYNAMIC SAMPLING ........................................... 51 
5.6.1 
Methods and timing of sample collection .................................................... 51 
5.6.1.1 Tumour samples ......................................................................................... 51 
5.6.2 
Analytical determinations ............................................................................. 52 
5.7 
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .................. 52 
5.8 
DATA QUALITY ASSURANCE .................................................................................. 52 
6. 
INVESTIGATIONAL PLAN ................................................................................ 54 
6.1 
VISIT SCHEDULE ........................................................................................................ 54 
6.2 
TRIAL PROCEDURES AT EACH VISIT .................................................................. 54 
6.2.1 
Screening ........................................................................................................ 54 
6.2.1.1 Screening Visit 1 (SV1) .............................................................................. 54 
6.2.1.2 Screening Visit 2 (SV2) .............................................................................. 55 
6.2.2 
Treatment phases .......................................................................................... 56 
6.2.2.1 Concomitant Radiotherapy treatment phase(s): Regimens U and M ......... 56 
6.2.2.2 Maintenance phase ..................................................................................... 59 
6.2.3 
End of treatment and follow-up ................................................................... 61 
6.3 
REMOVAL OF PATIENTS FROM THERAPY OR ASSESSMENT ...................... 63 
6.3.1 
Replacement of patients ................................................................................ 64 
7. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE .. 65 
7.1 
STATISTICAL DESIGN - MODEL ............................................................................. 65 
7.2 
NULL AND ALTERNATIVE HYPOTHESES ........................................................... 65 
7.3 
PLANNED ANALYSES ................................................................................................. 65 


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7.3.1 
Primary analyses ........................................................................................... 65 
7.3.2 
Secondary analyses ........................................................................................ 66 
7.3.2.1 Tumour response ........................................................................................ 66 
7.3.3 
Safety analyses ............................................................................................... 66 
7.3.4 
Interim analyses ............................................................................................. 66 
7.3.5 
Pharmacokinetic methods ............................................................................ 67 
7.4 
HANDLING OF MISSING DATA ............................................................................... 67 
7.4.1 
Pharmacokinetic parameters ....................................................................... 67 
7.5 
RANDOMISATION ....................................................................................................... 67 
7.6 
DETERMINATION OF SAMPLE SIZE ..................................................................... 67 
8. 
ADMINISTRATIVE MATTERS .......................................................................... 68 
8.1 
ETHICS ........................................................................................................................... 68 
8.1.1 
Independent Ethics Committee or Institutional Review Board ................ 68 
8.1.2 
Patient Information and Informed Consent ............................................... 68 
8.2 
RECORDS ....................................................................................................................... 69 
8.2.1 
Drug accountability ....................................................................................... 69 
8.2.2 
Emergency code break .................................................................................. 69 
8.2.3 
Case Report Forms (CRFs) .......................................................................... 69 
8.2.4 
Source documents .......................................................................................... 70 
8.2.5 
Direct access to source data - documents .................................................... 71 
8.3 
QUALITY ASSURANCE AUDIT ................................................................................ 71 
8.4 
PROCEDURES ............................................................................................................... 71 
8.4.1 
Adverse events ............................................................................................... 71 
8.4.2 
Emergency procedures.................................................................................. 73 
8.4.3 
Contraception and Pregnancy ...................................................................... 73 
8.5 
RULES FOR AMENDING PROTOCOL .................................................................... 74 
8.6 
DISCONTINUATION OF THE TRIAL BY THE SPONSOR .................................. 74 
8.7 
STATEMENT OF CONFIDENTIALITY ................................................................... 75 
8.8 
PUBLICATION POLICY .............................................................................................. 75 
8.9 
COMPLETION OF TRIAL .......................................................................................... 75 
9. 
REFERENCES........................................................................................................ 76 


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9.1 
PUBLISHED REFERENCES ....................................................................................... 76 
9.2 
UNPUBLISHED REFERENCES .................................................................................. 80 
10. 
APPENDICES ......................................................................................................... 81 
10.1 HANDLING PROCEDURE OF BLOOD SAMPLES FOR PLASMA 
CONCENTRATION-TIME MEASUREMENTS ....................................................... 81 
10.2 HANDLING OF MISSING DATA ............................................................................... 81 
10.2.1 
Plasma concentration - time profiles ........................................................... 81 
10.3 KARNOFSKY PERFORMANCE SCALE .................................................................. 82 
10.4 MINI MENTAL STATE EXAMINATION (MMSE) ................................................. 83 
10.5 COCKCROFT-GAULT-FORMULA ........................................................................... 87 
10.6 RADIOTHERAPY TECHNIQUE ................................................................................ 87 
10.7   LIST OF POTENT INHIBITORS AND INDUCERS OF P-GLYCOPROTEIN 
(MDR1) ............................................................................................................................ 89 
10.8 CLINICAL EVALUATION OF LIVER INJURY ...................................................... 90 
10.8.1 
Introduction ................................................................................................... 90 
10.8.2 
Procedures ...................................................................................................... 90 
 


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CLINICAL TRIAL PROTOCOL REVISION PAGE 
 
I herewith certify that this Clinical Trial Protocol Revision (Revision E) gives an accurate and 
complete revision of the protocol, including Amendment No. 1, 2, 3, 4 and 5 
 
Trial Clinical Monitor             _______________ _________________________________ 
 
Date 
 
 
 
 
 
 
 
 
The official documents are the original protocol and applicable amendments.  


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CLINICAL TRIAL PROTOCOL SYNOPSIS 
Name of company: 
Tabulated 
Trial Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: 
Not Applicable 
Name of active ingredient: 
 
BIBW 2992  
 
Protocol date 
Trial number 
Planned trial period 
July 2009 – Jun 2015 
3 April 2009 
1200.38 
Title of trial: 
Phase I, open label trial to explore safety of combining BIBW 2992 and Radiotherapy 
with or without Temozolomide in newly diagnosed GBM 
Co-ordinating 
Investigator: 
 
 
 
Tel: 
 /Fax: 
  
Trial sites: 
Multicenter Trial 
Clinical phase: 
I 
Objectives: 
Regimen U: Determination of the maximum tolerated dose (MTD) of BIBW 2992 
administered in combination with radiotherapy in patients with newly diagnosed 
malignant gliomas (WHO grade IV) with an unmethylated MGMT-promoter. 
Regimen M: Determination of the maximum tolerated dose (MTD) of BIBW 2992 in 
combination with TMZ and radiotherapy in patients with newly diagnosed malignant 
gliomas (WHO grade IV) with a methylated or an unmethylated  MGMT-promoter. 
Methodology: 
Open-label, stratified  (Phase I) study 
No. of patients:  
total: 
each treatment: 
Up to 60 patients 
Up to 30 patients in each regimen (2-regimen study);  
Diagnosis and main 
criteria for inclusion: 
- Newly diagnosed malignant glioma (WHO Grade IV).  
- Tumour material available for MGMT testing unless MGMT test results already 
available.  
 
Test products: 
BIBW 2992 (film-coated tablets)  
dose: 
During RT (6 weeks): Regimen U and M:  
Dose escalation of daily BIBW2992 (20,40 mg) with one de-escalation step (30 mg) in 
case 40mg is not tolerated. 
After RT: 
Regimen U: 40 mg/day BIBW 2992 until either progressive disease or undue adverse 
reaction, whichever occurs first. 
Regimen M: 40 mg/day during concomitant TMZ/ BIBW 2992 treatment period 
followed by 40 mg/day BIBW 2992 monotherapy until either progressive 
disease or undue adverse reaction, whichever occurs first. 


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Name of company: 
Tabulated 
Trial Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: 
Not Applicable 
Name of active ingredient: 
 
BIBW 2992  
 
Protocol date 
Trial number 
Planned trial period 
July 2009 – Jun 2015 
3 April 2009 
1200.38 
mode of admin. : Oral 
Temozolomide(TMZ): 
dose: 
Regimen M only: 75 mg/m2/day from day 1 to day 42 of radiotherapy. After a 4-week 
break of TMZ, patients receive up to six cycles of TMZ according to the standard 5-
day schedule every 28 days (150 mg/m2 for the first cycle, increased to 200 mg/m2 
with the second cycle and onward). 
mode of admin. : Oral 
Concomitant Therapy Radiotherapy 
dose: 
Focal radiation at a dose of 2 Gy per fraction for 5 days/week for 6 weeks, total dose of 
60 Gy.  
Criteria for efficacy: Objective tumour response according to the Macdonald criteria. 
Criteria for safety: 
Incidence and intensity of AE according to Common Terminology Criteria (CTCAE 
v.3), laboratory evaluations, patient performance.  
Statistical methods: 
Descriptive statistics.  


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FLOW CHART –REGIMEN U: UNMETHYLATED MGMT PROMOTER 
Study Periods 
Screening 
Period 
Concomitant Treatment Period (Day 1-42) 
C 1 & 
onward2  
End of 
Treatment 
Follow-up 
Visit abbreviation 
SV1 
SV2 
RT1  
RT2  
RT3  
RT4  
RT5  
CxV1a 
EOT3 
FU4 
Day 
-35 to -1 
1 
8 
15 
29 
42 
+d28 
 
 
Informed Consent1 
X 
X 
 
 
 
 
 
 
 
 
In-/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
MGMT test result 
 
X 
 
 
 
 
 
 
 
 
Cerebral MRI 
 
X5 
 
 
 
 
 
X5 
X5 
 
Demographics 
X 
X16 
 
 
 
 
 
 
 
 
Urine or Serum  β-HCG (females)6 
 
X 
 
 
 
 
 
 
X 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
Echo or MUGA7 
 
X 
 
 
 
 
 
 
X 
 
Physical Examination8 
 
X 
 
 
X 
 
X 
X  
X  
 
12 Lead Digital ECG 
 
X 
 
X 
 
 
 
X9 
X  
 
MMSE 
 
 
X 
 
 
 
 
X10 
X 
 
Karnofsky performance score 
 
X 
 
 
 
 
X 
X  
X 
X 
Concomitant Therapy 
 
X 
X 
X 
X 
X 
X 
X  
X 
X 
Vital Signs 
 
X 
X 
X 
X 
X 
X 
X  
X 
 
Safety lab11 
 
X 
X 
X 
X 
X 
X 
X  
X 
X 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X  
X 
X12 
Compliance check 
 
 
 
X 
X 
X 
X 
X  
X 
 
Blood samples for PK13 
 
 
 
X 
X 
X 
 
 
 
 
Dispense study medications 
 
 
X 
 
 
X 
X 
X  
 
 
Radiotherapy14 
 
 
2 Gy once daily five days per week, total dose 60 Gy 
 
 
 
BIBW 2992 administration 
 
 
Continuous oral once daily15 
 
 
Termination of study medication 
 
 
 
 
 
 
 
 
X 
 
a x is the number of treatment (cycle) 
1 Written informed consent must be obtained before any study specific procedures are performed. This is a 2 steps consent. Informed consent number 1 must include consent to 
collection of demographic data and consent to send tumour sample from surgery to central laboratory for MGMT status assessment. If MGMT status already available (see 
section 5.6.1.1), patients will not need to sign Informed consent number 1 but only Informed consent number 2. Informed consent number 2 will be obtained for patients who 
have their MGMT test status result available and must include consent to all study procedures.  


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2 Visit frequency will be as follows: every month for the first 6 months after RT (C1 to C6), every 2 months thereafter for the next six months (C8,C10,C12) and then every three 
months for the following year (C15,C18,C21, C24), and every 6 months thereafter (C30, C36……). During the maintenance treatment phase visits should be performed as 
scheduled wherever possible, but within 2 days of the schedule date. 
3 EOT: end of treatment visit; within 5 calendar days after permanent termination of trial drug intake. Investigations to be performed instead of the scheduled visit when a patient 
discontinues study treatment permanently. If permanent discontinuation of study drug falls on a scheduled visit, examinations as defined for EOT should be performed instead of 
the examinations of the scheduled visit.  
4  FU: Follow-up visit: 28 days (±4) after EOT.  
5 Early postoperative MRI (within 72 hours after initial surgery) preferable. In case a patient did not perform a Gd-enhanced MRI within 72 hours post surgery, a Gd-MRI is to be 
performed prior to start of study treatment MRIs should be performed between day 21 and day 28 of Cycle 2, 4, 6, 8, 10 and 12. In the second year, MRIs are performed every 3 
months (Cycle 15, 18, 21, 24) and every six months thereafter  (Cycle 30, 36…). The EOT MRI/tumour assessments are not required if performed in the previous 4 weeks. 
6 For women of childbearing potential only. 
7 Same method (Echo or MUGA) must be performed throughout study. 
8 Includes height (at screening only) and weight. 
9 ECG will be performed at Cycle 2 and every 8 weeks thereafter until cycle 12 (Cycle 4, 6, 8, 10, 12.) and then every three months for the following year (C15, C18, C21, C24), 
and every 6 months thereafter (C30, C36……). 
10 MMSE will be repeated at Cycle 2, 4, 6, 8,10 ,12 and then every three months for the following year (C15, C18, C21, C24), and every 6 months thereafter (C30, C36……). 
11 Includes CBC, serum biochemistry, and urinalysis, see Section 5.2.6 for details. 
12 If not recovered at EOT, or new drug related AE  
13 For detailed timing refer to Section 5.5.1 and 10.1 
14 RT should be performed between 2 weeks and 6 weeks post surgery 
15 Patients will receive adjuvant BIBW 2992 daily until either progressive disease or undue adverse reaction, whatever occurs first 
16 Only for patients who already had their proven MGMT promoter status before screening (section 5.6.1.1) and did not need to sign the informed consent number 1 


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FLOW CHART –REGIMEN M: METHYLATED OR UNMETHYLATED* MGMT PROMOTER 
Study Periods 
Screening 
Period 
 
Concomitant Treatment Period (Day 1-42) 
Four 
weeks 
TMZ 
break 
Maintenance 
Treatment Period2 
End of 
Treatm
ent 
Follow 
-up 
C1 to C6  
C8 & 
onward 
Visit abbreviation 
SV1 
SV2 
RT1 
RT2 
RT3 
RT4 
RT5 
 
BREAK 
CxV1a 
CxV1a 
EOT3 
FU4 
Day 
d-35 to -1 
1 
8 
15 
29 
42 
70 
+d28 
+d28 
 
 
Informed Consent1 
X 
X 
 
 
 
 
 
 
 
 
 
 
In-/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
MGMT test result 
 
X 
 
 
 
 
 
 
 
 
 
 
Cerebral MRI/ 
Tumour assessment 
 
X5 
 
 
 
 
 
 
X5 
X5 
X5 
 
Demographics 
X 
X17 
 
 
 
 
 
 
 
 
 
 
Urine or Serum β-HCG 
(females)6 
 
X 
 
 
 
 
 
 
 
 
X 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
Echo or MUGA7 
 
X 
 
 
 
 
 
 
 
 
X 
 
Physical Examination8 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
12 Lead Digital ECG 
 
X 
 
X 
 
 
 
X 
X9 
X9 
X 
 
MMSE  
 
 
X 
 
 
 
 
 
X10 
X10 
X 
 
Karnofsky performance score 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
Concomitant Therapy 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety lab11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
Compliance check 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood samples for PK13 
 
 
 
X 
X 
X 
 
 
 
 
 
 
Dispense study medications 
 
 
X18 
 
X18 
X18 
X18 
X 
X 
X 
 
 
Radiotherapy14 
 
 
2 Gy once daily five days per week, total dose 60 Gy 
 
 
 
 
 
Temozolomide administration 
 
 
Continuous oral once daily (75mg) 
 
X15 
 
 
 
BIBW 2992 administration 
 
 
Continuous oral once daily16 
 
 
Termination of study 
medication 
 
 
 
 
 
 
 
 
 
 
X 
 


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*  Patients with unmethylated MGMT status will be able to enter in the BIBW 2992 and TMZ in combination with radiotherapy group once the Maximum Tolerated Dose (MTD)  
    of the combination of BIBW 2992 with radiotherapy in the group of patients with unmethylated MGMT status is determined. 
a x is the number of treatment (cycle) 
1 Written informed consent must be obtained before any study specific procedures are performed. This is a 2 steps consent. Informed consent number 1 must include consent to collection of 
demographic data and consent to send tumour sample from surgery to central laboratory for MGMT status assessment. If MGMT status already available (see section 5.6.1.1), patients will 
not need to sign Informed consent number 1 but only Informed consent number 2. Informed consent number 2 will be obtained for patients who have their MGMT test status result and 
must include consent to all study procedures.  
2 Visit frequency will be as follows: every month during concomitant BIBW2992 and TMZ treatment period(C1 to C6), every 2 months thereafter for the next six months (C8,C10,C12) and 
then every three months for the next year (C15, C18 ,C21 ,C24), and every 6 months thereafter (C30, C36……). During the maintenance treatment phase visits should be performed as 
scheduled wherever possible, but within 2 days of the schedule date. 
3 EOT: end of treatment visit; within 5 calendar days after permanent termination of trial drug intake. Investigations to be performed instead of the scheduled visit when a patient 
discontinues study treatment permanently. If permanent discontinuation of study drug falls on a scheduled visit, examinations as defined for EOT should be performed instead of the 
examinations of the scheduled visit.  
4  FU: follow-up visit: 28 days (±4) after EOT. 
5 Early postoperative MRI (within 72 hours after initial surgery) preferable. In case a patient did not perform a Gd-enhanced MRI within 72 hours post surgery, a Gd-MRI is to be performed 
prior to start of study treatment. MRIs should be performed between day 21 and day 28 of Cycle 1, 3, 5, 8, 10 and 12. In the second year, MRIs are performed every 3 months (Cycle 15, 
18, 21, 24) and every six months thereafter (Cycle 30, 36….). The EOT MRI/tumour assessments are not required if performed in the previous 4 weeks. 
6 For women of childbearing potential only. 
7 Same method (Echo or MUGA) must be performed throughout study. 
8 Includes height (at screening only) and weight. 
9 ECG will be performed at Cycle 1, 3, 5, 8, 10, 12) and then every three months for the following year (C15, C18, C21, C24), and every 6 months thereafter (C30, C36……). 
10  MMSE will be repeated at Cycle 1, 3, 5, 8,10 ,12 and then every three months for the following year (C15, C18, C21, C24), and every 6 months thereafter (C30, C36……). 
11 Includes CBC, serum biochemistry, and urinalysis, see Section 5.2.6 for details. 
12 If not recovered at EOT, or new drug related AE 
13 For detailed timing refer to Section 5.5.1 and 10.1 
14 RT should be performed between 2 weeks and 6 weeks post surgery 
15 Cycle 1: 150mg/m2 days 1-5, Cycle 2 up to cycle 6: 200 mg/m2 days 1-5 of each cycle, if tolerated. 
16 Patients will receive adjuvant BIBW 2992 daily until either progressive disease or undue adverse reaction, whatever occurs first 
17 Only for patients who already had their proven MGMT promoter status before screening (section 5.6.1.1) and did not need to sign the informed consent number 1 
18During Radiotherapy: TMZ will be dispensed every 2 weeks (RT1,RT3, RT4) – BIBW2992 will be dispensed at RT1 and RT4 and RT5 


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ABBREVIATIONS 
AE 
Adverse Event 
Akt/AKT 
Serine-threonine kinase also known as protein kinase B (PKB) 
(Biomarker) 
ALT (SGPT) 
Alanine amino Transferase (Serum Glutamate Pyruvate Transaminase) 
ANC 
Absolute Neutrophil Count 
AST (SGOT) 
Aspartate amino Transferase (Serum Glutamic Oxaloacetic 
Transaminase 
AUCt1-t2 
Area under the concentration-time curve of the analyte in plasma over 
the respective time interval, where t1 and t2 define beginning and end 
times of the time interval [ng⋅h/mL] 
AUC 
Area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval τ 
BBB 
Blood-Brain-Barrier 
BI 
Boehringer Ingelheim 
BIBW 2992 
BIBW 2992 (dimaleinate salt – MA2) 
BLQ 
Below limit of quantification 
BP 
Blood Pressure 
C 
Cycle 
°C 
Degree Centigrade 
Cmax 
Maximum measured concentration of the analyte in plasma 
CML 
Clinical Monitor Local 
CR 
Complete Response 
CRA 
Clinical Research Assistant/Associate 
CRF/eCRF 
Case Report Form / electronic Case Report Form 
CTC(AE) 
Common Terminology Criteria (for Adverse Events) 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
CYP3A4 
Cytochrome P450 isoenzyme 
DILI 
Drug induced liver injury 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EGF 
Epidermal Growth Factor 
EGFR 
Epidermal Growth Factor Receptor 
EGFRvIII 
vIII mutant of the EGFR 
EOT(V) 
End of Treatment (Visit) 
F 
Absolute bioavailability factor 
FDA 
Food and Drug Administration 


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FISH 
Fluorescent In Situ Hybridization 
FU(V) 
Follow-up (Visit) 
GBM 
Glioblastoma multiforme 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
gMean 
Geometric mean 
HCG 
Human Chorionic Gonadotropin 
HDPE 
High Density Polyethylene 
HER 2, 3, 4 
Human Epidermal Growth Factor Receptor Class I tyrosine kinase 
receptor(s) 
HPLC 
High Performance Liquid Chromatography 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
KPS 
Karnofsky Performance Scale 
LVEF 
Left Ventricular Ejection Fraction 
µmol 
Micromol 
MGMT 
O6-methylguanine-DNA methyltransferase 
mmHg 
Millimeter mercury 
MCV 
Mean Corpuscular Volume 
MDR1 
Multi Drug-Resistance Protein 1 
MMSE 
Mini Mental State Examination 
MRI 
Magnetic Resonance Imaging 
MS/MS 
Tandem Mass Spectrometry 
MTD 
Maximum Tolerated Dose 
MUGA 
Multigated Acquisition Scan 
N 
Number, number of doses at uniform intervals τ 
nM 
Nanomolar 
nMh 
Nanomolar per hour 
NCI 
National Cancer Institute 
NOP 
No Peak Detectable 
NOR 
No valid Result 
NOS 
No sample available 
NSCLC 
Non-small cell lung cancer 
O*C 
Oracle Clinical 
PD 
Progressive Disease 
Per os 
orally 


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PFS 
Progression-free Survival 
 
PK 
Pharmacokinetic 
PO 
Per Os (by mouth) 
PP 
Polypropylene 
PR 
Partial Response  
PTEN 
Phosphatase and Tensin Homologue- a tumour suppressor gene/protein 
PTM 
Planned Time 
QT 
ECG interval/measurement 
RBC 
Red Blood cell Count 
RT 
Radiotherapy 
s 
Second 
SAE 
Serious Adverse Event 
SCC 
Squamous Cell Carcinoma 
SD 
Stable Disease 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
τ 
Dosing interval 
t1/2 
Terminal half-life of the analyte in plasma 
TGF-alpha 
Transforming Growth Factor-alpha 
TKI 
Tyrosinekinase Inhibitor 
tmax 
Time from dosing to the maximum concentration of the analyte in 
plasma 
TMZ 
temozolomide 
TTM 
Termination of trial medication 
WBC 
White blood cell count 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
1.1 
MEDICAL BACKGROUND 
Approximately 42,000 new cases of primary brain tumours are diagnosed annually in the US, 
EU-5 and Japan. Malignant gliomas are the most common type. Malignant gliomas comprises 
WHO grade IV tumours, such as glioblastoma multiforme (GBM; ~ 55% of all brain 
tumours) and WHO grade III tumours (e.g. anaplastic astrocytoma, oligodendroglioma, and 
oligoastrocytoma). 
Glioblastoma multiforme is the most frequent malignant glioma and is associated with a 
particularly aggressive course and poor prognosis. Little improvement in overall survival 
(OS) or progression-free survival (PFS) has been achieved in the past 20 years. Surgical 
resection and radiotherapy have been the mainstay of treatment; only recently the benefits of 
chemotherapy have been shown in a randomised trial testing the combination of 
temozolomide (TMZ) with radiotherapy followed by maintenance (adjuvant) TMZ against 
radiotherapy alone in patients with newly diagnosed GBM. Based on demonstrated improved 
OS, TMZ plus radiotherapy followed by TMZ maintenance therapy is considered standard 
treatment for newly diagnosed GBM (R08-1056). 
There are several reasons for the poor response of GBM. First, tumour cells extensively 
infiltrate the surrounding brain parenchyma, thereby limiting the overall utility of surgical 
resection. Second, the blood-brain barrier is an obstacle to the adequate delivery of 
chemotherapy agents for brain tumours, particularly the infiltrating component of tumour 
where the malignant cells are intercalated in the normal brain parenchyma. Only small and 
lipophilic molecules are able to cross the intact blood-brain barrier to reach these deep-sitting 
tumour cells. Although contrast enhancement on imaging studies does indicate a partial 
disruption of the blood-brain barrier, this represents only a part of these diffusely infiltrating 
tumours. Third, GBM is refractory to most cancer cytotoxic agents, and occasional responses 
are short-lived with development of resistance, a direct consequence of genetic 
transformation and tumour heterogeneity characteristic of this neoplasm. 
Patients with glioblastoma and malignant gliomas with a methylated promoter of the MGMT-
DNA-repair gene have a better survival and progression-free survival than patients with an 
unmethylated MGMT promoter who express high levels of this DNA-repair enzyme 
compromising the therapeutic effect of TMZ (R08-5066). 
Preclinical and clinical studies have suggested that EGFR activation may contribute to 
radiation resistance (R09-0092, R09-0099, R09-0094, R09-0097) and that EGFR-mediated 
radiation resistance can be abrogated by inhibiting EGFR (R09-0183, R09-0093). 
Several types of epidermal growth factor receptor (EGFR) gene mutations have been reported 
in GBMs, and in nearly all cases the alterations have been reported in tumours with EGFR 
amplification (R08-1064). Although mutations in the EGFR kinase regions have not been 
detected in malignant glioma as they have in some subtypes of non-small cell lung cancer, 
(R08-1064, R08-1063, R06-1645), about 40% of tumours with EGFR amplification express 
the mutant receptor EGFRvIII (R06-1645). The EGFRvIII mutation represents an in-frame 


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deletion of exons 2-7 from the EGFR extracellular domain that causes a defect in the 
extracellular ligand binding domain and constitutive activation in a ligand-independent 
manner. A recent analysis of 649 cases of GBMs revealed that EGFRvIII positivity is an 
independent prognostic factor for poor survival (R06-1645) and may provide a rationale for 
the clinical development of BIBW 2992 in GBM. Thus, EGFR plays a major role in the 
pathogenesis of malignant glioma and provides rational development of EGFR targeted 
therapies. 
1.2 
DRUG PROFILE 
1.2.1 
BIBW 2992 
BIBW 2992 is a highly selective and potent low molecular weight, irreversible inhibitor of 
the erbB-family of tyrosine kinase receptors EGFR (erbB1 / HER1) and HER 2 (erbB2). All 
references in this protocol concerning BIBW 2992 refer to the free base compound BIBW 
2992 BS which is used as the oral formulation (U03-3218).  
The potency of BIBW 2992 was determined in enzymatic assays using recombinant human 
wild-type EGFR (IC50 0.5 nM) and HER2 (IC50 14 nm) (U03-3218). A panel of 
recombinant human kinases tested in parallel was not inhibited, demonstrating the high target 
specificity of BIBW 2992 (U03-3218). Molecular modeling revealed that BIBW 2992 binds 
covalently and with high affinity to Cys773 within the catalytic cleft of the ATP-binding 
pocket of the EGF receptor. It has been reported that this specific molecular interaction 
results in irreversible inhibition of the EGFR tyrosine kinase domain (R02-2292). 
Experimental data from in vitro washout studies confirmed the irreversible binding of BIBW 
2992 to its molecular target. In constitutively EGFR-overexpressing A431 human epidermoid 
cancer cells, BIBW 2992 inhibition of EGFR-signaling lasted for up to 7 hours after removal 
of the compound from the cell cultures (U03-3218). In contrast, A431 cells exposed to 
reversible EGFR TKIs regained full receptor function almost immediately after inhibitor 
washout. 
The efficacy and potency of BIBW 2992 was demonstrated in vitro in receptor 
phosphorylation and cell proliferation assays in various human cancer cell models (P06-
08275, U07-1338-01). 
The specific activity of BIBW 2992 was determined in two independent in vitro assay 
systems: i) EGF-induced EGFR autophosphorylation using immunoprecipitation and Western 
blot and ii) clonogenic, anchorage-independent cell growth in a soft-agar assay system (P06-
08275). 
The in vivo activity of BIBW 2992 against EGFR was investigated in an A431 subcutaneous 
xenograft model (U03-3218). Daily oral treatment with BIBW 2992 at doses of 20 mg/kg 
resulted in an almost complete inhibition of tumour growth over a period of 25 days. Similar 
anti-tumour activity was observed in NCI-N87 tumour bearing mice treated with BIBW 2992 
at similar concentrations. In these in vivo studies, BIBW 2992 plasma concentrations of 80-
285 nM corresponding to an AUC0-24 of 589-3198 nM*h were required for anti-tumour 


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activity. All BIBW 2992 doses shown to be effective in mouse xenograft models were well 
tolerated. 
Limitations imposed by the Blood Brain Barrier (BBB) may have an impact on the clinical 
activity of EGFR TKIs. BIBW 2992 does not cross the BBB in healthy rats (U03-1562). It 
can be assumed that due to the disrupted BBB in human GBMs BIBW 2992 might reach the 
contrast-agent enhancing part of the tumor. Also, brain metastases in some patients with 
NSCLC have responded to treatment with BIBW 2992. 
BIBW 2992 is a potent, irreversible, orally available EGFR/HER2 tyrosine kinase inhibitor 
displaying significant anti-tumour activity in a once daily dosing schedule. It did not show 
relevant inhibition of cytochrome P450 isoenzymes, but BIBW 2992 is a CYP3A4 substrate 
(U05-1723-01), although this metabolic pathway is not the dominant one. Drug-drug 
interactions with CYP3A4 inducers or inhibitors are not expected. 
BIBW 2992 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 BIBW 2992  when 
taken simultaneously with or 6 h after BIBW 2992  but increased the bioavailability of BIBW 
2992  (single dose of 20 mg) by 48% and 39% for AUC0-∞ and Cmax when given 1 h before 
BIBW 2992, respectively. Pretreatment with the potent P-gp inducer rifampicin decreased the 
plasma exposure of 40 mg BIBW 2992 by 34 % BIBW 2992 (AUC0-∞) and 22 % (Cmax), 
respectively. Caution should be exercised when combining BIBW 2992 with potent P-gp 
modulators. 
 
Preclinical Pharmacology and toxicology profile 
The absolute bioavailability of BIBW 2992 after oral ingestion is 45% in rats with a median 
tmax reached after 4 hours and a terminal half-life (t1/2) of 4.5 hours. In rats the exposure was 
dose proportional and no gender-related effects or compound accumulation was observed. 
BIBW 2992 is primarily excreted via the faeces. No relevant inhibition of cytochrome P450 
isoenzymes was found. BIBW 2992 is however a CYP3A4 substrate (U05-1723-01). Since 
this is not considered a dominant metabolic pathway, in vitro drug-drug interactions with 
CYP3A4 inducers or inhibitors are not expected (U03-3218). 
In vivo BIBW 2992 was metabolised only to a minor extent and the metabolism was 
governed by adduct formation to proteins or nucleophilic small molecules. It was found that 
metabolism is of subordinate role for BIBW 2992 and that enzyme-catalyzed metabolic 
reactions play a negligible role for the metabolism of BIBW 2992 in vivo. Only approx. 2 % 
of the dose were metabolised by FMO3 in vivo. The CYP3A4-dependent N-demethylation 
was even too low to be quantitatively detected in human volunteers (U07-1737, U06-2055-
01, U07-1296-01). Therefore, intrinsic (e.g. genetic predisposition) or extrinsic (e.g. by 
comedications) effects on the activity of FMO3 or CYP3A4 in vivo are expected to be of 
little, if any, relevance for the pharmacokinetics of BIBW 2992. 


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The human ADME data confirmed the results of the preclinical [14C] ADME studies and all 
metabolites of the human [14C] ADME study were observed in the rat or the minipig (see 
U04-1028 and U06-1093), respectively). 
In acute toxicology studies, oral administration of single doses in rats and mice indicated a 
low acute toxic potential of BIBW 2992. Changes in renal and hepatic function occurred only 
at doses that were 10-30 fold above the levels required for antitumour activity. BIBW 2992 
had effects on gastrointestinal function that were dose-dependent and in high doses, leading 
to profound inhibition. No acute toxic effects on the central nervous system were detected. 
In oral repeated dose studies for up to 26 weeks in rats and minipigs, the main target organs 
were the gastrointestinal tract (rats and minipigs), kidneys (rat), and the skin (rats). In the 
gastrointestinal tract, increasing systemic exposure was associated with dose-dependent 
atrophy of the epithelium and concomitant focal erosions/ulcerations in the stomach of rats 
and minipigs. Clinically this resulted in diarrhoea in both species and faecal occult blood in a 
single minipig. In rat kidneys papillary necrosis and dilated tubules were found. Similar 
pathologic findings, i.e., papillary necrosis in rats and dogs have been described previously 
for the EGFR-small molecule inhibitor gefitinib. However, nephrotoxicity has not been 
reported as a side-effect of gefitinib therapy in humans. A secondary pathophysiologic effect 
on renal function in BIBW 2992-treated animals due to diarrhoea-induced dehydration and 
emaciation has to also be considered. 
Cutaneous alterations, i.e., epithelial atrophy were observed in rats. However, BIBW 2992 is 
not irritating to intact skin in albino rabbits and the effects observed in rats are most likely 
related to the specific pharmacodynamic mechanism of EGFR-inhibition (U03-3218). 
A variety of organs including the aerodigestive tract and reproductive organs were affected 
by epithelial atrophy. These atrophic changes were not severe and fully reversed during a 2-
week recovery period. 
Minor cardiovascular effects (increased blood pressure and heart rate) and a dose-dependent 
decrease of QT time in the electrocardiogram (ECG) occurred in BIBW 2992-treated 
minipigs. These data do not indicate a risk for QT-prolongation related arrhythmia. BIBW 
2992 had no pro-arrhythmic potential, as determined by the effects on HERG-mediated 
potassium current or on guinea pig papillary muscle action potential configuration. 
BIBW 2992 demonstrated mutagenic potential in bacteria but had no genotoxic potential in 
vivo even at highly toxic/lethal doses in animals. Because of its specific pharmacodynamic 
mechanism of action, BIBW 2992 is potentially embryo/foetotoxic and/or teratogenic. 
Preclinical GBM related pharmacology experiments 
Although BIBW 2992 did not sensitize head and neck cancer cells (FaDu) to radiotherapy in 
vitro, in a FaDu xenograft model the anti-tumour activity of a single 20 Gy irradiation dose 
was significantly improved by subsequent daily BIBW 2992 treatment (U04-2147). 
Therefore, the available preclinical data support further studies in combining BIBW 2992 
with radiation therapy. 


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In transfected cell lines, the EGFRvIII mutation confers a high level of resistance to 
reversible receptor kinase inhibitors such (first generation TKIs) such as gefitinib and 
erlotinib in contrast to irreversible inhibitors like HKI-272 and BIBW 2992, with the latter 
being the most potent compound in these cell lines. This might explain at least in part why 
reversible TKIs such as gefitinib and erlotinib have shown only modest activity when 
investigated in several studies in recurrent (R09-0277, R09-0095 R09-0524, R09-0525) or 
newly diagnosed malignant glioma (R09-0184). 
The above studies also demonstrated that dose escalations of gefitinib and erlotinib were 
necessary in patients on enzyme-inducing anti-epileptic drugs (EIAEDs), frequently used in 
patients with malignant gliomas. These compounds (EIAEDs) are known to profoundly 
diminish exposures to several molecular targeting cancer therapeutics as well as 
chemotherapeutics. In contrast, the metabolism of BIBW 2992 is not expected to be affected 
by concurrent administration of cytochrom P450-enzyme-inducing medications. Thus, it is 
expected that patients treated with BIBW 2992 will have more consistent drug exposure of 
the tumour compared to other EGFR inhibitors for GBM patients, regardless of concurrent 
anti-epileptic agent administration. 
BIBW 2992 Phase I and Phase II trial program 
Nine Phase I open-label trials are completed or ongoing with BIBW 2992 including a roll-
over trial. As of September 2008, 439 patients with advanced solid tumours have been 
exposed to BIBW 2992 alone or in combination with docetaxel or paclitaxel in these trials 
with doses ranging from 10mg to 160mg daily.  
BIBW 2992 showed moderately fast absorption with median tmax values between 1 h to 6 h 
after administration. The gMean terminal half-life (t1/2) of BIBW 2992 mainly ranged 
between 13 h to 57 h. In general, the maximum blood concentration (Cmax) and the integral of 
the concentration time curve (AUC) of BIBW 2992 increased in a dose-proportional way 
(U03-3218). BIBW 2992 displayed a food effect with a decreased systemic exposure in the 
fed state compared to administration of BIBW 2992 under fasted conditions. Steady state was 
reached within 8 days after the first administration. 
Currently, a combined phase I/II study (1200.36 study) in patients with recurrent GBM is 
conducted in the US. The study determines the MTD and pharmacokinetics of BIBW 2992 
administered in combination with TMZ (phase I part). In the phase II part of the study the 
efficacy and safety of BIBW 2992 monotherapy and BIBW 2992 / TMZ combination therapy 
compared to TMZ monotherapy (three treatment arms) is estimated. Data from the phase I 
part of this trial indicate that 40mg of BIBW 2992 in combination with TMZ is well 
tolerated. 
The maximum tolerated dose (MTD) of BIBW 2992 was identified as 50mg once daily in 
phase I continuous dosing monotherapy trials. 
The Adverse Events (AEs) observed to date in Phase I and Phase II trials are consistent with 
those reported for other EGFR tyrosine kinase inhibitors (dose dependent diarrhoea and skin-
related adverse events including rash and acne). Other AEs were in the expected range for 


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patients with advanced cancer disease (U03-3218). In the BIBW 2992 Phase I monotherapy 
trials, the most frequent drug-related adverse events were associated with gastrointestinal 
disorders (diarrhoea, nausea, vomiting, stomatitis), skin and subcutaneous tissue disorders 
(rash, dry skin, pruritus, acneiform rash, and acne), general disorders and administration site 
conditions (fatigue, mucosal inflammation), respiratory disorders (epistaxis), and metabolism 
and nutritional disorders (anorexia, dehydration). 
Diarrhoea is the single most often reported gastrointestinal AE. An increased incidence of 
diarrhoea grade 3 (22.4%) has been observed in phase II monotherapy trials (starting dose of 
50 mg qd). Prompt and proactive management of diarrhoea together with timely treatment 
pause and dose reduction is crucial to reduce the severity of diarrhoea and its potential 
complications such as dehydration leading to serum electrolyte changes (hyponatraemia, 
hypokalaemia and hypomagnesaemia) and/or renal impairment.  
Nausea and vomiting are the other commonly reported gastrointestinal adverse events and 
can be generally managed successfully with the use of antiemetics.   
Skin related adverse events present in a number of forms, i.e., rash (including erythematous, 
maculo-papular, papular, etc.), acne, dermatitis acneiform, dry skin, skin reaction and 
pruritis. Folliculitis as well as nail changes (including paronychia) are other reported 
manifestations of skin-related adverse events with BIBW 2992. Early and adequate 
management of skin-related adverse events can reduce the frequency and the severity of them 
(R07-4077). 
1.2.2 
Temozolomide 
Temozolomide (TMZ) is an orally administered, second generation imidazotetrazine prodrug 
with essentially 100% oral bioavailability. TMZ spontaneously converts to the active 
alkylating agent 5-(3-methyltriazen-1-yl) imidazole-4- carboximide (MTIC) with extensive 
tissue distribution, including penetration of the blood–brain barrier and the cerebrospinal 
fluid. TMZ has notable antitumour activity against recurrent GBM (R08-1057), recurrent 
anaplastic astrocytoma, and advanced malignant melanoma, and other refractory cancers. 
TMZ has shown activity when added to radiotherapy for treatment of newly diagnosed GBM 
(R08-1056).   
TMZ is rapidly absorbed and spontaneously converts to the active metabolite MTIC. 
Maximum plasma concentrations are observed 30 to 90 minutes after oral intake, and the 
plasma half-life is approximately 2 hours, with some delayed absorption when taken with 
food. Pharmacokinetics in the CSF compared with plasma showed an AUC of approximately 
20% of the AUC. Patients usually tolerate TMZ well; mild to moderate adverse effects are 
nausea and vomiting that are usually easily controlled with standard antiemetic drugs, 
constipation, and some fatigue. The most serious and dose-limiting toxicity, observed in less 
than 10% of patients, is noncumulative myelosuppression, particularly thrombocytopenia 
occurring 3 to 4 weeks after treatment start,  
TMZ is indicated for the treatment of patients with newly diagnosed glioblastoma multiforme 
concomitantly with radiotherapy and subsequently as monotherapy treatment. TMZ is also 


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indicated for treatment of malignant glioma, showing recurrence or progression after standard 
therapy. In the concomitant phase TMZ is administered orally at a dose of 75 mg/m2 daily for 
42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions) without 
dose reductions, but delay or discontinuation of TMZ can be considered weekly according to 
haematological and non-haematological side effect criteria. The TMZ is usually continued 
throughout the 42 day concomitant period (up to 49 days) in absence of adverse reaction.  
Four weeks after completing the TMZ + Radiotherapy phase, TMZ is administered for up to 
6 cycles of monotherapy treatment. The dose in cycle 1 (monotherapy) is 150 mg/m2 once 
daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is 
escalated to 200 mg/m2 in absence of side effects. 
In this study, patients are stratified according to the methylation status of the MGMT 
promoter: patients with unmethylated MGMT status will received BIBW 2992 only and 
patients with methylated MGMT status will received BIBW 2992 and TMZ, both in 
combination with radiotherapy. The rationale for this design is based on an increasing body 
of evidence that patients with an unmethylated MGMT promotor only marginally if at all 
benefit from the addition of TMZ to standard radiotherapy (R08-5066, R08-5067, R08-5252, 
R08-5253, R08-5254, R08-5255, R08-5256, R08-5429). Moreover, an international group of 
investigators from the US, Canada, and Europe is collaborating on trial RTOG 0525 in which 
both clinical and molecular markers are being used to prospectively assess MGMTpromoter 
methylation status. This trial results are expected to validate MGMT promoter methylation as 
a molecular marker of response and/or prognosis. The trial accrued 1,153 patients and results 
are expected in about 1.5 years. 
In 2005 Hegi et al showed an advantage regarding Progression Free Survival for treatment 
with TMZ in addition to RT only for patients whose tumours had a methylated MGMT 
promoter (R08-5067). However, results of the 5-year OS analysis of the EORTC-NCIC trial 
comparing RT with concomitant and adjuvant TMZ versus RT alone showed some survival 
benefit for patients treated with TMZ and RT regardless of the methylation status of their 
tumours. In a subgroup of 60 patients with unmethylated MGMT the median Overall Survival 
was 12.6 months in the combined treatment arm versus 11.8 months in the RT only arm [HR 
0.6, 95% CI 0.4-8 (R10-6416). While the study was not powered to show significant 
interaction between treatment and MGMT-status and the finding is based only on a few 
patients who were alive after more than 2 years, it suggests that at least no detrimental effect 
of combined treatment with TMZ and RT is to be expected in patients with unmethylated 
tumours. In view of these data, once the MTD of BIBW2992 in combination with 
Radiotherapy will be determined in patients with unmethylated MGMT status, patients with 
unmethylated MGMT status will be able to enter in the BIBW 2992 and TMZ in combination 
with radiotherapy group. 
1.2.3 
Radiotherapy 
Radiotherapy in combination with temozolomide is standard in the treatment of newly 
diagnosed glioma. Recent data published by Brown et al (R09-0184) about combining 
another small molecule TK-inhibitor (erlotinib) with radiotherapy and temozolomide did not 
show an increase in any of the known TKI related skin toxicities such as rash. This might be 


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explained by the fact the area of radiation exposed skin is rather small. In analogy, an 
increase in skin toxicities is not expected when combining radiotherapy with BIBW 2992. 
1.3 
RATIONALE FOR PERFORMING THE TRIAL 
The rationale of adding BIBW 2992 to standard radiotherapy (with or without TMZ, 
depending on the methylation status of the MGMT promotor) is based on findings that the 
tyrosine kinase EGFR has been implicated in supporting oncogenesis and progression of 
human solid tumours and is a promising target for anticancer therapy. EGFR is amplified in 
approximately 50% of GBMs (R08-1064) and is overexpressed in over 60% of malignant 
gliomas independent of amplification status (R08-1063). 
Because of the redundancy of the EGFR signaling pathway but also because of expected 
additive effects, combining BIBW 2992 with standard radiotherapy and alkylating agents like 
TMZ might result in complementary action and be superior compared to the single agent 
therapeutic approach in newly diagnosed malignant glioma. TMZ as the chemotherapeutic 
agent to be combined with BIBW 2992 is expected to show additive activity, complimentary 
mechanisms of action, non-overlapping toxicities, and a lack of PK interaction. 
Both, the preclinical profile of BIBW 2992 (superior efficacy in tumour cell lines harboring 
the EGFRvIII mutation compared to gefitinib and erlotinib, irreversible mode of action) and 
the clinical profile of this compound (efficacy in EGFR-driven tumours and favorable safety 
profile) supports this Phase I/II exploratory approach in GBM. 
1.4 
BENEFIT - RISK ASSESSMENT 
The outcome for patients diagnosed with GBM is poor, with a median overall survival of 
only little more than a year. In the past tyrosine kinase inhibitors have been developed to 
target the molecular pathways involved in tumour growth. There is evidence that these 
agents are effective in GBM and particularly in the subgroup of patients whose tumours 
harbour mutations like EGFRvIII. 
The currently available preclinical data indicate that BIBW 2992 has a potency which is 
potentially superior to reversible EGFR TKIs (gefitinib, erlotinib) (P08-06904). 
 
Since the adverse reaction profile of TMZ is different from BIBW 2992, significant 
overlapping side effects are not expected. In a phase I/II trial of erlotinib and TMZ with RT 
in the treatment of newly diagnosed GBM no cumulative effect between RT and the EGFR 
inhibitor have been reported (R09-0184). 
The most common side effects with BIBW 2992 are expected to be primarily gastrointestinal 
(including diarrhoea, nausea, vomiting and anorexia) as well as fatigue and rash. Proactive 
management of these common side effects and the proposed dose reduction scheme will 
ensure that the proposed regimen is well tolerated. Although skin and gastrointestinal adverse 
events are common with BIBW 2992, they are rarely serious and almost always reversible. 
Regular and frequent assessment of safety parameters and brain MRIs throughout Study 


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1200.38 will ensure that any patient not deriving clinical benefit will be withdrawn from the 
trial treatment. 
Although rare, a 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. 
Considering the poor outcome in this group of patients and the need for the development of 
specific treatments with less side effects, it is expected that the benefits of therapy with 
BIBW 2992 will outweigh the risks. 


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2. 
TRIAL OBJECTIVES 
2.1 
GENERAL AIM - OBJECTIVES 
Determine the Maximum Tolerated Dose (MTD), safety, pharmacokinetics, and efficacy of: 
- BIBW 2992 administered in combination with RT in patients with newly diagnosed 
malignant gliomas (WHO grade IV) with an unmethylated MGMT-promoter 
(Regimen U).  
- BIBW 2992 in combination with TMZ and radiotherapy (RT) in patients with newly 
diagnosed malignant gliomas (WHO grade IV) with a methylated or unmethylated* 
MGMT-promoter (Regimen M). 
 
* If MTD in Regimen U is defined before MTD in Regimen M. Patients may enter in 
Regimen M independently of their MGMT-promoter methylation status 
 
2.2 
PRIMARY ENDPOINTS 
Regimen U: 
 MTD of BIBW 2992 when given concomitantly with radiotherapy (section 5.2.4) 
Regimen M: 
 MTD of BIBW 2992 when given concomitantly with TMZ and radiotherapy (section 5.2.4) 
2.3 
SECONDARY ENDPOINTS 
1) Safety of BIBW 2992: Incidence and intensity of AEs according to Common 
Terminology Criteria (CTCAE v.3.0) (R04-0474) associated with increasing doses of 
BIBW 2992 in regimen U and M 
2) Objective tumour response according to the Macdonald criteria (R08-1053) (Section 
5.1.3). 
3) Pharmacokinetics of BIBW 2992 in combination with radiotherapy (RT) with 
(regimen M) or without (regimen U) concomitant TMZ therapy.  
 


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3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION 
3.1 
OVERALL TRIAL DESIGN AND PLAN – DESCRIPTION 
A standard, “3+3” Phase I dose escalation will be performed to determine the MTD of: 
- Regimen U: BIBW 2992 when administered concomitantly with standard RT in 
patients with histologically-confirmed WHO Grade IV newly diagnosed malignant 
glioma with an unmethylated promoter of the MGMT gene.  
- Regimen M: BIBW 2992 when administered concomitantly with daily TMZ and 
standard RT in patients with histologically-confirmed WHO Grade IV newly 
diagnosed malignant glioma with a methylated promoter of the MGMT gene (patients 
with an unmethylated MGMT-promoter status will be able to enter in Regimen M 
once the MTD in Regimen U is determined).  
 
Patients must have proven MGMT gene promoter methylation status or tumour tissue 
specimens available from the GBM surgery for MGMT status analysis per central pathology 
review. (Section 5.6) 
Informed consent number 1 will need to be signed of by all patients with unknown MGMT 
promotor status before tumour sample are shipped to the study central laboratory. 
Patient who already have proven MGMT gene promoter methylation status available prior 
screening and patients who have received their proven MGMT gene status promoter 
methylation from the study central laboratory will be proposed to take part in the trial (and 
will sign informed consent number 2) if the cohort corresponding to their MGMT gene 
methylation status is open at this time (Figure 3.1.1: 1). 
Once the MTD in Regimen U has been determined, patients will be able to enter in the trial 
before  knowing their MGMT methylation status, however the tumour sample will still need 
to be send to the central Laboratory for testing during the screening phase. These patients will 
only need to sign informed consent number 3. 
 
Both dose escalation arms (U and M) will recruit patients from the beginning of the study. 
 
 
 
 
 
 
 
 
 
 
 
 


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     Unmethylated MGMT 
                          Regimen U : RT+BIBW 2992 BIBW 2992 
 
   Initial Surgery  
   &  
   MGMT Status 
 
                            Regimen M : RT+TMZ+BIBW 2992 
                                                           BIBW 2992+TMZ 
   Methylated* MGMT 
*or Methylated and Unmethylated after determination of MTD in Regimen U 
Figure 3.1: 1 Study design 
In both regimens after RT, patients will receive maintenance BIBW 2992 daily until either 
progressive disease or undue side effect, whatever occurs first. 
In regimen M only, after a 4-week break of TMZ, patients will receive up to six 28-day-
cycles of maintenance TMZ according to the standard 5-day schedule every 28 days (R08-
1056).  
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP 
The aim of this study is to determine the MTD of BIBW 2992 administered in combination 
with a standard fixed dose of temozolomide and standard radiotherapy in patients with 
malignant glioma whose tumours harbor a methylated (or unmethylated) promoter of the 
MGMT gene (regimen M) or in combination with radiotherapy alone in such patients with an 
unmethylated promoter of the MGMT gene (regimen U). To achieve this aim the ‘3+3’ up-
and-down design has been chosen which is a classic dose-finding design for Phase I trials. 
Safety and response data will also be collected until either progression or undue side effects, 
whichever occurs first. 
3.3 
SELECTION OF TRIAL POPULATION 
The study will be performed at about 5 sites in UK. If center(s) are unable to recruit patients, 
additional centers may be recruited and underperforming centers may be closed. 
A log of all patients screened will be maintained in the Investigator Site File (ISF) at the 
investigational site. 
BIBW 2992 
Dose escalation 
Endpoint: MTD


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An estimated total of about 60 patients will be necessary to establish MTD for the 
concomitant administration of: 
- 
BIBW 2992 + TMZ +RT (up to 30 patients in regimen M) 
- 
BIBW 2992 +RT (up to 30 patients in regimen U) 
 
Actual accrual will depend on the number of dose levels tested and Adverse Events observed. 
 
3.3.1 
Inclusion criteria (Regimen U and Regimen M) 
1. Histologically-confirmed WHO Grade IV newly diagnosed malignant glioma.  
2. Proven MGMT gene promoter methylation status before determination of MTD in 
Regimen U only or tumour material available for MGMT testing unless MGMT test 
results already available  
3. Available early postoperative Gd-enhanced MRI (within 72 hours after initial surgery). In 
case a patient did not perform a Gd-enhanced MRI within 72 hours post surgery, a Gd-
MRI is to be performed prior to start of study treatment. 
4. Age ≥18 years and <70 years at entry 
5. KPS ≥70% 
6. Patients receiving corticosteroids have to receive a stable or decreasing dose for at least 
14 days before start of treatment.  
7. Written informed consent that is consistent with local law and ICH-GCP guidelines. 
 
3.3.2 
Exclusion criteria (Regimen U and Regimen M) 
1. Less than two weeks from surgical resection or other major surgical procedure at start of 
treatment. 
2. Planned surgery for other diseases  
3. Placement of Gliadel® wafer at surgery. 
4. Prior or planned radiotherapy of the cranium including brachytherapy and/or radiosurgery 
for GBM. 
5. Treatment with other investigational drugs; participation in another clinical study 
including exposure to the investigational product within the past 4 weeks before start of 
therapy or concomitantly with this study.  
6. Active infectious disease requiring intravenous therapy. 
7. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C. 
8. Gastrointestinal disorders that may interfere with the absorption of the study drug or 
chronic diarrhoea. 
9. Patients with known pre-existing interstitial lung disease 
10. Serious illness or concomitant non-oncological disease considered by the investigator to 
be incompatible with the protocol. 
11. Patient is <3 years free of another primary malignancy except: if the other primary 
malignancy is either not currently clinically significant or does not require active 
intervention (such as a basal cell skin cancer or a cervical carcinoma in situ). Existence of 
any other malignant disease is not allowed. 


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12. Cardiac left ventricular function with resting ejection fraction <50%. 
13. Absolute neutrophil count (ANC) less than 1500/mm3. 
14. Platelet count less than 100,000/mm3. 
15. Bilirubin greater than 1.5 x upper limit of institutional norm. 
16. Aspartate amino transferase (AST) greater than 3 x upper limit of institutional norm. 
17. Serum creatinine greater than 1.5 x upper limit of institutional norm. 
18. Patients who are sexually active and unwilling to use a medically acceptable method of 
contraception. 
19. Pregnancy or breast-feeding. 
20. Patients unable to comply with the protocol. 
21. Known or suspected active drug or alcohol abuse. 
22. Known hypersensitivity to BIBW 2992 or the excipients of any of the trial drugs. 
23. Requirement for treatment with any of the prohibited concomitant medications listed in 
section 4.2.2 


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4. 
TREATMENTS 
4.1 
TREATMENTS TO BE ADMINISTERED 
The study treatment(s) will be administered with standard radiotherapy (see section 4.2 and 
appendix 10.6).  
4.1.1 
Identity of investigational products 
Substance (INN): BIBW 2992 
Pharmaceutical form:  
Film-coated tablets, 30 count bottles. 
Source:  
 
 
Boehringer Ingelheim Pharma GmbH & Co. KG 
Unit strength dose: 
20 mg, 30 mg and 40mg film-coated tablets (the BIBW 2992 in 
the film-coated tablets is related to the free base equivalent of 
BIBW 2992).  
Dose: 
During RT (6 weeks): Dose-escalation cohorts of 20, (30) and 
40 mg (Regimen U and M)  
After RT(maintenance phase):  
Regimen U: 40 mg/day BIBW 2992 until either progressive 
disease or undue adverse reaction, whichever occurs first. 
Regimen M: 40 mg/day during: 
- the 4 week TMZ “break” period 
- the concomitant TMZ/ BIBW 2992 treatment period (up 
to 6 cycles)  
- the monotherapy treatment period (after TMZ/BIBW 
2992 cycles) until either progressive disease or undue 
adverse reaction, whichever occurs first. 
Duration of use: 
 
Continuous daily dosing, until either progressive disease or
 
 
 
 
undue side effect whatever occurs first.  
Route of administration:  
Oral (swallowed) 
Posology:  
 
 
Once daily 
 
Substance (INN): Temozolomide (TMZ) – Regimen M only 
Pharmaceutical form:  
Hard gelatine capsules 
Source:  
 
 
Provided by sponsor 
Unit strength:   
 
5, 20, 100 and 140 mg 


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Dose:  
 
 
RT concomitant phase: 75 mg/m2 daily  
Maintenance phase (4 weeks after end of RT):   
- cycle 1: 150 mg/m2, 
- from cycle 2 up to cycle 6: 200 mg/m2 (if tolerated)  
Duration of use: 
 
RT concomitant phase: Continuous daily dosing for 42 days 
Maintenance phase:  Four weeks after completing radiotherapy, 
once daily for 5 days followed by 23 days without treatment.  
Route of administration:  
Oral (swallowed) 
Posology:  
 
 
Once daily 
 
4.1.2 
Method of assigning patients to treatment groups 
Patients meeting all the inclusion and none of the exclusion criteria can be entered if they 
have provided written informed consent and if the dose cohort corresponding to their 
methylation MGMT status is not filled.  
Patients with a methylated (or unmethylated after determination of regimen U MTD) MGMT 
promoter will be assigned to regiment M and patients with an unmethylated MGMT promoter 
will be assigned to regiment U.  
All patients will receive treatment with BIBW 2992 and RT (regimen U) or TMZ, BIBW 
2992 and RT (regimen M) as described in Section 4.1.4 
BIBW 2992 dose will be escalated in cohorts of three in absence of DLT (Section 5.2.3 and 
5.2.4) 
In each regimen, treatment slots will be assigned by the sponsor’s Trial Clinical Monitor 
(TCM) in close communication (email/phone) with the recruiting sites. Recruitment will be 
based on a competitive basis between sites. 
Note: If participating sites identify two patients for a cohort at the same time, both patients 
may be entered into that dose cohort, resulting in more than three patients in that dose cohort. 
 
4.1.3 
Selection of doses in the trial 
For the concomitant radiochemotherapy phase, the chosen starting dose of BIBW 2992 in this 
study is 20 mg, which has been a tolerable dose when combining BIBW 2992 with different 
types of chemotherapy (U03-3218). In the current trial, BIBW 2992 dose escalation will stop 
at a maximum dose of 40 mg daily (section 4.1.4.1.1), which is an effective dose for BIBW 
2992 monotherapy for continuous dosing (U03-3218). 


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For the maintenance phase, 40 mg daily in both treatment regimens will be administered. 
Data from trial 1200.36 indicate that 40mg of BIBW 2992 in combination with TMZ is well 
tolerated.  
The dose schedule in Regimen U and M are described in figure 4.1.3: 1 and 4.1.3: 2 
respectively 
 
 
  
 
 
 
  0                                                    6            10        14        18         22        26        30      34  
                                                                                                                                        weeks 
         Focal RT daily (30 x 2Gy) –5 day/week for 6 weeks - Total dose 60 Gy  
 
        BIBW (20, (30),40 mg /day) until end of radiotherapy 
         After RT: 40 mg daily until either disease progression or undue side effect, whichever occurs 
first 
Figure 4.1.3: 1 Dosing schedule Regimen U (Unmethylated MGMT) 
 
 
  
 
                                                           
 
  0                                                    6            10        14        18         22        26        30      34 
weeks 
         Focal RT daily (30 x 2Gy) –5 day/week for 6 weeks - Total dose 60 Gy  
 
        BIBW2992 (20,(30),40 mg/day) until end of radiotherapy 
         After RT: 40 mg daily until either disease progression or undue side effect, whichever occurs 
first 
        TMZ 75 mg/m2 daily for 6 weeks 
 
        TMZ according to the standard 5-day schedule every 28 days.  
 
150 mg/m2 for the first cycle 
 
200 mg/m2 beginning with the second cycle, up to 6 cycles. 
 
Figure 4.1.3: 2 Dosing schedule Regimen M (Methylated MGMT or Unmethylated MGMT 
after determination of regimen U MTD) 


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4.1.4 
Selection and timing of doses for each patient 
4.1.4.1 BIBW2992 (Regimen  M and U) 
During RT: patients will take a single oral dose of BIBW 2992 from Day 1 to Day 42 (section 
4.1.4.1.1). 
During maintenance phase: 
Regimen M: patients will take a daily single oral dose of BIBW 2992 (40 mg): 
- in combination with TMZ up to end of cycle 6  
- followed by BIBW2992 monotherapy until either progression or 
undue side effect, whichever occurs first. 
Regimen U: patients will take a single oral dose of BIBW2992 monotherapy (40 mg)  
daily until either progression or undue side effect, whichever occurs first. 
 
Dose escalation is prohibited in any situation other than described in section 4.1.4.1.1 
BIBW 2992 should be taken at the same time each day (± 2 hours) in the morning at least one 
hour before food intake. Food is not allowed for at least 1 hour after dose administration due 
to an observed food effect with BIBW 2992.The tablet should be swallowed with a glass of 
water (~250 mL). BIBW 2992 tablets are film-coated and therefore should not be chewed or 
crushed. 
If patients can not swallow tablets (e.g G-Tube) BIBW 2992 can be dispersed according to 
the following procedure:   
- Place the tablet into a glass containing 50 mL isotonic sodium chloride solution.  
- Stir until the tablet is broken up into very fine particles (about 15 minutes). 
- Drink the suspension immediately or administer via a gastric tube.  
- Rinse the glass with another 50 ml of isotonic sodium chloride solution and drink or 
administer the supplementary solution via the gastric-tube again (to pick up any drug 
remaining in the glass/gastric-tube). 
Pharmacokinetic sampling will be performed on Day 8, 15 and 29 of concomitant RT 
treatment (PK-visits days). On these days patients should not take the trial medication at 
home and should not eat prior to their visit to the study site.  
Missed doses of BIBW 2992 can be made up if taken within 3 hours of the regularly 
scheduled time. Otherwise, the dose should be skipped and subjects should take the next 
scheduled dose at the usual time. Patients with emesis should not take a replacement dose. 
4.1.4.1.1 Dose escalation scheme for BIBW 
Initially, 3 evaluable patients will be treated per dose level. As soon as one patient 
experiences a DLT (see section 5.2.3), 3 new patients will be treated at that dose level, to 
treat a minimum of 6 evaluable patients. If no other patients experience DLT the dose will be 
escalated to the next level and 3 further patients treated. If two or more of six patients 


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experience DLT, three additional patients will be treated at one dose tier below unless six 
have already been treated at that dose tier. 
The MTD (see section 5.2.4) is the highest dose at which no more than one of 6 patients 
experiences DLT. Once the MTD is determined, patient enrolment at higher dose tiers will be 
suspended.  
The MTD cohort in each Regimen may be expanded to include up to 12 patients. 
Intra-patient dose escalation will not be permitted. 
The first three patients at each dose level will be treated and observed for at least 6 weeks (42 
days) during RT before the next cohort of new patients are treated at the next higher dose 
level (Table 4.1.4.1.1: 2 and 4.1.4.1.1: 3). 
Table 4.1.4.1.1: 1 
Rules for dose escalation for regimen M and U 
 
The decision regarding dose escalation steps will only be made after agreement with the 
sponsor’s Trial Clinical Monitor (TCM).  
Dose escalation and entry of patients into the next dose cohort will begin only after accrual of 
the required minimum number of patients has been achieved and all patients in the cohort are 
considered following completion of 6 weeks BIBW2992 treatment ((42 days ) during RT). 
Patients who are not treated until the end of these 6 weeks for any reasons other than DLT 
will be replaced (section 6.3.1).  
If for any reasons other than DLT the schedule of radiotherapy need to be changed (e.g. bank 
holidays..), missed treatment fractions should be compensated for by additional treatment 
fractions delivered beyond 42 days to a total of 60Gy). The DLTs will be assessed until the 
patients finish their RT treatment (60Gy).
Number of Patients with 
DLT at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
- If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
- If 1 or more of this group suffer DLT, then dose 
escalation is stopped. Three (3) additional patients will 
be entered at the next lower dose level if only 3 
patients were treated previously at that dose. 
>2 out of 3 
Dose escalation will be stopped.  Three (3) additional 
patients will be entered at the next lower dose level if 
only 3 patients were treated previously at that dose. 


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Regimen U 
Three patients will start at dose level U1. Dose escalation will proceed in each subsequent 
cohort according to the following scheme.  
Table 4.1.4.1.1: 2 
Treatment Schedule Regimen U 
 
Cohort 
BIBW 2992 
Regimen Dose Cohort 
mg/day 
U 
Cohort U1 
20 
U 
Cohort U2b 
30 * 
U 
Cohort U2 
40 
*An intermediate dose cohort of BIBW 2992 at 30 mg may be explored 
 if  40 mg is not tolerated (more than two patients with DLT). 
 
Regimen M 
Three patients will start at dose level M1. Dose escalation will proceed in each subsequent 
cohort according to the following scheme. 
 Table 4.1.4.1.1: 3 
Treatment Schedule  
 
Cohort 
TMZ Dose 
BIBW 2992 
Regimen Dose Cohort 
mg/m2x 42days 
mg/day 
M 
Cohort M1 
75 
20 
M 
Cohort M2b 
75 
30 * 
M 
Cohort M2 
75 
40 
* An intermediate dose cohort of BIBW 2992 at 30 mg may be explored if 40 mg is not tolerated (more than two patients 
with DLT). 
4.1.4.1.2 Dose reduction scheme for BIBW: Regimen U and M 
If a patient develops side effect that meets criteria for DLT (for definition refer to Section 
5.2.3) regardless of treatment cycle, treatment with BIBW 2992 must be paused. If all drug-
related adverse events recover to CTCAE Grade 1 or baseline (whichever is higher) within 14 
days of stopping treatment with BIBW 2992, treatment may be resumed with dose reductions 
according to Table 4.1.4.1.2: 1. Otherwise, the patient will be taken off study. Exceptions to 
this are patients who derive obvious clinical benefit according to the investigator’s judgment. 
These patients could be considered in agreement with BI’s Trial Clinical Monitor (TCM) for 
further treatment. 
If a patient need to dose reduced BIBW 2992 during RT, the dose of BIBW 2992 during the 
maintenance period will need to be discussed and decided on a case to case base between BI 
Trial Clinical Monitor and the investigator at site (keep BIBW2992 reduced daily dose or 
change as planned for 40mg BIBW2992 daily) 
  


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Table 4.1.4.1.2: 1 
Dose reduction scheme for Regimen M and U 
Treatment prior to 
treatment pause 
and dose reduction 
BIBW (mg) 
Dose reduction 
1st DLT 
BIBW (mg) 
2nd DLT 
BIBW (mg) 
3rd DLT 
20 
Off-study 
 
 
30 
20 
Off-study 
 
40 
30 
20 
Off-study 
 
4.1.4.2 Temozolomide (TMZ): Regimen M 
TMZ will be administered as follows: 
During RT: Temozolomide will be administered orally at a dose of 75 mg/m2 daily for 42 
days concomitant with focal radiotherapy.  
During the maintenance phase, four weeks after completing the RT, TMZ will be 
administered on day 1-5 of each cycle for up to 6 cycles: 
• Dose in Cycle 1 will be 150 mg/m2  
• At the start of Cycle 2, if 150 mg/m2 of TMZ was well tolerated in Cycle 1, the dose 
will be escalated to 200 mg/m2 
If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. 
Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequent 
cycle.  
TMZ dosage calculation is based on body surface area. For suggested capsule combinations 
on a daily dose please refer to the manufacturer guidelines. The dose should be rounded to 
the nearest 5 mg. 
Patients should swallow TMZ capsules with a glass of water (~250 mL). TMZ capsules 
should not be chewed. To reduce nausea and vomiting, TMZ capsules should be taken on 
empty stomach. TMZ should be taken each day at the same time and this should be in the 
morning together with BIBW 2992. 
Bedtime administration may be advised if not tolerated in the morning due to nausea, TMZ 
should then be taken at the same time each day to ensure a dose interval of approximately 24 
hours and this should be in the evening approximately two hours after food intake to reduce 
nausea and vomiting.  
 
 


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Antiemetic therapy may be administered prior to and/or following administration of TMZ 
capsules.  
Missed doses of TMZ can be made up if taken within 3 hours of the regularly scheduled time. 
Otherwise, the dose should be skipped and subjects should take the next scheduled dose at the 
usual time. Patients with emesis should not take a replacement dose. 
TMZ re-treatment criteria: 
Patients who show clinical benefit from treatment with the combination of BIBW 2992/TMZ 
may continue to receive treatment courses following the concomitant radiochemotherapy 
phase after a 4 weeks TMZ break for up to 6 cycles. Re-treatment criteria described in the 
package insert for Temodal® should be followed. In addition the following criteria should 
applied: 
• AST ≤ 2.5 x upper limit of institutional norm 
• Creatinine ≤ 1.5 x upper limit of institutional norm 
• Total bilirubin ≤ 1.5 x upper limit of institutional norm 
• resolution of rash≥Grade 3 or diarrhoea ≥Grade 3 to Grade 2 or less 
• resolution of any other Grade 3 or greater drug-related adverse reaction (either related 
to BIBW 2992 or to TMZ) to Grade 1 or baseline (whichever is higher). 
If a patient develops side effect due to TMZ, recommendation for dose reduction and dose 
interruption should be followed as per the most up to date Summary of Product Characteristic 
(SPC) recommendation of the manufacturer. 
 
4.1.5 
Blinding 
Not applicable, open-label. 
4.1.6 
Packaging, labelling, and re-supply 
BIBW 2992 will be supplied as film-coated tablets, supplied in, child-resistant, tamper-
evident bottles. Bottles will be labelled with Study number (1200.38), medication number, 
product name, tablet strength, contents of bottle, storage information, use-by date, batch 
number, instruction for use, sponsor name and address. “For clinical trial use only” and "keep 
out of reach of children" will be printed on each label. 
BIBW 2992 available dosage strengths will be 20 mg, 30 mg and 40 mg.  
Each bottle contains 30 film-coated tablets of identical dosage strength. Single panel labels 
will be used. Examples of the bottle labels can be found in the investigator site file. 
TMZ available dosage strength will be 5, 20, 100, 140 and 180 mg. TMZ capsules packaged 
will be in 5 ct (180 mg, 140 mg, 100 mg) or 20 ct (20 mg, 5 mg) amber glass bottles.  


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Drug accountability for BIBW 2992, and TMZ will be handled as outlined in Section 8.2.1. 
Re-supply for BIBW 2992 and TMZ will be actively managed by the sponsor according to 
the site’s requirements and the shelf life of the drugs. 
4.1.7 
Storage conditions 
BIBW 2992 tablets must remain in original containers. Tablets are humidity-sensitive; 
therefore, bottles must be kept tightly closed. BIBW 2992 must be stored at the study site in a 
limited access area not above 30°C and protected from light. 
TMZ should not be stored above 30°C. Tablets are humidity and light sensitive; therefore, 
tablets should stay in the original bottle and bottles must be kept tightly closed. 
4.2 
CONCOMITANT THERAPY 
Concomitant medication 
Hematopoietic growth factors and/or transfusions are not permitted during the 
concomitant chemoradiation phase (unless patients have experienced a DLT or medical 
emergency for which they are appropriately indicated). Supportive care medications for rash, 
diarrhoea and nausea/emesis are permitted . 
In regimen M: 
•  PCP prophylaxis is required for all patients receiving concomitant TMZ and RT. 
• Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant RT 
and TMZ 
• Anti-emetic prophylaxis is strongly recommended during TMZ maintenance phase 
Treatment with certain agents which may interfere with trial medication is prohibited (See 
section 4.2.2). 
All concomitant (non-oncological) therapies starting or changing during the trial are allowed 
but should be recorded in the patient file and in the eCRF except for vitamins, appetizers or 
nutrient supplements. 
Trade name, indication, dose and dates of administration will be documented. If patients 
receive parenteral nutrition during the trial, the components are not required to be 
documented in details. It should just be indicated as “parenteral nutrition” and the form be 
completed. If a patient requires anesthesia, it will be sufficient to indicate “anesthesia” 
without specifying the details. 
Radiotherapy 
The study treatment will be administered with standard radiotherapy. Radiotherapy will be 
given as fractionated focal irradiation at a dose of 2 Gy per fraction given once daily five 
days per week (Monday through Friday) over a period of six weeks with a total dose of 60 Gy 
(see appendix 10.6). 


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4.2.1 
Rescue medication and additional treatment 
Rescue medications to reverse the action of BIBW 2992 or TMZ are not available.  
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude Interstitial 
Lung Disease (ILD). Study drugs 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 BIBW 2992 should be interrupted or discontinued. If keratitis is 
diagnosed, the benefits and risks of continuing treatment with BIBW 2992 should be 
carefully considered. BIBW 2992 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. 
 
4.2.2 
Restrictions 
Additional experimental anti-cancer treatment and/or standard chemo-, immunotherapy, 
hormone treatment  is not allowed concomitantly with the administration of study treatment. 
BIBW 2992 is a substrate of the P-gp transporter. Caution should be exercised when 
combining BIBW 2992 with P-gp modulators.  For a list of potent P-gp inhibitors and 
inducers see Appendix 10.7.  
In any patient ongoing in the trial receiving BIBW 2992 and a concomitant potent P-gp 
inhibitor or inducer at the time of amendment 2 being implemented (26th of April 2010), the 
decision for continuation of either drug will be based on the individual circumstances of the 
patient upon discussion with the responsible BI clinical monitor. 
4.2.3 
Management of expected adverse events 
Management of diarrhoea 
Close monitoring and proactive management of diarrhoea is essential for successful treatment 
of patients with BIBW 2992 and/or TMZ. Early and appropriate intervention can prevent the 
development of more severe diarrhoea. In most cases, loperamide controls diarrhoea caused 
by BIBW 2992 and/or TMZ. 
Loperamide should be available at the start of therapy and kept with the patient at all times; it 
is therefore advisable that patients be given a prescription at the time of initiating study 
treatment. 
The recommendations for management are as follows: 


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• 
If any diarrhoea is experienced (CTCAE Grade 1), two 2 mg loperamide tablets 
should be taken immediately, followed by one 2 mg tablet with every loose bowel 
movement, up to a maximum daily dose of 10 tablets (20 mg). 
• 
Patients should be advised to avoid lactose-containing products or any foods known to 
aggravate diarrhoea. 
• 
Oral hydration is essential regardless of severity; appropriate rehydration 
(1.5 litres/m2/day plus equivalent of actual fluid loss) has to be ensured in the event of 
CTCAE Grade 2 and Grade 3 adverse reaction. 
• 
For CTCAE Grade 3 diarrhoea lasting>2 days or CTCAE Grade 2 diarrhoea lasting>5 
days despite adequate antidiarrhoeal treatment, BIBW 2992 and/or TMZ must be 
paused until recovery to CTCAE<Grade 1 or baseline in the individual treatment 
course. Upon recovery, BIBW 2992 and/or TMZ should be resumed at a reduced dose 
according to the dose reduction scheme outlined in Section 4.1.4. 
The occurrence of diarrhoea and the outcome of treatment will be recorded in the AE section 
of the eCRF. Antidiarrhoeal treatments should be documented in the concomitant medication 
section of the eCRF.  
If despite optimal supportive care and the treatment pause, diarrhoea does not resolve to 
CTCAE Grade<1 or baseline within 14 days, the patient must be removed from the study. 
Exception to this in patients who derive obvious clinical benefit according to the 
investigator’s judgment could be considered upon discussion with BI’s Clinical Monitor 
Local (CML). 
Management of nausea and vomiting 
Nausea and vomiting may significantly affect patients’ adherence to the treatment and their 
quality of life. In order to reduce the occurrence and the intensity of emesis, the patients 
should be treated according to the recommendation given in Table 4.2.3: 1. 
Table 4.2.3: 1 Management of nausea and vomiting 
CTCAE Grade 
Antiemetic treatment 
Nausea = grade 1 
and 
Vomiting = grade 0 
No antiemetic treatment unless judged 
necessary by investigator 
 
Nausea = grade 2 
and 
Vomiting = grade 0 
 
Nausea = grade 0, 1 or 2 
and 
Vomiting = grade 1 or 2 
Antiemetic treatment1 
 
Pause BIBW 2992 and/or TMZ treatment if 
grade 2 vomiting or grade 2 nausea persist 
for 7 or more consecutive days despite 
optimal supportive care. Resume treatment 
when CTCAE grade ≤ 1. 
Vomiting ≥ grade 3 
or 
Nausea ≥ grade 3 
Antiemetic treatment1 
 
Pause BIBW 2992 and/or TMZ treatment 


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until return to CTCAE grade ≤ 1 or 
baseline2. 
 
1 Antiemetic treatment should follow the recommendations given in the Consensus Statement of the Antiemetic 
Subcommittee of the Multinational Association of Supportive Care in cancer (MASCC): Prevention of 
chemotherapy- and radiotherapy-induced emesis: Results of the Perugia Consensus Conference (R06-0986). 
2 Baseline is defined as the CTCAE grade at the start of treatment. 
 
After a treatment pause the dose of BIBW 2992 should be reduced according to the dose 
reduction scheme in Table 4.1.4.1.2: 1. The occurrence of nausea and/or vomiting and the 
outcome of treatment will be recorded in the AE section of the eCRF. Antiemetic treatments 
should be documented in the concomitant medication section of the eCRF with the start and 
end of treatment dates and daily dose. In case of nausea and/or vomiting ≥ CTCAE grade 2, 
appropriate hydration (1.5 L/m2/day plus hydration deficit) must be ensured. 
 
Management of rash and acne  
A proactive and early approach to management of rash is crucial. Rash can be managed by a 
variety of treatment options to relieve symptoms and improve the rash.  
General/Prevention: strict sun protection; use of a sunscreen of SPF 15 or higher, preferably 
containing zinc oxide; use of a thick, alcohol-free emollient cream; avoid harsh detergents, 
avoid using a solarium.  
• 
CTCAE Grade 1 rash: mild rash may not need treatment. However, if treatment is 
considered necessary, topical hydrocortisone (1% or 2.5%) cream and/or clindamycin 
1% gel can be used. 
• 
CTCAE Grade 2 rash: relief from major symptoms caused by CTCAE Grade 2 skin 
adverse reaction should be achieved by a combination of local and systemic therapies  
including: 
1) Systemic antibiotics (doxycycline or minocycline etc.) 
2) Topical treatment (hydrocortisone 2.5% cream, clindamycin 1% gel, pimecrolimus 
1% cream) and/or antihistamines (diphenhydramine, etc.) 
3) Oral prednisone (short term i.e.<14 days treatment) may be added at investigator’s 
discretion. 
Systemic and topical treatment should be initiated at the start of CTCAE Grade 2 rash and 
continue until improvement or resolution to CTCAE Grade≤1 or baseline. 
 
• 
CTCAE Grade 3 (or greater) rash: may be treated in a manner similar to CTCAE 
Grade 2 rash. However, if CTCAE Grade≥3 rash persists despite optimal supportive 
care (including systemic antibiotics), treatment with BIBW 2992 and/or TMZ should 
be discontinued until recovery to≤CTCAE Grade 1 rash or baseline CTCAE Grade 
(whichever is higher). 


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Thereafter patients can resume BIBW 2992 treatment at the next lower dose level as outlined 
in Section 4.1.4. If CTCAE Grade≥3 rash does not resolve to CTCAE Grade≤1 or baseline 
within 14 days after stopping BIBW 2992 and/or  TMZ treatment and despite optimal 
supportive care, the patient will be taken off drug and off protocol. Exception to this in 
patients who derive obvious clinical benefit according to the investigator’s judgment could be 
considered upon agreement with BI’s Trial Clinical Monitor (TCM). 
 
4.3 
TREATMENT COMPLIANCE 
The study medications will be given in accordance with the protocol and under the instruction 
of the investigator at each visit. At all other time points, patients will take the trial drugs at 
home. Patients will be asked to bring the remaining trial medication at each visit to the 
investigator for compliance check. The remaining film-coated tablets and/or capsules will be 
counted by the investigator/site staff and recorded at the study site. 
Discrepancies between the number of film-coated tablets and/or capsules taken and the 
calculated number of film-coated tablets and/or capsules the patient should have taken must 
be documented and explained. At the end of each treatment cycle leftover medication will be 
collected. 
During the maintenance phase, a maximum of six consecutive doses of BIBW 2992 or seven 
non-consecutive doses may be missed per cycle (i.e., 28 days) for reasons other than recovery 
from a drug-related adverse event. These patients will be allowed to continue therapy on the 
trial. Patients who miss treatment medication more than that are considered non-compliant. 
Their treatment should be discontinued, and patients will be withdrawn from the study. 
Patients who discontinue or interrupt the study medication due to AE for less than 14 days are 
considered compliant. 


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5. 
OBSERVATIONS 
5.1 
EFFICACY - CLINICAL PHARMACOLOGY OR PHARMACODYNAMICS 
5.1.1 
Primary endpoints 
Determination of the MTD of: 
- BIBW 2992 when given concomitantly with radiotherapy  (Regimen U) 
- BIBW 2992 when given concomitantly with TMZ and radiotherapy  (Regimen M) 
5.1.2 
Secondary endpoints 
1. Incidence and intensity of AE according to Common Terminology Criteria (CTCAE v.3, 
(R06-1666))  
2. Objective tumour response rate according to the Macdonald criteria (R08-1053)  
3. Pharmacokinetics of BIBW 2992 (Sections 5.5 and 7.3.5). 
5.1.3 
Tumour assessment 
Response will be evaluated according to the Macdonald criteria (R08-1053): 
Complete Response (CR): Disappearance of all enhancing tumour on consecutive MRI 
scans at least 28 days apart, off steroids, and neurologically stable or improved. 
Partial Response (PR): At least 50% reduction in size of enhancing tumour on 
consecutive MRI scans at least 28 days apart, steroids stable or reduced, and 
neurologically stable or improved. 
Progressive Disease (PD): a)  at least 25% increase in size of enhancing tumour or 
 
b)  any new tumour on MRI scans or 
 
c) unequivocal neurological deterioration (due to underlying 
 
 
tumour progression and not due to co-morbid event or 
 
 
concurrent medication) with steroids being stable or  
 
 
increased. 
Stable Disease (SD): All other situations 
 
‘Size’, will be defined as the tumour’s largest cross-sectional area. Multifocal lesions are 
defined as PD if any measurable lesion increases by >25%, or if there is an assessment of any 
evaluable lesion(s) as progressive. 
‘Unequivocal neurological deterioration’ will be assessed locally by each investigator. The 
clinical decline must be attributed to the underlying tumour progression and not due to 
co-morbidity or concomitant medication. 


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Objective tumour response rate is defined as the sum of all CRs and PRs as a fraction of all 
patients. For a detailed time schedule of tumour assessment please refer to the Flow Chart 
and Section 6 of this protocol. 
Pseudo-progression based on imaging parameters only is a common phenomenon in GBM 
patients after prior radiotherapy. In order to avoid labelling progressive enhancement or 
oedema which develops immediately after the end of RT as tumour progression, treatment 
should not be delayed or stopped within 3 months of RT as suggested by. the “Canadian 
GBM Recommendations committee” (R09-6378) 
If a patient shows radiological progression on his/her first scan occurring within 2 months 
post RT, the patient should not stop study medication and be removed from the study. 
Instead, the patient should stay on the study until the second MRI scan (scheduled at 4 
months post RT) confirms the patient has progressed or not. If the course of events shows 
that true progression indeed occurred, the date of the first increase in tumor size is to be 
considered as the date of progression. 
5.2 
SAFETY 
5.2.1 
Adverse events 
Upon inclusion into the trial, the patient’s condition is assessed (e.g., documentation of 
history / concomitant diagnoses and diseases), and all relevant changes from baseline are 
noted subsequently. 
AEs will be collected from the date of signature of informed consent number 2. Once the 
MTD in Regimen U is determined, AEs will be collected from the date of signature of 
informed consent number 3. 
 
Patients will be required to report spontaneously any adverse events (AEs) as well as the 
dates of onset and end of these events. These include all events that affect the well-being of 
the patients irrespective their relatedness to the treatment. Specific questions will be asked 
wherever required or useful to more precisely describe an AE and to allow a grading 
according to CTCAE, Version 3 (R06-1666). 
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the date of onset, end date and CTCAE grading of the 
event as well as any treatment or action required for the event and its outcome. 
Regular and continuing assessment of safety will be performed for both parts of the study as 
outlined in the Flow Chart of this protocol. A dose reduction scheme is provided in 
Section 4.1.4.1.2 for patients who experience specified adverse events and who, at the 
discretion of the investigator, could derive benefit from continuing treatment on the protocol. 
Adverse events with an onset during therapy with trial medication or within 28 days after 
discontinuation of drug intake are considered as “on-treatment”. Adverse events which are 
not yet recovered at the EOT visit will be followed up until recovery or in case of persistence 
sufficient characterization of the toxic effects has been achieved and the investigator and 


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Boehringer Ingelheim agree not to pursue them further. Adverse events that occur more than 
28 days after last administration of study drug will only be reported if they are considered 
drug- or trial procedure-related. 
Definitions and requirements for documentation and reporting of AEs and serious adverse 
events (SAEs) are provided in Sections 8.4.1. A list of expected adverse events with BIBW 
2992 can be found in the current version of the investigator brochure. 
The EU prescribing information for Temozolomide (current SPC) will be used for assessment 
of international listedness/expectedness of temozolomide. 
Hospitalizations for administrative reasons or hospitalizations already planned prior to 
informed consent need not be reported as an SAE, unless other serious criteria are met. 
Changes in safety tests including blood pressure, pulse rate, electrocardiogram (ECG) and 
laboratory tests will be recorded as AEs, if they are not associated with an already reported 
AE, symptom or diagnosis, and: 
• 
action is required and taken with the investigational drug, i.e., dose reduction or 
treatment discontinuation, or 
• 
treatment is required (i.e., a concomitant medication is added or changed). 
 
Specific secondary safety-related endpoints are defined in Section 7.3.3 
5.2.2 
Worsening of pre-existing conditions 
Expected fluctuations or expected deterioration of the underlying disease will not be recorded 
as an AE. If progressive disease occurs and is associated with symptoms or meets one of the 
seriousness criteria (see section 8.4.1), the signs and symptoms of progressive disease will be 
reported as an adverse event or a serious AE (if applicable). 
A pre-existing condition present at baseline, which remains unchanged during the trial, does 
not need to be recorded as adverse event. However, any worsening of any pre-existing 
baseline condition should be reported as an adverse event. Example of worsening of a 
preexisting condition that should be recorded as an AE are given below; 
• 
Worsening of condition meets the criteria for an SAE 
• 
Action is taken with the investigational drug (i.e. dose is reduced or treatment is 
• 
Discontinued or increased) 
• 
Treatment is required (concomitant medication is added or changed) 
• 
The investigator believes a patient has shown a clear deterioration from baseline 
symptoms 
 


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5.2.3 
Dose-limiting Toxicity (DLT) 
A dose-limiting toxicity (DLT) is defined as an adverse event or laboratory abnormality that 
is: a) considered to be related to BIBW 2992 as used in regimen U or M and b) meets any of 
the following criteria: 
a) Hematologic adverse reaction: 
1)  CTCAEv3 Grade 4 neutropenia (ANC, including bands, <500/mm3) for more than 
7 days; or 
2) CTCAEv3 Grade 3 or 4 neutropenia of any duration associated with fever >38.3°C. 
3) CTCAEv3 Grade 3 thrombocytopenia (platelet count < 50,000 - 25,000/ mm3); or 
4) All other hematological toxicities of CTCAE Grade ≥3 leading to an interruption of 
treatment with both study drugs for more than 14 days until recovery to baseline or Grade 
1, whichever is higher. 
b) Non-hematologic adverse reaction: 
1. CTCAEv3 Grade ≥3 nausea or vomiting is occurring despite appropriate use of standard 
anti-emetics for at least three days. 
2. CTCAEv3 Grade ≥3 diarrhoea despite appropriate use of standard anti-diarrheal therapy 
for at least three days. 
3. CTCAEv3 Grade ≥3 rash despite standard medical management as outlined in Section 
4.2.3 and lasting >7 days. 
4. CTCAEv3 Grade ≥2 cardiac left ventricular function. 
5. CTCAEv3 Grade ≥2 worsening of renal function as measured by serum creatinine, newly 
developed proteinuria, or newly developed decrease in glomerular filtration rate. 
6. All other non-hematological toxicities of CTCAEv3 Grade ≥3  
5.2.4 
Maximum Tolerated Dose (MTD) 
7. The MTD is defined as: 
8. The dose of BIBW 2992 when given concomitantly with TMZ and RT (Regimen M) or 
BIBW 2992 when given concomitantly with radiotherapy (Regimen U) which is one dose 
tier below that dose at which two or more out of six patients experienced drug-related 
DLTs during the 6 weeks (42-day) RT treatment period. DLT experienced after the start 
of the maintenance treatment period will be examined separately. At the MTD, no more 
than one patient out of six patients may experience DLT, i.e., MTD is defined as the 


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highest dose studied for which the incidence of DLT is no more than 17% (i.e. 1/6 
patients). 
5.2.5 
Significant Adverse Events 
DLTs are termed significant Adverse Events.  
Although rare, drug-induced liver injury is under constant surveillance by sponsors and 
regulators and is considered a protocol-specified significant adverse event.  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.  The following are considered as Protocol-specified significant 
events: 
Hepatic injury defined by the following alterations of liver parameters:  
o 
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. Patients showing these lab abnormalities 
need to be followed up according to APPENDIX 10.8 of this clinical 
trial protocol and the "DILI checklist" provided in the ISF 
o 
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 10.8 of this clinical trial protocol and the "DILI checklist" 
provided in the ISF.      
Protocol-specified significant events are to be reported in an expedited manner similar to 
Serious Adverse Events, even if they do not meet any of the seriousness criteria - for details 
please see chapter 8.4.1. 
 
If the investigator determines any protocol-specific significant event is related to study drug, 
the administration of the study drug must be managed according to section 4.1.4.1.2 of the 
protocol. 
 
 
5.2.6 
Safety laboratory investigations 
Blood samples for safety analysis will be collected at the time points specified in the Flow 
Chart and analyzed in the investigator’s local laboratories. Safety laboratory examinations 
will include hematology, biochemistry, urine examination and a pregnancy test. In case of 
neutropenia, blood will be examined as clinically indicated at the discretion of the 
investigator until recovery. 


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The following parameters will be determined  
 
Hematology:  
red blood cell count (RBC), haemoglobin, hematocrit, white blood cell count (WBC) and 
differential, platelets. 
 
Biochemistry:  
glucose, sodium, potassium, calcium, creatinine, aspartate, aminotransferase (AST), alanine 
amino transferase (ALT), alkaline phosphatase, lactase dehydrogenase, bilirubin, urea, total 
protein, uric acid, creatine phosphokinase (CPK), in case of pathological CPK further 
evaluation (e.g., by Troponin assays, CK-MM, CKMB, ECG exam) should be performed and 
the findings documented. GFR will be estimated by the Cockgroft-Gault formula utilizing 
serum creatinine values (appendix 10.5). 
 
Urine examination   
pH, glucose, erythrocytes, leukocytes, protein, nitrite will be analyzed at the time points 
specified in the protocol. In case of abnormal findings, further evaluation should be 
performed and the findings documented. 
 
Pregnancy test 
 
β-HCG testing in urine or serum will be performed as outlined in the Flow Chart in women of 
childbearing potential. 
5.2.7 
Physical examination, performance score 
A physical examination will be performed at screening and at the time points specified in the 
Flow Chart. The physical exam serves as a clinical tumour assessment and should include a 
thorough exam, particularly of the neurological status. Additional symptoms which have not 
been reported during a previous examination should be clarified. Wherever possible the same 
investigator should perform this examination throughout the study. Measurement of height (at 
baseline only) and body weight (in kg) should be included in the physical examination. 
Evaluation of the Karnofsky performance score (Appendix 10.4) will be performed at the 
time points specified in the Flow Chart. 
5.2.8 
Mini Mental State Examination (MMSE) 
MMSE assessment (appendix 10.4) will be performed at baseline and at the time points 
specified in the Flow Chart. 
5.2.9 
ECG 
A 12-lead resting ECG will be performed at the time points specified in the Flow Chart.  
5.2.10 
Left ventricular function 
Left Ventricular Ejection Fraction (LVEF) as measured by echocardiography or MUGA scan 
will be assessed at time points specified in the Flow Chart. The same method of measurement 
has to be used throughout the study. 


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MUGA Scan 
The Multiple Gated Acquisition scan (MUGA) is recommended as a non-invasive method for 
the assessment of diseases of the heart muscle. It is used for the monitoring of the ejection 
fraction of the cardiac ventricles, especially the left ventricular ejection fraction (LVEF). 
Echocardiography (ECHO) 
Echocardiography should be performed to assess the LVEF according to the standard 
guidelines of the American Society of Echocardiography (R06-1414). 
5.2.11 
Vital signs 
Vital signs (blood pressure, pulse and respiratory rate after 2 minutes supine rest) and 
temperature will be recorded at the screening visit and at the time points specified in the Flow 
Chart. 
5.3 
OTHER 
5.3.1 
Demographics and history 
Demographics (sex, birth date, race), smoking, alcohol history and baseline conditions will be 
collected during the screening visit. History of malignant brain tumour will be obtained at 
diagnosis and at the inclusion into the trial and reported in the eCRF: 
• the date of first histological diagnosis (month and year may be sufficient) 
• the primary tumour location (frontal, parietal, occipital, temporal) 
5.3.2 
Concomitant therapies and diagnoses 
Concomitant diagnoses and/or therapies present at study entry and/or during screening and 
relevant to the patient’s safety during the trial as judged by the investigator will be recorded 
in the eCRF. 
5.4 
APPROPRIATENESS OF MEASUREMENTS 
The Macdonald criteria (R08-1053) to be used for evaluation of tumour response are well 
established and scientifically accepted. The CTCAEv3 criteria (R06-1666) are used in the 
assessment of adverse events in cancer patients as well as the Karnofsky Performance Scale 
(Appendix 10.3). 
The MMSE assessment (R96-2656) to assess cognitive impairment at a given point in time 
and to follow the course of cognitive changes in an individual over time is a widespread tool 
used in neuro-oncology (appendix 10.4). 
5.5 
DRUG CONCENTRATION MEASUREMENTS - PHARMACOKINETICS 
Date and exact clock time of administration as well as of PK plasma sampling times have to 
be recorded. 


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5.5.1 
Methods and timing of sample collection 
• For quantification of BIBW 2992 plasma concentrations 4 ml of venous blood will be 
collected at the following time points: 
• Visit 2 (Day 8): Before (-0:05 h) the administration of BIBW 2992. 
• Visit 3 (Day 15): Before (-0:05 h) the administration of BIBW 2992, around 1 hour 
(within a time frame between 0.5-2.0 hours) and around 3 hours (within a time frame 
between 2.0 and 4.0 hours) after drug administration. One voluntary PK sample may 
be taken at any time within the time frame of 4 hours to 24 hours (preferentially 6 
hours) after BIBW 2992 administration. 
• Visit 4 (Day 29): Before (-0:05 h) the administration of BIBW 2992. 
Date and exact clock time of BIBW 2992 administration, as well as blood collection times, 
must be recorded in the eCRF. Additionally, the date and time of drug intake of the patients 
for the last four (4) days prior to pharmacokinetic sampling should be documented in the 
eCRF. 
Correct, complete and legible documentation of drug administration and blood sampling 
times is mandatory to obtain data of adequate quality for the population pharmacokinetic 
analysis. 
The detailed timing of PK sampling is attached to this protocol as Appendix 10.1. The 
detailed procedures for collecting the samples are attached to the ISF. For storing and 
shipping conditions of these samples please refer to the ISF. 
5.5.2 
Analytical determinations 
BIBW 2992 drug concentrations will be determined by a validated by a high performance 
liquid chromatography-mass spectrometry (HPLC-MS/MS) assay. The procedure and 
specification of the analytical method are available at the determination site (Department of 
Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH and Co. KG, 
Biberach, Germany). 
5.6 
BIOMARKER - PHARMACODYNAMIC SAMPLING 
5.6.1 
Methods and timing of sample collection 
5.6.1.1 Tumour samples 
Tumour samples from enrolled patients will be collected as early as possible after informed 
consent 1 have been obtained. They will need to be sent to a central laboratory for 
methylation MGMT promotor status determination. Only tumour slices from open surgery 
are suitable (4 x 10 micron slices). 
 


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Note: If a patient already has proven MGMT promotor methylation status prior to screening 
and the test performed by the same laboratory used in the 1200.38 study, the patient will be 
able to enter in the study without re-testing.  
For patients who received trial medication for more than a year: 
Archived tumour samples may be collected after informed consent has been obtained. 
Samples can date back to surgery and/or biopsy. Block or tumour slices (11 x 4 micron 
slices) are suitable. No new biopsy or surgery will be required for this purpose. 
All tumour specimens must be adequately labeled by the Pathology Department providing the 
specimen for analysis.  
Details with regards to tissue collection, labeling and shipping instruction can be found in the 
ISF at each investigational site. 
5.6.2 
Analytical determinations 
Tumour samples will be analyzed for MGMT methylation status. 
For patients who received trial medication for more than a year: 
Archived tumour samples may be analysed for acquired mutations in genes associated with 
cancer, including but not limited to EGFR, EGFRvIII, PTEN, P-AKT, by a centralized third 
party vendor. In addition, fluorescent in situ hybridization (FISH) analyses could be 
performed for EGFR and PTEN. As medical knowledge in this field is constantly evolving, 
additional tissue biomarkers that come to be known as potentially relevant 
prognostic/predictive markers of treatment response may also be explored. The results of 
these analyses will be reported. 
 
 
5.7 
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP 
No analysis of PK/PD relationship is planned. However, if the data suggest a PK/PD 
relationship of special parameters described in 5.6 or correlation of efficacy of safety data to 
PK, a detailed analysis of PK/PD relationship might be performed. 
5.8 
DATA QUALITY ASSURANCE 
The trial will be conducted in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, local law and according to the principles of GCP and the company 
standard operating procedures (SOPs). 
An investigator meeting or conference call will be performed prior to start of the trial to 
inform all investigators about the trial drug and the procedures of the trial. Alternatively, each 
investigator could also be visited individually by one of BI’s clinical research associates 
(CRA). 


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Each investigator will receive an ISF with all information relevant for the performance of the 
trial. Investigators will be visited intermittently for on-site monitoring by a Boehringer 
Ingelheim employee or a CRA authorized by BI. On these occasions, source data verification 
will be performed and a check will be done whether the eCRFs are kept current. The 
information in the eCRF that has to be documented in source documents will be 
cross-checked as described in Section 8.2.4. 
A quality assurance audit of this study may be conducted by the sponsor or sponsor’s 
designees. The quality assurance auditor will have access to all medical records, the 
investigator's study related files and correspondence, and the informed consent 
documentation that is relevant to this clinical study. 
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. Coding of the 
Adverse events and Concomitant Diagnoses will be done by using the medical dictionary for 
regulatory activities (MedDRA). Coding of the Concomitant therapies will be done by using 
the WHO drug dictionary (WHO-DD). 


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6. 
INVESTIGATIONAL PLAN 
6.1 
VISIT SCHEDULE 
Patients will visit the investigator at the time points specified in the Flow Chart.  
The screening process is divided into two visits, Screening Visit 1 and Screening Visit 2. At 
Screening Visit 1, tumour sample from open surgery will be analysed by a central laboratory 
for MGMT gene methylation status. 
Patients will be able to proceed to Screening visit 2 if: 
- the patient has a proven MGMT promotor methylation status 
- the cohort corresponding to the patient MGMT promotor methylation status is not full 
 
The decision to pursue to screening visit 2 will be made after agreement with the Trial 
Clinical Monitor (TCM) 
During the maintenance treatment phase visits should be performed as scheduled wherever 
possible, but within 2 days of the schedule date. 
All patients should be evaluated within 5 calendar days after permanent termination of trial 
drug intake (EOT visit) 
All patients should also have a follow-up visit 28 days (+/- 4days) after the EOT visit.  
The clinical trial will be considered completed as soon as the last patient receiving treatment 
has completed the follow-up assessment 28 days after EOT. 
In case the trial will be finished by the sponsor for safety reasons, patients will not continue 
treatment with the trial drug.  
6.2 
TRIAL PROCEDURES AT EACH VISIT 
6.2.1 
Screening  
The screening visit assessments are identical in Regimens U and M (Day -35 to Day -1) 
6.2.1.1 Screening Visit 1 (SV1) 
Once MTD in Regimen U will be determined, all patients will be able to enter in regimen M 
and therefore the patients will only performed SV2 
Informed consent number 1 
Written informed consent must be obtained before 
any study specific procedures are performed 
Informed consent number 1 must include consent to 
collection of demographic data and consent to send 
tumour sample from surgery to central laboratory 
for MGMT status assessment. 


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Demographics 
sex, birth date, race 
 
If proven MGMT promoter status already available prior screening as described in section 
5.6.1.1, patients will not need to perform the screening visit 1. 
 
6.2.1.2 Screening Visit 2 (SV2) 
Informed consent number 2 or 3* 
Written informed consent number 2 must be 
obtained before any study specific procedures are 
performed. 
* Once the MTD in Regimen U is determined, 
written informed consent number 3 must be 
obtained before any study specific procedures are 
performed 
In-/Exclusion criteria 
Patient eligibility will be assessed  
MGMT test result  
Before determination of the MTD in Regimen U, 
the MGMT test result will decide if the patient will 
take part in Regimen U or Regimen M.  
Cerebral MRI 
Early postoperative MRI (within 72 hours after 
initial surgery) if available. In case a patient did not 
perform a Gd-enhanced MRI within 72 hours post 
surgery, a Gd-MRI is to be performed prior to start 
of study treatment. 
Demographics 
Sex, birth date, race (only for patients who did not 
need to perform Screening visit 1) 
Serum β-HCG test (Pregnancy test) 
For women of childbearing potential only 
Medical history 
Oncological and relevant non-oncological 
information (section 5.3.1) 
Echo or MUGA 
Cardiac left ventricular function assessment Section 
5.2.10) 
Physical examination 
Including weight and height 
ECG 
12-lead resting ECG will be performed 
Karnofsky performance score 
See Appendix 10.3 
Concomitant therapy 
All concomitant medications will be documented 
Vital signs 
Temperature, blood pressure, pulse and respiratory 
rate after 2 min supine rest  
Safety lab parameters 
Hematology (including differential), biochemistry, 
and urine analysis (section 5.2.6) 


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6.2.2 
Treatment phases 
6.2.2.1 Concomitant Radiotherapy treatment phase(s): Regimens U and M 
Visit RT1 - Day 1 
MMSE assessment 
See Appendix 10.4 
Concomitant therapy 
Changes in concomitant medications will be 
documented 
Vital signs 
Temperature, blood pressure, pulse and respiratory 
rate after 2 min supine rest 
Safety lab parameters 
Hematology (including differential), biochemistry, 
and urine analysis (section 5.2.6) 
Adverse events 
Occurrence of adverse events since the last visit 
Dispense study medication 
BIBW 2992: supply sufficient for 30 days should be 
dispensed. 
TMZ: supply sufficient for 14 days should be 
dispensed (for regimen M only) 
BIBW 2992 administration  
 
For the 1st dose, study drug should be taken under the 
supervision of the investigator/site staff. For timing 
and restrictions on food intake see Section 4.1.4 
TMZ administration 
Regimen M only 
For the 1st dose, TMZ tablets should be taken under 
the supervision of the investigator/site staff. For 
timing and restrictions on food intake see Section 
4.1.4.2 
Radiotherapy 
2Gy once daily (five days per week, total dose 60Gy) 
(See appendix 10.6) 
 
Visit RT2 - Day 8 
ECG 
12-lead resting ECG will be performed 
Concomitant therapy 
Changes in concomitant medications will be 
documented 
Vital signs 
Temperature, blood pressure, pulse and respiratory rate 
after 2 min supine rest 
Safety lab parameters 
Hematology (including differential), biochemistry, and 
urine analysis (Section 5.2.6) 
Adverse events 
Occurrence of adverse events since the last visit 


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Compliance check 
The patient should bring his/her medication and the 
number of remaining tablets and capsules should be 
counted. 
BIBW 2992 administration  
 
Just before drug administration, a PK sample should be 
taken. For timing and restrictions on food intake see 
Section 4.1.4 
Blood sampling for PK 
For specific time schedule refer to Section 5.5.1 and 
Appendix 10.1 
Administration of TMZ 
Only for regimen M 
For further information refer to Section 4.1.4.2 
Radiotherapy 
2Gy once daily (five days per week, total dose 60Gy) 
(See appendix 10.6) 
 
Visit RT3 - Day 15 
Physical examination 
including weight  
Concomitant therapy 
changes in concomitant medications will be 
documented 
Vital signs 
Temperature, blood pressure, pulse and respiratory rate 
after 2 min supine rest 
Safety lab parameters 
Hematology (including differential), biochemistry, and 
urine analysis (section 5.2.6) 
Adverse events 
Occurrence of adverse events since the last visit 
Compliance check 
The patient should bring his/her medication and the 
number of remaining tablets and capsules should be 
counted. 
Blood sampling for PK 
For specific time schedule refer to Section 5.5.1 and 
Appendix 10.1 
Dispense study medication 
TMZ: supply sufficient for 14 days should be 
dispensed (for regimen M only) 
BIBW 2992 administration  
 
Just before drug administration, a PK sample should be 
taken. For timing and restrictions on food intake see 
Section 4.1.4 
Administration of TMZ 
Only for regimen M 
For further information refer to Section 4.1.4.2 
Radiotherapy 
2Gy once daily (five days per week, total dose 60Gy) 
(See appendix 10.6) 
 
Visit RT4 - Day 29  


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Concomitant therapy 
changes in concomitant medications will be 
documented 
Vital signs 
Temperature, blood pressure, pulse and respiratory rate 
after 2 min supine rest 
Safety lab parameters 
Hematology (including differential), biochemistry, and 
urine analysis (section 5.2.6) 
Adverse events 
Occurrence of adverse events since the last visit 
Compliance check 
The patient should bring his/her medication and the 
number of remaining tablets and capsules should be 
counted. 
Blood sampling for PK 
For specific time schedule refer to Section 5.5.1 and 
Appendix 10.1 
Dispense study medication 
BIBW 2992: 1 bottle should be dispensed. 
TMZ: supply sufficient for 14 days should be 
dispensed (for regimen M only) 
BIBW 2992 administration  
 
Just before drug administration, a PK sample should be 
taken. For timing and restrictions on food intake see 
Section 4.1.4. 
Administration of TMZ 
Only for regimen M 
For further information refer to Section 4.1.4.2 
Radiotherapy 
2Gy once daily (five days per week, total dose 60Gy) 
(See appendix 10.6) 
 
Visit RT5 - Day 42 
Physical examination 
Including weight  
Karnofsky performance score 
See Appendix 10.3 
Concomitant therapy 
Changes in concomitant medications will be 
documented 
Vital signs 
Temperature, blood pressure, pulse and respiratory rate 
after 2 min supine rest 
Safety lab parameters 
Hematology (including differential), biochemistry, and 
urine analysis (section 5.2.6) 
Adverse events 
Occurrence of adverse events since the last visit 
Compliance check 
The patient should bring his/her medication and the 
number of remaining tablets and capsules should be 
counted. 
Dispense study medication 
Study medication (BIBW 2992) supply sufficient for 1 
month should be dispensed. 


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BIBW 2992 administration  
For timing and restrictions on food intake see Section 
4.1.4 
Administration of TMZ 
Only for regimen M 
For further information refer to Section 4.1.4.2 
Radiotherapy 
2Gy once daily (five days per week, total dose 60Gy) 
(See appendix 10.6) 
 
6.2.2.2 Maintenance phase 
Regimen U 
CxV1 (day 28 +/- 3) 
Visit frequency: every 4 weeks for the first 6 months after RT, every 8 weeks thereafter for 
the next six months and then every 12 weeks for the next year, and every 6 months (24 
weeks) thereafter. 
Cerebral MRI 
Cycle 2, 4, 6, 8, 10 ,12 
Cycle 15, 18, 21, 24  
Cycle 30, 36 (every 6 months 
thereafter) 
MRIs need to be prepared between day 21 and day 28 
of each cycle. 
Tumour assessment / restaging will routinely be 
performed at the same time that the MRI is performed.  
Physical examination 
Including weight 
ECG 
Cycle 2, 4, 6, 8,10,12 
Cycle 15, 18, 21, 24  
Cycle 30, 36 (every 6 months 
thereafter) 
12-lead resting ECG will be performed 
MMSE assessment 
Cycle 2, 4, 6, 8,10,12 
Cycle 15, 18, 21, 24  
Cycle 30, 36 (every 6 months 
thereafter) 
See Appendix 10.4 
Karnofsky performance score 
See Appendix 10.3 
Concomitant therapy 
Changes in concomitant medications will be 
documented 
Vital signs 
Temperature, blood pressure, pulse and respiratory rate 
after 2 min supine rest 
Safety lab parameters 
Hematology (including differential), biochemistry, and 
urine analysis (section 5.2.6) 


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Adverse events 
Occurrence of adverse events since the last visit 
Compliance check 
The patient should bring his/her medication and the 
number of remaining tablets and capsules should be 
counted. 
BIBW 2992 administration  
For timing and restrictions on food intake see Section 
4.1.4 
Dispense study medication 
Study medication supply sufficient for 28 days should 
be dispensed. 
 
Regimen M 
Visit frequency: every 4 weeks for the first 7 months (4 weeks TMZ break followed by 
BIBW2992 + TMZ treatment period), every 8 weeks thereafter for the next six months and 
then every 12 weeks (three months) for the next year, and every 24 weeks (6 months) 
thereafter. 
BREAK- Day 70 (day 28 +/- 3) 
ECG 
12-lead resting ECG will be repeated  
Concomitant therapy 
Changes in concomitant medications will be 
documented 
Karnofsky performance score 
See Appendix 10.3 
Vital signs 
Temperature, blood pressure, pulse and respiratory rate 
after 2 min supine rest 
Safety lab parameters 
Hematology (including differential), biochemistry, and 
urine analysis (section 5.2.6) 
Adverse events 
Occurrence of adverse events since the last visit 
Administration of BIBW 2992 
For timing and restrictions on food intake see Section 
4.1.4 
Compliance check 
The patient should bring his/her medication and the 
number of remaining tablets and capsules should be 
counted. 
Dispense study medication 
Study medication supply sufficient for 28 days should 
be dispensed. 
 
CxV1 (day 28 +/- 3) 


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Cerebral MRI 
Cycle 1, 3, 5, 8,10 ,12 
Cycle 15, 18, 21, 24  
Cycle 30, 36(every 6 months 
thereafter)  
MRIs need to be prepared between day 21 and day 28 
of each cycle 
Tumour assessment / restaging will routinely be 
performed at the same time that the MRI is performed.  
Physical examination 
Including weight 
ECG 
Cycle 1, 3, 5, 8,10,12 
Cycle 15, 18, 21, 24  
Cycle 30, 36(every 6 months 
thereafter) 
12-lead resting ECG will be performed 
MMSE assessment 
Cycle 1, 3, 5, 8,10 ,12 
Cycle 15, 18, 21, 24  
Cycle 30, 36(every 6 months 
thereafter)  
See Appendix 10.4 
Karnofsky performance score 
See Appendix 10.3 
Concomitant therapy 
Changes in concomitant medications will be 
documented 
Vital signs 
Temperature, blood pressure, pulse and respiratory rate 
after 2 min supine rest  
Safety lab parameters 
Hematology (including differential), biochemistry, and 
urine analysis (section 5.2.6) 
Adverse events 
Occurrence of adverse events since the last visit 
Compliance check 
The patient should bring his/her medication and the 
number of remaining tablets and capsules should be 
counted. 
Administration of TMZ 
Only up to Cycle 6 
For dose timing and restrictions on food intake see 
Section 4.1.4.2 
Administration of BIBW 2992  
 
For timing and restrictions on food intake see Section 
4.1.4 
Dispense study medication 
Study medication supply sufficient for 28 days should 
be dispensed. 
 
6.2.3 End of treatment and follow-up 
End of treatment (EOT) visit: within 5 calendar days after permanent termination of trial 
treatment. 


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The end of treatment visit is performed as close as possible (no longer than 5 calendar days) 
after a patient discontinues study medication permanently. The termination of trial 
medication form (eCRF page) must be completed for all patients who discontinue or 
complete the study regardless of reason. This includes patients who develop adverse events 
requiring permanent discontinuation of treatment on either stage of the protocol, or patients 
who were withdrawn for other reasons. 
Perform investigations as defined by EOT instead of the scheduled visit when a patient 
discontinues study treatment permanently. If permanent discontinuation of study drug falls on 
a scheduled visit, examinations as defined for EOT should be performed instead of the 
examinations of the scheduled visit. Imaging and tumour assessment needs to be done only to 
diagnose/confirm progression or response. 
 
Serum β-HCG test (Pregnancy test) 
For women of childbearing potential only 
Echo or MUGA 
Cardiac left ventricular function assessment (see 
section 5.2.10) 
Physical examination 
Including weight. 
Cerebral MRI 
Imaging and tumour assessment needs to be done 
only to diagnose/confirm progression or response. 
The EOT MRI/tumour assessments are optional if 
performed in the previous 4 weeks.  
ECG 
12-lead resting ECG will be performed 
MMSE assessment 
See Appendix 10.4 
Karnofsky performance status 
See Appendix 10.3 
Concomitant therapy 
Changes in concomitant medications will be 
documented 
Vital signs  
Temperature, blood pressure, pulse and respiratory 
rate after 2 min supine rest 
Safety lab parameters 
Hematology (including differential), biochemistry, 
and urine analysis (section 5.2.6). 
Adverse events 
Occurrence of adverse events since the last visit 
Compliance check 
The patient should bring his/her medication and the 
number of remaining tablets and capsules should be 
counted 
Termination of study medication 
 
 
 
 


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Follow-up visit: 28 days (±4) after EOT 
Karnofsky performance status 
See Appendix 10.3 
Concomitant therapy 
Changes in concomitant medications will be 
documented 
Safety lab parameters 
Hematology (including differential), biochemistry, 
and urine analysis (section 5.2.6). 
Adverse events 
Will be documented, if not recovered at EOT or 
new drug related AE  
 
6.3 
REMOVAL OF PATIENTS FROM THERAPY OR ASSESSMENT 
A patient can be withdrawn from study treatment after discussion between the BI Clinical 
Monitor and the investigator. 
A patient will be withdrawn from the study treatment: 
• the patient is no longer able to participate in the study (e.g., AE, surgery, concomitant 
diagnoses, concomitant therapies or administrative reasons); in such a case the 
investigator’s reason for a patient’s removal must be recorded on the EOT page of the 
eCRF. 
• significant deviation from the protocol or eligibility criteria; such patients will be 
considered protocol violations and removed from study. 
• non-compliance with study or follow-up procedures. 
• Patient not recovered from any DLT 14 days after the last administration of the study 
drugs. Recovery is defined as return to baseline level or CTCAE Grade 1, whichever 
is higher. Exception to this in patients who derive obvious clinical benefit according 
to the investigator’s judgement could be considered upon discussion with BI’s 
Clinical Monitor Local (CML). The dose reduction scheme provided in Table 
4.1.4.1.2: 1 should be followed in this case. 
• repeated episodes of drug related adverse reaction despite dose reductions 
• documented progressive disease as defined in Section 5.1.3 
• Cardiac left ventricular systolic dysfunction CTCAE Grade ≥2 at any time during the 
previous cycle or >20% decline in the resting ejection fraction from baseline. 
 
 


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A patient will be withdrawn from the study if: 
• patient withdrawal of consent and election to discontinue participation in the trial. 
Dates of patient withdrawal will be documented and the reason(s) for withdrawal 
recorded and discussed in the final study report. 
• termination of the study by the sponsor 
As soon as a patient is withdrawn from the trial, the next scheduled visit and the EOT have to 
be performed if feasible (not in case patient has withdrawn consent). Every effort should be 
made to follow-up patients in case an adverse event is still ongoing at the time of withdrawal. 
The sponsor may remove patients from the study, after approval of amendment 5, if the 
patients have access to BIBW 2992 (Afatinib) through marketed product, an expanded-access 
program, named patient use program, compassionate use protocol or other means based on 
local regulation. If a patient is removed from the study, an end of treatment and follow up 
visit will need to be performed to ensure all adverse events are followed up. The cost of any 
on-going supply of BIBW 2992 (Afatanib) will be incurred by the Sponsor. 
6.3.1 
Replacement of patients 
Patients who do not receive study treatment during the chemoradiation phase for more than 5 
consecutive days or more than 8 non-consecutive days for any reasons other than DLT will 
be replaced. 


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7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
7.1 
STATISTICAL DESIGN - MODEL  
This trial will use safety, pharmacokinetic and preliminary therapeutic effects of BIBW 2992 
to identify the optimal dose to investigate in future studies. Cohorts of patients will be entered 
sequentially into escalating dosage tiers with the aim of establishing the optimal dosage of 
BIBW 2992 to administer in combination with TMZ in combination with radiotherapy in 
patients with newly diagnosed GBM with a methylated or unmethylated MGMT-promoter 
(regimen M). Cohorts of patients will also be entered sequentially into escalating dosage tiers 
with the aim of establishing the optimal dosage of BIBW 2992 to administer in combination 
with radiotherapy in patients with newly diagnosed GBM with an unmethylated MGMT-
promoter (regimen U). 
This "3+3" dose escalation design is conventional for Phase I oncology studies. This trial is 
open-labelled, which allows the safety of each dose of BIBW 2992 to be assessed before 
treating additional patients with higher doses. Patients will not be randomised; they will be 
assigned to the cohort that is being filled at the time the patient is ready to enter the trial.   
The dose escalation procedure is described in Section 4.1.4. 
7.2 
NULL AND ALTERNATIVE HYPOTHESES 
No formal hypothesis testing is planned. 
7.3 
PLANNED ANALYSES  
All patients who receive at least one administration of a study treatment regimen will be 
included in the analysis of efficacy and safety. Results will be presented by treatment 
regimen and dosage cohort but comparisons will not be carried out between regimens or 
cohorts.  
7.3.1 
Primary analyses  
The primary analysis will summarise DLT with the aim of determining the MTD and the 
recommended dosage of BIBW 2992. 
All adverse events and laboratory abnormalities that meet the criteria for DLT described in 
Section 5.2.3 (irrespective of relatedness to study regimen) will be tabulated by treatment 
regimen and dosage cohort. This table will list the key characteristics for each AE, to include 
whether it was judged to have been a DLT, the preferred term, maximum CTCAE grade, 
clinical consequences, and study period at onset and study day at onset. 
A second table will summarise the number and percentage of patients who experienced DLT 
within each dosage cohort, by treatment regimen.  Furthermore, for each cohort, this table 
will summarise by key characteristics, to include preferred terms, maximum CTCAE grade, 
clinical consequences and timing of onset. 


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7.3.2 
Secondary analyses 
7.3.2.1 Tumour response 
Tumour response for each patient will be assigned according to the Macdonald criteria as 
specified in Section 5.1.3. Objective tumour response is defined as complete response (CR) 
or partial response (PR). 
Tumour response according to the separate components of the MacDonald criteria (CR, PR, 
SD or PD) will be tabulated by treatment regimen and dosage cohort according to the 
patient's best response during the study.  
7.3.3 
Safety analyses 
The primary analysis of safety, that is DLT for dose determination, is described in Section 
7.3.1. 
Further safety analyses will tabulate adverse events graded according to CTCAE, Version 3.0 
(R04-0474) by dosage cohort. 
In-depth analyses will describe the onset, CTCAE grades, duration and clinical consequences 
of: 
• 
Diarrhoea; 
• 
Nausea and vomiting; 
• 
Rash and acne; 
• 
Worsening of cardiac left ventricular function; 
• 
Worsening of laboratory abnormalities; 
• 
Other AEs that occur with sufficient overall frequency (>10%). 
In addition, laboratory evaluations will be summarised by calculating descriptive statistics for 
difference from baseline. 
7.3.4 
Interim analyses 
No formal interim analysis of efficacy is planned. 
A safety analysis may be performed after the last patient remaining in the last dose cohort of 
each treatment regimen (Regimen M and Regimen U) has completed the concomitant 
treatment period (6 weeks of concomitant radiochemotherapy) or has dropped out of the 
study. A database snapshot will be performed for this purpose. Objectives of this analysis will 
be: 
• 
To determine the MTD for each regimen (Regimen M and Regimen U); 
• 
To recommend the optimal dose of BIBW 2992 to investigate in future studies. 
 
This analysis will therefore summarise incidence of DLT, for MTD determination. The 
analysis will also report safety observations collected beyond the concomitant treatment 
period where feasible, to facilitate selection of the optimal dose. Additional details of this 


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safety analysis will be specified in the Trial Statistical Analysis Plan (TSAP) and the results 
will be documented and archived. 
7.3.5 
Pharmacokinetic methods 
BIBW 2992 plasma concentrations will be summarized by time point by descriptive statistics 
and, if feasible, graphically inspected. Predose (trough) plasma concentrations will be 
compared to historical data to estimate a possible effect of RT and/or TMZ on the 
pharmacokinetics of BIBW 2992. 
7.4 
HANDLING OF MISSING DATA  
The primary objective of this study is related to safety and as such will be based on observed 
data only. 
7.4.1 
Pharmacokinetic parameters 
See Appendix 10.3. 
7.5 
RANDOMISATION  
Patients will be assigned sequentially to the dose cohort that is being filled at the time the 
patient is ready to enter the trial according to the scheme described in Section 4.1.4; therefore 
no randomisation is necessary.  
7.6 
DETERMINATION OF SAMPLE SIZE  
Forty eight patients will be required; if for each of the study treatment regimens (Regimen M 
and Regimen U), the MTD cohort is expanded to include 12 patients and the other two dose 
cohorts require 6 patients each.    


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8. 
ADMINISTRATIVE MATTERS 
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, version as of October 1996 (as long as local laws do not require to 
follow other versions), in accordance with the ICH Harmonised Tripartite Guideline for Good 
Clinical Practice (GCP) and relevant BI SOPs. Standard medical care (prophylactic, 
diagnostic and therapeutic procedures) remains in the responsibility of the treating physician 
of the patient. 
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 
ETHICS 
8.1.1 
Independent Ethics Committee or Institutional Review Board 
The trial will not be initiated before the protocol and informed consent and patient 
information form have been reviewed and received approval / favourable opinion from the 
local Independent Ethics Committee (IEC) and approval by the Competent Authority (CA). 
Should a CTP amendment be made that needs IEC approval and authority 
notification/approval, the changes in the CTP will not be instituted until the amendment and 
revised informed consent (if appropriate) have been reviewed and received approval / 
favourable opinion from the local IEC and the CA. A CTP amendment intended to eliminate 
an apparent immediate hazard to patients may be implemented immediately providing that 
the regulatory authority and IEC are notified as soon as possible and an approval is requested. 
CTP amendments exclusively for logistical or administrative changes may be implemented 
with notification to the IEC and CA only. 
The constitution of the IEC must meet the requirements of ICH GCP and of the participating 
country / countries. A list of the IEC members who attended the meeting when the CTP / 
CTP amendment was discussed, including names and qualifications, needs to be provided by 
the IEC to sponsor. The Sponsor must provide to the regulatory authorities the name and 
address of the IEC along with a statement from the IEC that it is organised according to GCP 
and the applicable laws and regulations. The IEC must perform all duties outlined by the 
requirements of ICH GCP and of the participating country / countries.  
8.1.2 
Patient Information and Informed Consent 
Prior to patient participation in the trial, written informed consent(s) must be obtained from 
each patient (or the patient’s legally accepted representative) 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(s) and any additional patient information must be given to each patient or 
the patient’s legally accepted representative.  


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The patient 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. 
The patient 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 IEC members, and by inspectors from regulatory authorities.   
Should a CTP amendment become necessary, the patient consent form and patient 
information form may need to be revised to reflect the changes to the CTP. It is the 
responsibility of the sponsor to ensure that an amended consent form is reviewed and has 
received approval / favourable opinion from the IEC and CA, and that it is signed by all 
patients subsequently entered in the trial and those currently in the trial, if affected by the 
amendment. 
8.2 
RECORDS 
8.2.1 
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 / pharmacist / investigational drug storage manager 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 / 
pharmacist / investigational drug storage manager 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 return to the sponsor (or 
appointed CRO), the investigator / pharmacist / investigational drug storage manager must 
verify that all unused or partially used drug supplies have been returned by the clinical trial 
patient and that no remaining supplies are in the investigator’s possession. 
8.2.2 
Emergency code break 
Not applicable  
8.2.3 
Case Report Forms (CRFs) 
All of the clinical data will be captured via electronic data capture (EDC) using the Oracle 
Clinical Remote Data Capture system, a web-based tool. The investigator site staff will enter 
and edit the data via a secure network, with secure access features (username, password and 
secure identification or username and password – an electronic password system). A 
complete electronic audit trail will be maintained. The investigator will approve the data 


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using an electronic signature (Ref: 21 CFR Part 11), and this approval is used to confirm the 
accuracy of the data recorded. 
Electronic CRFs (eCRFs) will be used for all patients. The investigator’s data will be 
accessible from the investigator’s site throughout the trial. Relevant medical history prior to 
enrolment will be documented at the baseline visit. Thereafter during the trial, narrative 
statements relative to the patient’s progress during the trial will be maintained. The electronic 
CRFs must be kept current to reflect patient status at each phase during the course of the trial. 
The patients must not be identified on the electronic CRF by name. Appropriate coded 
identification (i.e. Patient Number) must be used. The investigator must make a separate 
confidential record of these details (patient identification code list) to permit identification of 
all patients enrolled in a clinical trial in case follow-up is required. While a trial is ongoing 
and until the access to the database has been terminated, there will be no Documentation of 
Changes (DOCs). All changes will be requested from the investigator through the EDC 
system. If a change is necessary once the investigator has no further access to the database, a 
DOC will be sent to the investigator for confirmation of the change. The investigator’s 
signature is requested to show he/she agrees with the change that was made. The original 
DOC is kept by the investigator. 
Copies of the electronic CRF together with all data changes made will be supplied to the 
investigator at the end of the trial. The investigator will be responsible for retaining all 
records pertaining to the trial as specified in the appropriate contract. 
8.2.4 
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 (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) 
• 
Conclusion of Patient’s Participation in the trial 


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8.2.5 
Direct access to source data - documents 
The investigator / institution will permit trial-related monitoring, audits, 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 8.2.4. 
8.3 
QUALITY ASSURANCE AUDIT 
A quality assurance audit of this trial may be conducted by the sponsor or sponsor’s 
designees. 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. 
8.4 
PROCEDURES 
8.4.1 
Adverse events 
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 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment. 
All adverse events occurring during the course of the clinical trial (i.e., from signing the 
informed consent number 2 or 3 onwards to follow up visit (28 days after EOT)) will be 
collected, documented and reported to the sponsor by the investigator according to the 
specific definitions and instructions detailed in the ‘Adverse Event Reporting’ section of the 
Investigator Site File. 
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. 
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”, if a non serious 
AE is identified to be serious per BI definition, a query will be raised. 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. 


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Progressive disease will not be recorded as an SAE if it is considered the natural course of the 
malignant disease but it will be recorded in the eCRF as outcome. Signs and symptoms of 
progressive disease may be reported as an AE (for details see Section 5.2.2) 
All adverse events, serious and non-serious, will be fully documented on the appropriate 
eCRFs. For each adverse event, the investigator will provide the onset, end, intensity, 
treatment required, outcome, seriousness and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined in 
the 'Adverse Event Reporting' Section of the Investigator Site File.  
The basis for judging the intensity of the AE has to follow the criteria laid out in the common 
terminology criteria for adverse events (CTCAE Version 3, R04-0474). 
In addition the intensity of the SAE is also described as below. 
Intensity of event 
• 
Mild:  
Awareness of sign(s) or symptom(s) which is/are easily tolerated 
• 
Moderate: 
Enough discomfort to cause interference with usual activity 
• 
Severe:  
Incapacitating or causing inability to work or to perform usual 
Activities 
The basis for judging the causal relationship between the investigational product at the AE is 
described below, 
Causal relationship 
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 
drug administered and the AE.  
• 
No: 
There is no reasonable causal relationship between the investigational 
drug administered and the AE.  
If a SAE is reported from a still blinded trial, the causal relationship must be provided by the 
investigator for all potential trial drugs, i.e. the BI trial drug and for all other trial drugs (i.e. 
any active comparator or placebo according to the trial design). 
The investigator has the obligation to report AEs/SAEs occuring between inform consent and 
the follow-up visit (28 days after EOT visit), regardless of causality. Adverse events that 
occur more than 28 days after last administration of study drug will only be reported if they 
are considered drug- or trial procedure-related. Deaths occurring after the follow-up visit (28 
days after EOT visit) do not need to be reported as SAEs unless considered related to study 
treatment or procedures. Any AEs reported to the sponsor during this phase must be 
documented in the safety database. 


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SAEs and significant AEs are to be reported to the sponsor using the BI Serious Adverse 
Event Report Form including a documented causal relationship assessment and providing as 
much detail regarding the SAE as possible. With receipt of follow-up information, all 
remaining fields on the SAE form are to be completed or updated. 
Any serious or significant AE, whether or not considered related to the investigational 
product, and whether or not the investigational product has been administered, must be 
reported immediately by telephone / fax to the sponsor. Expedited reporting of serious 
adverse events, e.g. suspected unexpected serious adverse reactions (SUSARs), will be done 
according to local regulatory requirements. Further details regarding this reporting procedure 
are provided in the ISF. 
Following every such telephone / fax report, the Clinical Monitor must provide a written 
report of the serious or significant AE and any sequelae to Corporate Drug Safety according 
to the appropriate Corporate SOP(s). These narratives, which confirm the information 
collected by telephone, may give additional information not available at the time of the initial 
report. 
8.4.2 
Emergency procedures 
Any serious or significant AE, whether or not considered related to the investigational 
product, and whether or not the investigational product has been administered, must be 
reported immediately by telephone / fax to the sponsor. Details regarding this reporting 
procedure are provided in the Investigator Site File. 
8.4.3 
Contraception and Pregnancy 
Female patients who are not of childbearing potential due to being postmenopausal (2 years 
without menses) or surgical sterilisation (oophorectomy, hysterectomy and/or tubal ligation) 
do not need to use contraception. 
All other female patients are considered to have childbearing potential and should use 
adequate contraception throughout the study (from screening until end of study participation 
or 28 days after last dose of trial medication, whichever is later). 
Acceptable methods of contraception for females include hormonal contraception and double 
barrier method. Double barrier method of contraception is defined as two barrier methods 
used simultaneously each time the patient has intercourse. Accepted barrier methods include 
diaphragm, female condom, cervical cap, male condom and IUD (the diaphragm and cervical 
cap must be used in conjunction with spermicidal jelly/cream). If hormonal contraceptives 
are used, at least one barrier method should also be used. Partner vasectomy, natural 'rhythm' 
and spermicidal jelly/cream are not acceptable as methods of contraception. 
Male patients should use adequate contraception throughout the study (e.g. condom and 
spermicidal jelly).Female patients must have a negative pregnancy test (β-HCG test in urine 
or serum) prior to commencing study treatment. 


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If a patient is found to be pregnant during study participation, this should be handled as 
follows; 
Table 8.4.3: 1 Pregnancy reporting 
Timing of pregnancy 
Action 
Prior to commencing 
study medication 
Patient should be withdrawn from the study immediately. 
No reporting necessary. 
During study treatment 
 
Treatment must be stopped immediately and the pregnancy should 
be reported to the sponsor immediately using the pregnancy form. 
If the investigator wishes to give any further treatment with study 
medication, this must be discussed and agreed with the BI clinical 
monitor. The pregnancy should be followed up to final outcome 
and the outcome, including any premature termination should be 
reported to the sponsor on the pregnancy form. 
In addition, any event leading to the termination of pregnancy (i.e. 
spontaneous, accidental, or induced abortion; as well as 
miscarriage, intrauterine foetal demise/death) must be reported as 
an SAE. 
During follow-up (after 
finishing treatment but 
before end of study 
participation). 
The pregnancy should be reported to the sponsor immediately 
using the pregnancy form. 
The pregnancy should be followed up to final outcome and the 
outcome, including any premature termination should be reported 
to the sponsor on the pregnancy form. 
In addition, any event leading to the termination of pregnancy (i.e. 
spontaneous, accidental, or induced abortion; as well as 
miscarriage, intrauterine foetal demise/death) must be reported as 
an SAE. 
Within 28 days of last 
dose of study medication 
(even if no longer 
participating in study) 
 
8.5 
RULES FOR AMENDING PROTOCOL 
All CTP amendments must be documented, dated and signed by all signatories (or their 
successors) of the original protocol. This also applies to any local amendment that may 
become necessary. Amendments (excluding those exclusively for administrative or logistical 
changes) need to be submitted to the IEC for review/approval and to the competent authority 
(CA) for approval. 
8.6 
DISCONTINUATION OF THE TRIAL BY THE SPONSOR 
Boehringer Ingelheim reserves the right to discontinue the trial at any time for the following 
reasons: 
1. Failure to meet expected enrolment goals overall or at a particular trial site, 


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2. emergence of any efficacy/safety information that could significantly affect continuation 
of the trial, or any other administrative reasons, 
3. violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing the 
appropriate conduct of the trial. 
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason). 
8.7 
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 i.e. the CA. 
8.8 
PUBLICATION POLICY 
Boehringer Ingelheim is as much as possible dedicated to support process of free exchange of 
relevant scientific information.  Any publication of the result of this trial must be consistent 
with the Boehringer Ingelheim publication policy.  The rights of the investigator and of the 
sponsor with regard to publication of the results of this trial are described in the investigator 
contract. As a general rule, no trial results should be published prior to finalisation of the 
Clinical Trial Report (CTR). 
 
8.9 
COMPLETION OF TRIAL 
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial or early termination of the trial.  
 
 


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9. 
REFERENCES  
9.1 
PUBLISHED REFERENCES 
P06-08275 
Solca F, Schweifer N, Baum A, Rudolph D, Amelsberg A, Himmelsbach F, 
Beug H. BIBW 2992, an irreversible dual EGFR/HER2 kinase inhibitor, 
shows activity on L858R/T790M EGFR mutants. AACR-NCI-EORTC Int 
Conf 'Molecular Targets and Cancer Therapeutics: Discovery, Biology, and 
Clinical Applications', Philadelphia, 14 - 18 Nov 2005 Clin Cancer Res 
2005;11(23)(Suppl) Abstr A242 
P08-06904 
Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, 
Padera RF, Shapiro GI, Baum A, Himmelsbach F, Rettig WJ, Meyerson M, 
Solca F, Greulich H, Wong KK. BIBW2992, an irreversible EGFR/HER2 
inhibitor highly effective in preclinical lung cancer models. Oncogene, 
advance online publication, 14 April 2008; doi:10.1038/onc.2008.109 
Oncogene 2008;27(34):4702-4711 
R02-2292 
Fry DW, Bridges AJ, Denny WA, Doherty A, Greis KD, Hicks JL, Hook 
KE, Keller PR, Leopold WR, Loo JA, McNamara DJ, Nelson JM, Sherwood 
V, Smaill JB, Trumpp-Kallmeyer S, Dobrusin EM. Specific, irreversible 
inactivation of the epidermal growth factor receptor and erbB2, by a new 
class of tyrosine kinase inhibitor. Proc Natl Acad Sci USA 1998;95:12022-
12027. 
R04-0474 
Common terminology criteria for adverse events Version 3.0 (CTCAE) 
(Publish Date: 12 December 2003). 
http://ctep.cancer.gov/forms/CTCAEv3.pdf; Cancer therapy evaluation 
program, common terminology criteria for adverse events, Version 3.0, 
DCTD, NCI, NIH, DHHS, 31 March 2003, Publish Date:12 December 2003. 
R06-0986 
Antiemetic Subcommittee of the Multinational Association of Supportive 
Care in Cancer (MASCC). Prevention of chemotherapy- and radiotherapy-
induced emesis: results of the 2004 Perugia International Antiemetic 
Consensus Conference. Ann Oncol 17 (1), 20 - 28 (2006). 
R06-1414 
Thomas JD, Adams DB, DeVries S, Ehler D, Greenberg N, Garcia M et al. 
Guidelines and recommendations for digital echocardiography: a report from 
the Digital Echocardiography Committee of the American Society of 
Echocardiography. J Am Soc Echocardiogr 18(3),287-297(2005). 
R06-1645 
Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ et 
al. Molecular determinants of the response of glioblastomas to EGFR kinase 
inhibitors.N Engl J Med. 2005 Nov 10;353(19):2012-24. 
R06-1666 
Common terminology criteria for adverse events v3.0 (CTCAEAE) (publish 
date: August 9, 2006). Cancer Therapy Evaluation Program, DCTD, NCI, 


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NIH, DHHS (March 31, 2003 (http://ctep.cancer.gov), publish date: August 
9, 2006); http://ctep.cancer.gov/forms/CTCAEAEv3.pdf (2006). 
R07-4077 
Giaccone G, Melosky B, Reck M. Epidermal growth factor receptor 
inhibitor (EGFRI)-associated rash: a suggested novel management 
paradigm. A consensus position from the EGFRI dermatologic toxicity 
forum. ECCO 14, 14th Eur Cancer Conf, Barcelona, 23 - 27 Sep 2007 
(Poster). 
R08-1053 
Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG.Response criteria 
for phase II studies of supratentorial malignant glioma.J Clin Oncol. 1990 
Jul;8(7):1277-80. 
R08-1056 
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ et 
al. Radiotherapy plus concomitant and adjuvant temozolomide for 
glioblastoma.N Engl J Med. 2005;352(10):987-96. 
R08-1057 
Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD et al. A 
phase II study of temozolomide vs. procarbazine in patients with 
glioblastoma multiforme at first relapse.Br J Cancer. 2000;83(5):588-93.
 
 
R08-1063 
Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP et al. 
Epidermal growth factor receptor variant III status defines clinically distinct 
subtypes of glioblastoma.J Clin Oncol. 2007;25(16):2288-94. 
R08-1064 
Frederick L, Wang XY, Eley G, James CD.Diversity and frequency of 
epidermal growth factor receptor mutations in human glioblastomas.Cancer 
Res. 2000;60(5):1383-7. 
R08-5066  
Hegi ME, Liu L, Herman JG, Stupp R, Wick W, Weller M et al. Correlation 
of O6-methylguanine methyltransferase (MGMT) promoter methylation 
with clinical outcomes in glioblastoma and clinical strategies to modulate 
MGMT activity. J Clin Oncol 2008;26(25):4189-4199. 
R08-5067 
Hegi ME, Diserens AC, Gorlia T, Hamou MF, Tribolet N de, Weller M, 
Kros et al. MGMT gene silencing and benefit from temozolomide in 
glioblastoma. N Engl J Med 2005;352:997-1003.  
R08-5252 
Belanich M, Pastor M, Randall T, Guerra D, Kibitel J, Alas L, et al. 
Retrospective study of the correlation between the DNA repair protein 
alkyltransferase and survival of brain tumor patients treated with carmustine. 
Cancer Res 1996;56:783-788. 
R08-5253 
Chen ZP, Yarosh D, Garcia Y, Tampieri D, Mohr G, Malapetsa A et al. 
Relationship between O6-methylguanine-DNA methyltransferase levels and 
clinical response induced by chloroethylnitrosourea therapy in glioma 
patients. Can J Neurol Sci 1999;26(2):104-109. 


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R08-5254 
Jaeckle KA, Eyre HJ, Townsend JJ, Schulman S, Knudson HM, Belanich M 
et al. Correlation of tumor O6 methylguanine-DNA methyltransferase levels 
with survival of malignant astrocytoma patients treated with bis-
chloroethylnitrosourea: a Southwest Oncology Group Study. J Clin Oncol 
1998;16(10):3310-3315. 
R08-5255 
Friedman HS, et al. DNA mismatch repair and O6-alkylguanine-DNA 
alkyltransferase analysis and response to temodal in newly diagnosed 
malignant glioma. J Clin Oncol 1998;16(12):3851-3857. 
R08-5256 
Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, 
Vanaclocha V et al. Inactivation of the DNA-repair gene MGMT and the 
clinical response of gliomas to alkylating agents. N Engl J Med 
2000;343(19):1350-1354. 
R08-5429 
Paz MF, Yaya-Tur R, Rojas-Marcos I, Reynes G, Pollan M, Aguirre-Cruz L 
et al. CpG island hypermethylation of the DNA repair enzyme 
methyltransferase predicts response to temozolomide in primary gliomas. 
Clin Cancer Res 2004;10:4933-4938. 
R09-0277 
Rich JN; Reardon DA; Peery T; Dowell JM; Quinn JA; Penne KL; 
Wikstrand CJ;Duyn LB van; Dancey JE; McLendon RE; Kao JC; Stenzel 
TT; Rasheed BKA; Tourt-Uhlig SE; Herndon JE; Vredenburgh JJ; Sampson 
JH; Friedman AH; Bigner DD; Friedman HS; Phase II trial of gefitinib in 
recurrent glioblastoma.J Clin Oncol 2004 ; 22(1) ; 133-142. 
R09-0092 
Schmidt-Ullrich RK, Mikkelsen RB, Dent P, Todd DG, Valerie K, 
Kavanagh BD et al. Radiation-induced proliferation of the human A431 
squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. 
Oncogene 1997;15:1191-1197. 
R09-0093 
Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor 
blockade with C225 modulates proliferation, apoptosis, and radiosensitivity 
in squamous cell carcinomas of the head and neck. Cancer Res 
1999;59:1935-1940. 
R09-0094 
Goldkorn T, Balaban N, Shannon M, Matsukuma K. EGF receptor 
phosphorylation is affected by ionizing radiation. Biochim Biophys Acta 
Mol Cell Res 1997;1358(3):289-299. 
R09-0095 
Prados MD; Chang SM; Butowski N; DeBoer R; Parvataneni R; Carliner H; 
Kabuubi P; Ayers-Ringler J; Rabbitt J; Page M; Fedoroff A; Sneed PK; 
Berger MS; McDermott MW; Parsa AT; Vandenberg S; James CD; 
Lamborn KR; Stokoe D; Haas-Kogan DA; Phase II study of erlotinib plus 
temozolomide during and after radiation therapy in patients with newly 
diagnosed glioblastoma multiforme or gliosarcoma.; Journal of Clinical 
Oncology, Published Ahead of Print on December 15, 2 as 10.1200/JCO 
.2008.18.9639; 2008. 


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R09-0097 
Barker FG, Simmons ML, Chang SM, Prados MD, Larson DA, Sneed PK et 
al. EGFR overexpression and radiation response in glioblastoma multiforme. 
Int J Radiat Oncol Biol Phys 2001;51(2):410-418. 
R09-0099 
Dent P, Reardon DB, Park JS, Bowers G, Logsdon C, Valerie K et al. 
Radiation-induced release of transforming growth factor alpha activates the 
epidermal growth factor receptor and mitogen-activated protein kinase 
pathway in carcinoma cells, leading to increased proliferation and protection 
from radiation-induced cell death. Mol Biol Cell 1999;10:2493-2506. 
R09-0183 
Lammering G, Valerie K, Lin PS, Mikkelsen RB, Contessa JN, Feden JP et 
al. Radiosensitization of malignant glioma cells through overexpression of 
dominant-negative epidermal growth factor receptor. Clin Cancer Res 
2001;7:682-690. 
R09-0184 
Brown PD, Krishnan S, Sarkaria JN, Wu W, Jaeckle KA, Uhm JH et al.. 
Phase I/II trial of erlotinib and temozolomide with radiation therapy in the 
treatment of newly diagnosed glioblastoma multiforme: North Central 
Cancer Treatment Group Study N0177. J Clin Oncol 2008;26(34):5603-
5609. 
R09-0524 
Franceschi E, Cavallo G, Lonardi S, Magrini E, Tosoni A, Grosso et al.  
Gefitinib in patients with progressive high-grade gliomas: a multicentre 
phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia 
(GICNO).Br J Cancer. 2007 Apr 10;96(7):1047-51. 
R09-0525 
Vogelbaum MA, Peereboom DM, Stevens G, Barnett G, Brewer C. Phase II 
study of erlotinib single agent therapy in recurrent glioblastoma multiforme. 
Eur J Cancer Suppl 2005;3:135. 
R96-2656 
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state".A practical 
method for grading the cognitive state of patients for the clinician. J 
Psychiatr Res 1975;12(3):189-198. 
R09-6378  
W.P Mason, R. Del Maestro, D Eisenstat, P.Forsynth, D. Fulton, N. 
Laperriere, D.Macdonald, J.Perry, and B. Thiessen. Canadian 
recommendations for the treatment of glioblastoma multiforme. 
R10-6416  
Stupp R, et al, European Organisation for Research and Treatment of Cancer 
Brain Tumour Group, European Organisation for Research and Treatment of 
Cancer Radiation Oncology Group, National Cancer Institute of Canada 
Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant 
temozolomide versus radiotherapy alone on survival in glioblastoma in a 
randomised phase III study: 5-year analysis of the EORTC-NCIC trial. 
Lancet Oncol 2009;10:459-466. 
 


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9.2 
UNPUBLISHED REFERENCES 
U03-1562 
 BIBW 2992 MA2: Whole body autoradiography after intravenous 
administration of [14C]BIBW 2992 MA2 in male albino and male 
pigmented rats and oral administration in male albino rats (A058/03UB). 11 
Aug 2003. 
U03-3218 
 M.D and 
 Investigator's Brochure. Oral 
Treatment of Cancer (A173/05LU). Version 8. 27 November 2008. 
U04-1028 
 Metabolism of BIBW 2992 MA2 in rats and covalent 
binding of BIBW 2992 MA2 to blood constituents. A224/02TE,B2211         
5 February 2004 
U04-2147 
 Evaluation of the combination 
of EGFR/HER2-tyrosine kinase-inhibition by BIBW 2992 or BIBW 2669 
with radiation therapy on the human squamous cell-carcinoma cell line 
FaDu,22-04 11 January 2005. 
U05-1723-01 
 Investigation of the human cytochrome P450 
enzymes involved in the metabolism of [14C]BIBW 2992 MA2 
(A173/05LU). 7 July 2005. 
U06-1093 
. Absorption, distribution and metabolism of 
BIBW 2992 MA2 in minipigs. A239, 05TE, A129/05RB, B2705, B2706   
13 February 2006 
U06-2055-01 
 A Phase I open label dose escalation study of 
once-daily oral treatment with BIBW 2992 for 14 days in patients with 
advanced solid tumors. 1200.1 10 November 2006. 
U07-1296-01 
Metabolism of BIBW 2992 MA2 in human. A445/05BC, B3144  
31 May 2007 
U07-1338-01 
 BIBW 2992, An irreversible dual EGFR/HER2 kinase 
inhibitor, shows activity on L858R – and L858R/T790M-EGFR mutants, 
07-06 May 06, 2007. 
U07-1737 
 Metabolism of [14C]BIBW 2992 MA2 in healthy 
volunteers. A256/06TE, B3159 11 September 2007. 


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10. 
APPENDICES 
10.1 
HANDLING PROCEDURE OF BLOOD SAMPLES FOR PLASMA 
CONCENTRATION-TIME MEASUREMENTS 
Table 10.1: 1 Time schedule for PK blood sampling  
Treatm
ent 
Period 
Visit 
Event 
Name 
Day 
Time Frame 
[hh:min] 
CRF Time 
/PTM 
Event 
Sample 
No 
 
 
 
 
During 
RT 
2 
V2 
8 
Just before BIBW 
intake 
-0:05 
PK Blood 
1 
3 
V3 
15 
 
Just before BIBW 
intake 
-0:05 
PK Blood 
2 
0:30 – 2:00 
1:00 
PK Blood  
3 
2:00 – 4:00 
3:00 
PK Blood  
4 
4:00 – 24:00 
6:00 
PK Blood 
5 
voluntary 
4 
V4 
29 
Just before BIBW 
intake 
-0:05 
PK Blood 
6 
 
10.2 
HANDLING OF MISSING DATA 
10.2.1 
Plasma concentration - time profiles 
Concentration data identified with NOS (no sample available), NOR (no valid result), NOA 
(not analyzed), BLQ (below the limit of quantification), and NOP (no peak detectable) will 
be ignored and not replaced by zero at any time point (applies also to the lag phase including 
the pre-dose value). Descriptive statistics of concentrations at specific time points will be 
calculated only when at least 2/3 of the individuals have concentrations within the validated 
concentration range. The overall sample size to decide whether the “2/3 rule” is fulfilled will 
be based on the total number of samples intended to be drawn for that time point (i.e. BLQ, 
NOR, NOS, NOA, NOP are included). 
 


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10.3 
KARNOFSKY PERFORMANCE SCALE 
Able to carry on normal 
activity and to work; no 
special care needed. 
  100   
Normal no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms 
of disease.  
Unable to work; able to 
live at home and care for 
most personal needs; 
varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on normal activity or to 
do active work. 
60 
Requires occasional assistance, but is able to care for 
most of his personal needs. 
50 
Requires considerable assistance and frequent 
medical care.  
Unable to care for self; 
requires equivalent of 
institutional or hospital 
care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated 
although death not imminent. 
20 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead 
 


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10.4 
MINI MENTAL STATE EXAMINATION (MMSE) 
 
Reproduced by special permission of the publisher, Psychological Assessment Resources, Inc., 16204 North 
Florida Avenue, Lutz, Florida 33549, from the Mini Mental State Examination, by Marshall Folstein and Susan 
Folstein, Copyright 1975, 1998, 2001 by Mini Mental LLC, Inc. Published 2001 by Psychological Assessment 
Resources, Inc. Further reproduction is prohibited without permission of PAR, Inc. The MMSE can be 
purchased from PAR, Inc by calling (813) 968-3003. 


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10.5 
COCKCROFT-GAULT-FORMULA 
The Cockroft-Gault-Formula is commonly used to estimate GFR and is the recommended 
formula to calculate GFR in this trial. 
 
(140 - age)  x  weight  x  FS 
 
GFR =  
───────────────────── 
 
serum creatinine  x  72 
Units: GFR [ml/min], age [years], weight [kg], serum creatinine [mg/dl], FS is a correction 
Factor for Sex: in males FS = 1, in females FS = 0,85 
 
10.6 
RADIOTHERAPY TECHNIQUE 
Patients should be treated with localised irradiation to the planning target volume (PTV) 
including the tumour [gross tumour volume (GTV), clinical target volume (CTV)] and a 
defined margin.  Dose prescription and planning should follow the ICRU 50 guidelines. 
Immobilisation and imaging 
All patients should be immobilised in an individually moulded immobilisation device 
(usually TP shell) specific to the department in a stable position (usually but not exclusively 
supine). 
Target volumes 
The target volume is to be defined on post-operative planning CT/MRI together with pre-
operative images. For enhancing tumours, the CTV is defined as the region of enhancement 
using the combination of the two sets of images. The PTV will be defined as the CTV with a 
margin of between 2 and 5cm, based on local practice although it is recommended that a 
standard 3cm margin is used around the CTV. For unenhancing tumours, the CTV should 
comprise the region of low intensity on T1 and high signal intensity on T2 and FLAIR 
sequences (low attenuation on CT). The PTV is defined as the CTV with a margin of 2 to 4 
cm although it is recommended 2cm is used. For patients with a presumed transformed 
glioma which has both enhancing and unenhancing components, the CTV should be as for 
unenhancing tumours, including the full extent of the disease. In patients who have had 
complete macroscopic resection of the tumour, the CTV should be estimated from 
preoperative CT/MRI appropriately adjusted for a recognized shift due to resolution of a 
mass effect.  In practice the CTV should at least cover the full excision cavity margins (not 
necessarily margins which would have been away from the primary tumour). The CTV – 
PTV margin should be as specified for unenhancing and enhancing tumours. In all instances 
the PTV should be adjusted/reduced when traversed by anatomical barriers to tumour 
migration and spread, such as the skull, falx or tentorium. This should therefore lead to 
outlining of volume to avoid  extension into the orbit and below the cranial cavity beyond 
that necessary to account for immobilization and machine uncertainties. It is recommended 
that the same volume is used throughout the course of treatment 


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Planning and delivery 
Radiotherapy should be given conformally, using a multiple field technique and appropriate 
shielding or beam shaping to achieve PTV dose homogeneity as defined in ICRU 50.  All 
fields should be treated daily. QA checks of delivery with on treatment imaging should be 
carried out according to local practice. 
Dose limits 
The planning priority is to treat CTV and a minimum of 1cm margin to the prescribed dose. It 
is suggested that dose to critical structures such as the brain stem and the optic apparatus is 
kept below 55Gy although this should not be at the expense of CTV coverage. Peripheral 
portion of PTV may be adjusted to achieve normal tissue sparing. Scalp sparing techniques to 
avoid permanent hair loss should be used as is standard practice in the department but they 
must not compromise on a minimum 1cm CTV-PTV margin. 
Radiotherapy schedule 
Radiotherapy should be given as fractionated treatment, delivering a total dose of 60 Gy in 6 
weeks specified at 100%, given as a once daily schedule of 2 Gy per fraction, for a total of 30 
fractions.  All fields should be treated daily.  
Delays in Radiotherapy 
Delays should be avoided if at all possible. There is a potential risk of bleeding in patients 
with low platelets, and if a platelet count < 25 x 109/l is recorded, radiotherapy should be 
delayed until the platelets have recovered to > 50 x 109/l.   
Medical management during radiotherapy 
Cortisosteroids should not be prescribed routinely for patients during radiotherapy.  However 
in patients with raised intracranial pressure and/or progressive  neurological deficit 
responsive to steroids, they can be prescribed at the discretion of the clinical team.  The aim 
should be to titrate the dose to the lowest necessary to control the problems. 
 
 
 
 
 
 
 


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10.7   
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-glycoprotein may evolve, it is 
important for the investigator to assess such status on concomitant therapies and in case of 
questions contact BI clinical monitor. 
 
 
 
 
 
 
 


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10.8 
CLINICAL EVALUATION OF LIVER INJURY 
10.8.1 
Introduction 
Alerations of liver parameters, as described in section 5.2.2.1 (Protocol-Specified Significant 
Events), are to be further evaluated using the following procedures: 
10.8.2 
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 intial 
sample, the following must be completed; 
1) Evaluate the patient within 48 hours and,   
2) Perform the following laboratory tests: 
1. Repeat  of AST, ALT, bilirubin (with fractionation to total and direct)  
2. Haptoglobin 
3. Complete blood count and cell morphology 
4. Reticulocyte count 
5.  Creatinine Kinase (CK) 
6. Lactate dehydrogenase (LDH) 
7. Alkaline Phosphatase 
The results of these laboratory tests must be reported to BI as soon as possible. 
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 etiology 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: 
 
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; 


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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, coeruloplasmin*, α-1 antitrypsin*, transferrin*, amylase, lipase, 
fasting 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), Anti-Smooth Muscle antibody (titre), Anti-nuclear 
antibody (titre), Anti-LKM (liver-kidney microsomes) antibody, Anti-
mitochondrial antibody, Epstein Barr Virus (VCA IgG, VCA IgM), 
cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, IgM)*, varicella 
(IgG, IgM)*, parvovirus (IgG, IgM)* 
 
• Hormones, tumor-marker 
Thyroid-stimulating hormone(TSH)* 
 
• Haematology 
Thrombocytes, eosinophils 
 
*If clinically indicated (e.g. immunocompromised patients) 
 
- 
Long term follow-up 
 
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). 
 
and report these via the eCRF (for data not provided by a central laboratory). 
 
 
 

SAP_001.pdf: 
 
SIGNATURE INFORMATION 
 
Document: 
                               
                           
Document No.:                                                                                                                        
 
Title 
                             
 
 
 
 
 
 
                         
 
SIGNATURES  (ELECTRONICALLY OBTAINED)  
 
Meaning of Signature: 
Signed by: 
Date signed: (GMT) 
                                   
 
 
 
                               
                                                                            
                                   
 
 
 
                               
                                                                            
                                   
 
 
 
                               
                                                                            
                                   
 
 
 
                               
                                                                            
                                   
 
 
 
                               
                                                                            
                                  
 
 
 
                               
                                                                                                                     
                                   
 
 
 
                               
                                                                                                                       
1200-0038--tsap
T11-1081-01
Phase I, open label trial to explore safety of combining BIBW 2992 and
Radiotherapy with or without Temozolomide in newly diagnosed GBM
Author-Trial Statistician
12/1/2011 10:01:36
Author-Trial Clinical
Pharmacokineticist
12/1/2011 10:10:50
Author-Trial Clinical Monitor
12/1/2011 11:09:50
Verify Paper Signature Completion
12/1/2011 14:25:56
Approval-Project Statistician
12/1/2011 15:22:51


 
SIGNATURE INFORMATION (continued) 
Document 
                              
                          
Document No.:                                                                                                                        
 
Title 
                             
 
 
 
 
 
 
                         
SIGNATURES  (ELECTRONICALLY OBTAINED)  
(There are no entries on this page if there are up to seven signatures.) 
Meaning of Signature: 
Signed by: 
Date signed: (GMT) 
                                   
 
 
 
                               
                                                                                                                      
                                   
 
 
 
                               
                                                                                                                      
                                   
 
 
 
                               
                                                                                                                      
                                     
 
 
 
                                 
                                                                                                                      
                                     
 
 
                                 
                                                                                                                      
                                     
 
 
                               
                                                                                                                       
                                     
 
 
                                
                                                                                                                       
                                     
 
 
                                 
                                                                                                                     
 
1200-0038--tsap
T11-1081-01
Phase I, open label trial to explore safety of combining BIBW 2992 and
Radiotherapy with or without Temozolomide in newly diagnosed GBM


TITLE PAGE 
 
ABCD 
Trial Statistical Analysis Plan  
T11-1081-01 
BI Trial No.: 
1200.38 
Title: 
Phase I, open label trial to explore safety of combining BIBW 
2992 and Radiotherapy with or without Temozolomide in newly 
diagnosed GBM 
(Including Protocol Amendment 1 [U09-1323-01-AM1], Protocol 
Amendment 2 [U09-1323-01-AM2], Protocol Amendment 3 [U09-
1323-01-AM3]) 
Test substance: 
Tomtovok ®, afatinib (BIBW 2992) 
Responsible trial 
statistician: 
Phone: 
Fax:     
Date of statistical 
analysis plan: 
01 December 2011 SIGNED 
Version: 
Final 
Page 1 of 22
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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 .................................................................................. 6 
4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ...... 7 
5. 
ENDPOINTS .......................................................................................... 8 
5.1 
PRIMARY ENDPOINTS .................................................................................... 8 
5.2 
SECONDARY ENDPOINTS .............................................................................. 8 
5.2.1 
Key secondary endpoints ................................................................................ 8 
5.2.3 
(Other) Secondary endpoints ......................................................................... 8 
..................................... 8 
..................................... 8 
..................................... 8 
..................................... 9 
6. 
GENERAL ANALYSIS DEFINITIONS ........................................... 10 
6.1 
TREATMENTS .................................................................................................. 10 
6.2 
IMPORTANT PROTOCOL VIOLATIONS .................................................. 10 
6.3 
PATIENT SETS ANALYSED .......................................................................... 13 
.................................................................................................... 14 
6.5 
POOLING OF CENTRES ................................................................................ 14 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS ................................... 14 
6.7  
BASELINE, TIME WINDOWS AND CALCULATED VISITS .................. 14 
7. 
PLANNED ANALYSIS ....................................................................... 15 
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........ 15 
7.2 
CONCOMITANT DISEASES AND MEDICATION .................................... 15 
7.3 
TREATMENT COMPLIANCE ....................................................................... 15 
7.4 
PRIMARY ENDPOINTS .................................................................................. 15 
7.5 
SECONDARY ENDPOINTS ............................................................................ 16 
7.5.1 
Key secondary endpoints .............................................................................. 16 
7.5.2 
(Other) Secondary endpoints ....................................................................... 16 
............................................................................... 16 
7.7 
EXTENT OF EXPOSURE ................................................................................ 16 
7.8 
SAFETY ANALYSIS ......................................................................................... 16 
7.8.1 
Adverse events ............................................................................................... 16 
7.8.1.1 
Adverse events of special interest .............................................................. 17 
7.8.2 
Laboratory data ............................................................................................. 18 
7.8.3 
Vital signs ....................................................................................................... 18 
7.8.4 
ECG ................................................................................................................ 18 
7.8.5 
Others ............................................................................................................. 18 
8. 
REFERENCES ..................................................................................... 20 
............................................................... 21 
.......................................................................... 21 


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. 21 
10. 
HISTORY TABLE ............................................................................... 22 
 


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LIST OF TABLES 
Table 6.2: 1 
Important Protocol Violations ......................................................................... 11 
 


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2. 
LIST OF ABBREVIATIONS 
Term 
Definition / description 
AE 
Adverse event 
BI 
Boehringer Ingelheim 
BIBW 2992 
Afatinib 
BMI 
Body mass index 
BSA 
Body surface area 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTP 
Clinical Trial Protocol 
DLT 
Dose limiting toxicity 
EMA 
European Medicines Agency 
ICH 
International Conference on Harmonisation 
IPV 
Important protocol violation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGMT 
O6-methylguanine-DNA methyltransferase 
NCI 
National Cancer Institute 
PK 
Pharmacokinetics 
PR 
Partial response 
PT 
Preferred term 
RT 
Radiotherapy 
SAE 
Serious adverse event 
SD 
Standard deviation 
SIAE 
Significant adverse event 
SOC 
System Organ Class 
TMZ 
Temozolomide 
TSAP 
Trial statistical analysis plan 
 


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3. 
INTRODUCTION 
As per International Conference on Harmonisation (ICH) E9, 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 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, randomisation. 
SAS® Version 9.2 (or later version) will be used for all analyses. 
 


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4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY 
See statistical changes described in: 
• Protocol amendment 3, dated 07 February 2011 (1). 
 
In addition the following changes were not documented in CTP amendments. 
 
Section 7.3.3 of the CTP states: 
 
In-depth analyses will describe the onset, CTCAE grades, duration and clinical 
consequences of: 
• Diarrhoea; 
• Nausea and vomiting; 
• Rash and acne; 
• Worsening of cardiac left ventricular function; 
• Worsening of laboratory abnormalities; 
• Other AEs that occur with sufficient overall frequency (>10%). 
 
However project defined special grouped-term search categories have not been identified for 
either worsening of cardiac left ventricular function or laboratory abnormalities as reported 
adverse events (AEs), therefore in-depth analyses will not be performed as described above. 
Instead, descriptive statistics are planned for left ventricular ejection fraction which will 
include worst value on treatment and change from baseline. Furthermore, clinically 
significant laboratory abnormalities will be analysed according to Boehringer Ingelheim (BI) 
standards. Also, dependent on the final sample size, it is possible that all AEs will occur with 
frequency >10%; thus the other AEs that will be analysed in-depth will be determined 
pragmatically by the trial team. 


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5. 
ENDPOINTS 
5.1 
PRIMARY ENDPOINTS 
Investigator defined dose limiting toxicity during concomitant treatment period: 
At least one AE meeting the criteria for dose limiting toxicity (DLT; as determined by the 
investigator and defined in Section 5.2.3 of the CTP) with onset during the 42 day 
concomitant treatment period when trial medication is given concomitantly with radiotherapy 
(RT). 
5.2 
SECONDARY ENDPOINTS 
5.2.1 
Key secondary endpoints 
This section is not applicable as no key secondary endpoints have been specified in the CTP. 
5.2.3 
(Other) Secondary endpoints 
Adverse events: 
Maximum grade (severity) of AEs according to the United States National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. 
Objective response: 
Best overall response of complete response (CR) or partial response (PR), where best overall 
response is the best overall response to trial medication (without clinical disease assessment) 
according to the Macdonald criteria (defined in Section 5.1.3 of the CTP) recorded since first 
administration of trial medication and until disease progression or start of further anti-cancer 
treatment. 
Pharmacokinetic (PK) parameters: 
The derivation of standard PK parameters is performed according to BI standards. (2) 


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6. 
GENERAL ANALYSIS DEFINITIONS 
6.1 
TREATMENTS 
For safety analyses, data up to and including 28 days after last treatment intake will be 
considered as on-treatment. 
Patients will be analysed according to the treatment group initially assigned. All planned 
analysis will be presented by this treatment group. Handling of patients where treatment 
group assignment has not been followed will be handled on a case-by-case basis, to be agreed 
at report planning meetings. 
Analyses for Regimen M and Regimen U will be presented separately. 
6.2 
IMPORTANT PROTOCOL VIOLATIONS 
Important protocol violations (IPVs) are defined according to BI standards (3) and are 
specified in Table 6.2: 1 of this document. A per protocol set will not be defined for the 
analysis of this trial but IPVs will be described for patients in the treated set (as defined in 
Section 6.3 of this document). 


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Table 6.2: 1 
Important Protocol Violations 
Category / 
Code 
Description 
Comment/Example 
A 
 
Entrance criteria not met 
 
 
A1 
Diagnosis of trial disease questionable 
 
Inclusion criteria IN1 not met. 
or 
Trial diagnosis is not histologically-confirmed 
WHO Grade IV newly diagnosed malignant 
glioma. 
 
A2 
MGMT testing 
 
 
A2.1 
Methylated MGMT status not proven 
(Regimen M only) 
For patients in Regimen M enrolled before 
implementation of CTP amendment 3 only: 
Inclusion criteria IN2 not met. 
or 
MGMT test result is not methylated. 
or 
Date of MGMT test is missing. 
 
A2.2 
Unmethylated MGMT status not proven 
(Regimen U only) 
For patients in Regimen U enrolled before 
implementation of CTP amendment 3 only: 
Inclusion criteria IN2 not met. 
or 
MGMT test result is not un-methylated.  
or 
Date of MGMT test is missing. 
 
A2.3 
Tumour material not available for MGMT 
testing or MGMT test results not available 
For patients in Regimen M enrolled after 
implementation of CTP amendment 3 only: 
Inclusion criteria IN2 not met. 
or 
Both of the following: 
MGMT test result not already available. 
and  
Date of MGMT test is missing. 
 
A3 
Safety exclusion criteria met 
 
 
A3.1 
Prohibited baseline condition or diagnosis 
At least one of exclusion criteria EX6-E11is 
met. 
or 
At least one baseline condition meeting 
exclusion criteria (defined in Section 3.3.2 of 
the CTP). 
 
A3.2 
LVEF assessment indicating inadequate 
cardiac function 
Exclusion criteria EX12 is met. 
or 
Screening left ventricular ejection fraction 
(LVEF) both missing or < 50%. 
 
A3.3 
Laboratory result indicating inadequate 
organ function 
At least one of exclusion criteria EX13-E17 is 
met. 
or 
Screening and baseline laboratory results both 
missing or meeting exclusion criteria (defined in 
Section 3.3.2 of the CTP). 
 
A3.4 
Negative pregnancy test result not 
obtained 
Exclusion criteria EX19 is met. 
or 
For female patient with reproductive potential, 
screening pregnancy test is positive or not done. 
 
A3.5 
Hypersensitivity to trial medication 
Exclusion criteria EX22 is met. 


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Table 6.2: 1 
Important Protocol Violations (continued) 
Category / 
Code 
Description 
Comment/Example 
 
A3.6 
Requirement for treatment with P-gp 
inhibitors 
or P-gp inducers 
For patients enrolled after implementation of 
CTP amendment 2 only:  
Exclusion criteria EX23 is met. 
B 
 
Informed consent 
 
 
B1 
Informed consent not given 
 
 
B1.1 
Informed consent 1 not given 
For patients enrolled before implementation of 
CTP amendment 3 and who do not already have 
an MGMT test result only: 
Inclusion criteria IN7 is not met. 
or 
Date of informed consent 1 is missing. 
 
B1.2 
Informed consent 2/3  not given 
Inclusion criteria IN7 is not met. 
or  
Date of informed consent 2/3 is missing. 
 
B2 
Informed consent given too late 
  
 
B2.1 
Informed consent 1 given too late 
For patients enrolled before implementation of 
CTP amendment 3 and who do not already have 
an MGMT test result only: 
Date of any study specific procedures before 
date of informed consent 1. 
 
B2.2 
Informed consent 2/3 given too late 
Date of any study specific procedures before 
date of informed consent 2/3. 
C 
 
Trial medication and randomisation 
 
 
C1 
Incorrect trial medication taken 
 
 
C1.1 
Incorrect TMZ dosing during concomitant 
treatment period (Regimen M only) 
For patients in Regimen M only: 
At least one TMZ dose during concomitant 
treatment period not according to the dose 
described in Section 4.1.4.2 of the CTP. 
 
C2 
Treatment group assignment not followed 
 
 
C2.1 
Afatinib treatment during concomitant 
treatment period in discordance with 
treatment group assignment 
Initial dose of afatinib does not correspond to 
treatment group assignment. 
or 
Afatinib dose changes during concomitant 
treatment period not according to the dose 
reduction scheme described in Section 4.1.4.1.2 
of the CTP. 
 
C2.2 
TMZ treatment during concomitant 
treatment period in discordance with 
treatment group assignment 
For patients in Regimen M only: 
No dose of TMZ during concomitant period. 
or 
For patients in Regimen U only: 
At least one dose of TMZ during concomitant 
treatment period. 
 
C3 
Non-compliance 
 
 
C3.1 
Afatinib non-compliance during 
concomitant treatment period 
Total number of doses of afatinib missed for 
reasons other than AE is more than 8 during 
concomitant treatment period. 
or 
Number of consecutive doses of afatinib missed 
for non-AE reasons is more than 5 during 
concomitant treatment period. 


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Table 6.2: 1 
Important Protocol Violations (continued) 
Category / 
Code 
Description 
Comment/Example 
 
C3.2 
TMZ non-compliance during concomitant 
treatment period (Regimen M only) 
For patients in Regimen M only: 
Total number of doses of TMZ missed for 
reasons other than AE is more than 8 during 
concomitant treatment period. 
 
C4 
Trial specific PVs related to trial 
medication 
 
 
C4.1 
Dose reduction scheme for afatinib not 
followed 
Regardless of treatment period, incidence of 
DLT without subsequent adherence to the dose 
reduction scheme described in Section 4.1.4.1.2 
of the CTP. 
 
C4.2 
TMZ treatment continued but re-treatment 
criteria not met (Regimen M only) 
For patients in Regimen M only: 
Following the concomitant treatment period, 
TMZ not terminated despite re-treatment criteria 
described in Section 4.1.4.2 of CTP not met. 
D 
 
Concomitant medication 
 
 
D1 
Prohibited concomitant medication 
 
 
D1.1 
Prohibited medication use before the start 
of study treatment period 
Inclusion criteria IN6 is not met. 
or 
At least one of exclusion criteria EX1-EX5 is 
met. 
or 
Prohibited concomitant therapy use before start 
of study treatment (defined in Sections 3.3.1 and 
3.3.2 of the CTP). 
 
D1.2 
Prohibited medication use during study 
treatment period 
Prohibited concomitant therapy use during study 
treatment (defined in Section 4.2.2 of the CTP). 
 
D2 
Mandatory medication not taken 
 
 
D2.1 
Incorrect dose of radiotherapy 
administered during the concomitant 
treatment period 
Radiotherapy total dose not equal to 60 Gy.  
 
D2.2 
Pneumocytis pneumonia prophylaxis not 
taken during concomitant treatment period 
(Regimen M only) 
For patients in Regimen M only: 
Concomitant therapy use during concomitant 
treatment period does not include appropriate 
prophylaxis. 
G 
 
Trial specific protocol violations 
 
 
G1 
Non-adherence to safety withdrawal 
criteria 
Trial medication continued despite withdrawal 
criteria in Section 6.3 of the CTP met. 
 
G2 
Other protocol violations affecting 
patient rights or safety 
Any other protocol violation that affects the 
rights or safety of trial patients. 
 
6.3 
PATIENT SETS ANALYSED 
Treated set: 
This patient set includes all patients who were dispensed trial medication and were 
documented to have taken at least one dose of investigational treatment. The treated set is to 
be used for all planned analysis. 


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6.5 
POOLING OF CENTRES 
This section is not applicable because centre/country is not included in the statistical model. 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS 
PK parameters: 
Missing data and outliers of PK data are handled according to BI standards. (2) 
Time from first histological diagnosis: 
If day of first histological diagnosis is missing it will be imputed using 15. 
If both day and month of first histological diagnosis is missing they will be imputed using 1st 
July. 
Adverse events: 
Missing or incomplete AE dates are imputed according to BI standards. (4) 
6.7  
BASELINE, TIME WINDOWS AND CALCULATED VISITS 
Baseline: 
The measurement observed immediately preceding start of trial medication will be assigned 
to baseline; note that for some trial procedures (vital signs, mini mental state examination and 
laboratory tests) this may be the value measured on the same day trial medication was started.  


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7. 
PLANNED ANALYSIS 
For end of text tables, unless otherwise specified, the set of summary statistics is: N, mean, 
standard deviation (SD), minimum, median and maximum. 
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. Percentages will be given in whole numbers. The category 
missing will be displayed only if there are actually missing values. Unless otherwise 
specified, percentages will be based on all patients in the respective patient set whether they 
have non-missing values or not. 
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 ENDPOINTS 
DLT during concomitant treatment period: 
The analysis of the primary endpoint will summarise DLT using descriptive statistics with the 
aim of determining the maximum tolerated dose (defined in Section 5.2.4 of the CTP) of: 
• Afatinib in combination with TMZ when given concomitantly with RT (Regimen M); 
• Afatinib when given concomitantly with RT (Regimen U). 
An overall summary of AE occurrences with onset during the concomitant treatment period, 
which were defined to be DLTs by the investigator, will be presented. This will include the 
following AE attributes: 
• Preferred term, 
• Maximum CTCAE grade, 
• Outcome, 
• Time to first occurence (relative to start of trial medication; see Section 9.2 of this 
document). 
Any AE meeting the criteria for DLT, regardless of date of onset, will be considered a 
significant adverse event (SIAE). The analysis of non-serious SIAEs and serious adverse 
events (SAEs) is described in Section 7.8.1 of this document. 
DLTs with onset after the concomitant treatment period will be listed separately. 


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7.5 
SECONDARY ENDPOINTS 
7.5.1 
Key secondary endpoints 
This section is not applicable as no key secondary endpoints have been specified in the CTP. 
7.5.2 
(Other) Secondary endpoints 
Adverse events: 
See Section 7.8.1 of this document.  
Objective response: 
Only descriptive statistics are planned for this section of the report. 
PK parameters: 
The analysis of standard PK parameters is performed according to BI standards. (2) 
7.7 
EXTENT OF EXPOSURE 
Only descriptive statistics are planned for this section of the report. 
7.8 
SAFETY ANALYSIS 
7.8.1 
Adverse events 
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of patients with AEs (not the number of AEs). For this purpose, AE data will be 
combined in a 2-step procedure into AE records. 
In a first step, AE occurrences, i.e. AE entries on the case report form, will be collapsed into 
AE episodes provided that all of the following applies: 
• The same Medical Dictionary for Regulatory Activities (MedDRA) lowest level term was 
reported for the occurrences, 
• The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
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 onset of the occurrences, but no deterioration was observed for the later 
occurrence. 
In a second step, AE episodes will be condensed into AE records provided that the episodes 
were reported with the same term on the respective MedDRA level and that the episodes are 


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assigned to the same treatment. For further details on summarisation of AE data, please refer 
to BI standards for AEs. (5) 
CTCAE grade and investigator-defined DLT will be included as additional AE attributes. For 
the purposes of collapsing, additional deterioration rules will be defined for both attributes. In 
addition, in this trial, the standard AE attribute 'action taken with trial drug' is separated for 
afatinib and TMZ; the standard condensing rules will be applied for both. 
The analysis of AEs will be based on the concept of treatment emergent adverse events. That 
means that all AEs occurring between first administration of trial medication until 28 days 
after last administration of trial medication will be assigned to trial medication. All AEs 
occurring before first administration of trial medication will be assigned to ‘screening’ and all 
AEs occurring after last administration of trial medication + 28 days will be assigned to 
‘post-study’. 
Any AE meeting the criteria for DLT (defined in Section 5.2.2 of the CTP), regardless of date 
of onset, will be considered an SAE or SIAE. 
According to ICH E3 (6), AEs classified as ‘other significant’ will include those non-serious 
and non-significant AEs: 
(i) with ‘action taken = discontinuation’ or ‘action taken = reduced’, or 
(ii) with marked haematological and other lab abnormalities or which lead to significant 
concomitant therapy as identified by the Trial Clinical Monitor/Investigator at a report 
planning meeting.  
An overall summary of AEs will be presented, this will include the additional AE attributes 
maximum CTCAE grade and investigator defined DLT. 
The frequency of patients with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for patients with other 
significant AEs according to ICH E3 (5), for patients with non-serious SIAEs, for patients 
with SAEs, for patients with investigator defined DLTs and for patients with related AEs. An 
additional table will be produced of AEs stratified by the attribute maximum CTCAE grade. 
The SOCs will be sorted according to the standard sort order specified by European 
Medicines Agency (EMA), PTs will be sorted by frequency (within SOC). 
7.8.1.1 Adverse events of special interest 
The following AEs are considered of special interest for this trial: 
• Diarrhoea, 
To be identified by the PT ‘Diarrhoea’; 
• Nausea and vomiting, 
To be identified by the PTs ‘Nausea’ and ‘Vomiting’; 
• Rash and acne, 
To be defined by the PTs contained within the project-defined special grouped-term 
category 'RASH/ACNE'; 


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• Other AEs that occur with sufficient overall frequency, 
To be determined by the trial team at the report planning meeting prior to database lock. 
An overall summary of each of these AEs of special interest will be presented. This will 
include the additional AE attributes ‘Patients with investigator-defined DLTs’, ‘Maximum 
CTCAE grade’ and ‘Time to first occurrence’ (see Section 9.2 of this document).  
In addition, the frequency of patients with AEs will be summarised by treatment and project-
defined special grouped-term category or preferred term. Where applicable, AE PTs will be 
re-categorised into one of the following grouped-term categories: 
• Fatigue (FATIGUE); 
• Nail effect (NAILS); 
• Ocular effect (OCULAR); 
• Rash and acne (RASH/ACNE); 
• Stomatitis (STOMA). 
Otherwise, AEs will be categorised according to MedDRA PT. Further tables will be 
provided for patients with related AEs for AEs stratified by the attribute maximum CTCAE 
grade. 
The PTs identified within each of the project-defined special grouped-term categories will be 
listed. 
7.8.2 
Laboratory data 
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards. (7) 
7.8.3 
Vital signs 
Only descriptive statistics are planned for this section of the report. 
7.8.4 
ECG 
This section is not applicable because only limited ECG data are collected. Clinically relevant 
ECG findings will be reported as AEs. 
7.8.5 
Others 
Left ventricular ejection fraction: 
Only descriptive statistics are planned for this section of the report. 
Karnofsky performance scale:  
Only descriptive statistics are planned for this section of the report. 
Mini mental state examination:  


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Only descriptive statistics are planned for this section of the report. 


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8. 
REFERENCES 
 
1 
U09-1323-01-AM3:
 Phase I, open label trial to explore safety of 
combining BIBW 2992 and Radiotherapy with or without Temozolomide in newly 
diagnosed GBM (trial 1200.38) 07 February 2011. 
2 
029-DCP-102: "Noncompartmental Pharmacokinetic Analyses of Clinical 
Studies", current version; IDEA for CON. 
3 
001-MCG-158: “Handling of Protocol Violations ", current version, IDEA for 
CON. 
4 
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON. 
5 
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON. 
6 
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study
Reports, current version. 
7 
001-MCG-157: "Display and Analysis of Laboratory Data", current version, IDEA 
for CON. 
 


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10. 
HISTORY TABLE 
Version 
No. 
Date 
(dd Mmm yyyy) 
Author 
Sections 
changed 
Brief description of change