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BIBW 2992 (Afatinib) With or Without Daily Temozolomide in the Treatment of Patients With Recurrent Malignant Glioma

Sponsor
Boehringer Ingelheim (Industry)
Overall Status
Completed
CT.gov ID
NCT00727506
Collaborator
(none)
151
Enrollment
28
Locations
3
Arms
94.4
Actual Duration (Months)
5.4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Phase I Part: To determine the maximum tolerated dose (MTD) and pharmacokinetics of BIBW 2992 administered in combination with TMZ in patients with recurrent malignant gliomas (WHO Grade III and IV).

Phase II Part: To estimate the efficacy and safety of BIBW 2992 monotherapy and BIBW 2992 / TMZ combination therapy compared to TMZ monotherapy (three treatment arms) in patients with recurrent GBM. To evaluate molecular determinants of response to BIBW 2992.

Condition or Disease Intervention/Treatment Phase
  • Drug: BIBW 2992
  • Drug: TMZ
  • Drug: BIBW 2992 plus TMZ
 Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
151 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase I/II Trial of BIBW 2992 (Afatinib) in Treating Patients With Recurrent Glioblastoma Multiforme
Actual Study Start Date :
Jul 14, 2008
Actual Primary Completion Date :
May 12, 2011
Actual Study Completion Date :
May 25, 2016

Arms and Interventions

Arm Intervention/Treatment
Experimental: BIBW 2992

BIBW 2992 once daily

Drug: BIBW 2992
BIBW 2992 once daily
Active Comparator: TMZ

TMZ 21/28 days

Drug: TMZ
TMZ 21/28
Experimental: BIBW 2992 plus TMZ

BIBW 2992 once daily plus TMZ 21/28 days

Drug: BIBW 2992 plus TMZ
BIBW 2992 once daily plus TMZ 21/28 days

Outcome Measures

Primary Outcome Measures

  1. Number of Participants With DLT- Phase I [From randomization till data cut-off (10 Jun 2009), with a mean treatment duration of 51 days]

    Number of Participants With Dose Limiting Toxicities (DLT) - Phase I Part

  2. Progression-free Survival (PFS-6) at Six Months - Phase II [At six months after randomization]

    PFS-6 is defined as probability of patients surviving to six months after randomization without progression. Disease progression was evaluated by an independent review committee and by the investigators, independently. The evaluation by the independent review committee was used for the primary outcome measure. The measurement "Number" the estimated PFS-6 value from the Kaplan-Meier curve of PFS.

Secondary Outcome Measures

  1. Objective Tumor Response in Phase I [From treatment start until the date of first documented progression or data cutoff at May 12, 2011, whichever came first, with a mean treatment duration of 69.7 days.]

    Objective Tumor Response is defined as complete response (CR) and partial response (PR) according to the MacDonald criteria assessed by central independent review.

  2. Objective Tumor Response in Phase II [From randomization to until the date of first documented progression or data cutoff on July 15, 2016, whichever came first, with a mean treatment duration of 110.0 days]

    Objective Tumor Response is defined as complete response (CR) and partial response (PR) according to the MacDonald criteria assessed by central independent review. Only data collected until cut-off date July 15, 2016 were considered.

  3. Progression-free Survival (PFS)- Phase II Part [from date of randomization until the date of first documented progression or death by any cause, whichever came first, assessed up to 9 Months.]

    Progression-free survival was defined as the duration between randomization and the date of the first of the two following events: progression or death.

  4. AUCτ,ss for Afatinib [Before (-0.05 h) the drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h and 24 h after drug administration on Day 15 (in presence of temozolomide) and Day 28 (in absence of temozolomide) of treatment Cycle 1]

    Area under the plasma concentration-time curve of afatinib after multiple administration (AUCτ,ss) of 50 mg afatinib in presence and absence of 75 mg/m² temozolomide (TMZ).

  5. Cmax,ss for Afatinib [Before (-0.05 h) the drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h and 24h after drug administration on Day 15 (in presence of temozolomide) and Day 28 (in absence of temozolomide) of treatment Cycle 1]

    maximum measured plasma concentration of afatinib after multiple administration of 50 mg afatinib in presence and absence of 75 mg/m² temozolomide.

  6. Tmax,ss for Afatinib [Before (-0.05 h) the drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h and 24h after drug administration on Day 15 (in presence of temozolomide) and Day 28 (in absence of temozolomide) of treatment Cycle 1]

    time from dosing to the maximum plasma concentration of afatinib after multiple administration of 50 mg afatinib in presence and absence of 75 mg/m² temozolomide

  7. AUC (0-8) for Temozolomide [Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1]

    Area under the plasma concentration-time curve over the time interval from zero to 08h (AUC (0-8)) of temozolomide in presence and absence of afatinib.

  8. Cmax for Temozolomide [Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1]

    maximum measured plasma concentration following the first dose of uniform intervals τ (Cmax) of temozolomide in presence and absence of afatinib.

  9. Tmax for Temozolomide [Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1]

    time from dosing to the maximum plasma concentration following the first dose of uniform intervals τ (tmax) of temozolomide in presence and absence of afatinib.

  10. t1/2 for Temozolomide [Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1]

    terminal half-life (t1/2) of temozolomide in presence and absence of afatinib

  11. Phase II - Trough Plasma Concentration of Afatinib [Before (-0.05 h) the drug administration of afatinib on Day 15 of Cycle 2 & 3]

    Trough plasma concentration of afatinib after multiple administration of 40 mg afatinib administered as monotherapy or in combination with 75 mg/m² temozolomide

  12. Number of Participants With EGFRvIII Assessed by IHC Test. [Baseline (during screening)]

    Number of participants with the epidermal growth factor receptor variant III (EGFRvIII) assessed by IHC test for the evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for EGFRvIII by immunohistochemistry (IHC) test.

  13. Number of Participants With MGMT Marker Assessed by IHC Test. [Baseline (during screening)]

    Number of participants with MGMT marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for O6-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry (IHC) test.

  14. Number of Participants With EGFR Marker Assessed by IHC Test. [Baseline (during screening)]

    Number of participants with EGFR marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Epidermal Growth Factor Receptor (EGFR) by immunohistochemistry (IHC) test

  15. Number of Participants With PTEN Marker Assessed by IHC Test. [Baseline (during screening)]

    Number of participants with PTEN marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Phosphatase and Tensin Homologue - a tumor suppressor gene/protein (PTEN) by immunohistochemistry (IHC) test.

  16. Number of Participants With PAKT Marker Assessed by IHC Test. [Baseline (during screening)]

    Number of participants with PAKT marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Serinethreonine kinase (PAKT) by immunohistochemistry (IHC) test.

  17. Number of Participants With EGFR Assessed by FISH [Baseline (during screening)]

    Number of participants with EGFR assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for EGFR by fluorescent in situ hybridization (FISH).

  18. Number of Participants With PTEN Assessed by FISH [Baseline (during screening)]

    Number of participants with PTEN assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for PTEN by fluorescent in situ hybridization (FISH).

  19. Number of Participants With Chromosomes (CEP7) Assessed by FISH [Baseline (during screening)]

    Number of participants with Chromosomes (CEP7) assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Chromosomes (CEP7) by fluorescent in situ hybridization (FISH).

  20. Number of Participants With Chromosomes (CEP10) Assessed by FISH [Baseline (during screening)]

    Number of participants with Chromosomes (CEP10) assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Chromosomes (CEP10) by fluorescent in situ hybridization (FISH).

  21. Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I [From first administration of treatment until 28 days after last drug administration, up to 491 days.]

    Safety was assessed based on number of participants with investigator defined drug-related AEs, AEs leading to discontinuation of trial drug, All Serious Adverse events (AE) and other significant AEs (according to International Conference on Harmonisation (ICH) E3).

  22. Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I [From first administration of treatment until 28 days after last drug administration, up to 491 days.]

    Safety of afatinib as indicated by number of participants with adverse events based on intensity and incidence of AE's, especially skin reactions (rash, acne), gastrointestinal (GI) (Vomiting, nausea, diarrhea) and neurological

  23. Number of Participants With Adverse Events, Graded According CTCAE - Phase I [From first administration of treatment until 28 days after last drug administration, up to 491 days.]

    Safety of Afatinib assesed based on Number of participants with adverse events, graded according to United States National Cancer Institute Common terminology Criteria for Adverse Events (US NCI CTCAE) Version 3.0. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).

  24. Causes of Death - Phase I [From first administration of treatment until 28 days after last drug administration, up to 491 days.]

    Cause of the death reported during on treatment was due to disease progression.

  25. Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II [From first administration of treatment until 28 days after last drug administration, up to 518 days.]

    Safety was assessed based on number of participants with investigator defined drug-related AEs, AE leading to dose reduction, Adverse events (AEs) leading to discontinuation of trial drug and All Serious Adverse events (SAE).

  26. Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II [From first administration of treatment until 28 days after last drug administration, up to 518 days.]

    Safety of afatinib as indicated by number of participants with adverse events based on intensity and incidence of AE's, especially skin reactions (rash, acne), gastrointestinal (GI) (Vomiting, nausea, diarrhea) and neurological.

  27. Number of Participants With Adverse Events, Graded According CTCAE - Phase II [From first administration of treatment until 28 days after last drug administration, up to 518 days.]

    Safety of Afatinib assessed based on the number of participants with adverse events, graded according to United States National Cancer Institute Common terminology Criteria for Adverse Events (US NCI CTCAE) Version 3.0. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).

  28. Causes of Death - Phase II [From first administration of treatment until 28 days after last drug administration, up to 518 days.]

    Causes of death during on treatment.

  29. Number of Participants With Clinically Relevant Abnormalities for Decreased Cardiac Left Ventricular Function - Phase II [From first administration of treatment until 28 days after last drug administration, up to 518 days.]

    Number of participants with Clinically Relevant Abnormalities for decreased Cardiac left ventricular function.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion criteria:
Phase I Part:

  1. Histologically-confirmed WHO Grade III or IV malignant glioma that is recurrent after prior chemoradiotherapy. Patients with prior low-grade glioma are eligible if histologic assessment demonstrates transformation to WHO Grade III or IV malignant glioma.

  2. Age at least 18 years at entry

  3. KPS at least 60%

  4. Patients must have recovered from previous surgery and chemotherapy.

  5. Written informed consent that is consistent with local law and ICH-GCP guidelines.

Phase II Part:

  1. Histologically-confirmed WHO Grade IV malignant glioma at first episode of recurrence after prior combined chemoradiotherapy. Patients with prior low-grade glioma are eligible if histologic assessment demonstrates transformation to WHO Grade IV malignant glioma and if prior treatment included temozolomide chemotherapy and radiotherapy.

  2. Bi-dimensionally measurable disease with a minimum measurement of 1 cm (10 mm) in one diameter on Gd MRI performed within 14 days prior to first treatment (Day 1).

  3. Age at least 18 years at entry

  4. KPS at least 70%

  5. Patients must have recovered from previous surgery and chemotherapy.

  6. Written informed consent that is consistent with local law and ICH-GCP guidelines.

  7. Patients receiving corticosteroids have to receive a stable or decreasing dose for at least 14 days before start of study treatment.

Exclusion criteria:
Phase I and Phase II Parts:

  1. Less than 12 weeks between radiotherapy and start of study treatment, unless new enhancing lesion outside of radiation field or radiologically progressive on two consecutive MRI scans at least four weeks apart or biopsy-proven recurrence.

  2. Less than two weeks from surgical resection (one week from prior stereotactic biopsy) or major surgical procedure.

  3. Less than two weeks after previous chemotherapy (6 weeks from nitrosureas).

  4. Treatment with other investigational drugs; participation in another clinical study within the past 2 weeks before start of therapy or concomitantly with this study.

  5. Progressive disease or toxicity =CTCAEv3 Grade 3 to protracted temozolomide dosing (defined as temozolomide administered more than 5 days/28 day cycle).

  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 diarrhea.

  9. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol.

  10. 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.

  11. Cardiac left ventricular function with resting ejection fraction <50%.

  12. Absolute neutrophil count (ANC) less than 1500/mm3.

  13. Platelet count less than 100,000/mm3.

  14. Bilirubin greater than 1.5 x upper limit of institutional norm.

  15. Aspartate amino transferase (AST) greater than 3 x upper limit of institutional norm.

  16. Serum creatinine greater than 1.5 x upper limit of institutional norm.

  17. Patients who are sexually active and unwilling to use a medically acceptable method of contraception.

  18. Pregnancy or breast-feeding.

  19. Patients unable to comply with the protocol.

  20. Known pre-existing interstitial lung disease (ILD).

Phase I part only:
  1. Less than four weeks from prior treatment with bevacizumab.
Phase II Part only:

  1. Prior EGFR-directed therapy.

  2. Prior bevacizumab therapy.

  3. Patients presenting with second or higher number of episodes of recurrence.

  4. Requirement of treatment with any of the prohibited concomitant medications listed in Section 4.2.2 (Restrictions regarding concomitant treatment).

Contacts and Locations

Locations

Site City State Country Postal Code
1 1200.36.0016 Boehringer Ingelheim Investigational Site Birmingham Alabama United States
2 1200.36.0012 Boehringer Ingelheim Investigational Site Phoenix Arizona United States
3 1200.36.0005 Boehringer Ingelheim Investigational Site Duarte California United States
4 1200.36.0014 Boehringer Ingelheim Investigational Site Los Angeles California United States
5 1200.36.0019 Boehringer Ingelheim Investigational Site Orlando Florida United States
6 1200.36.0023 Boehringer Ingelheim Investigational Site Atlanta Georgia United States
7 1200.36.0008 Boehringer Ingelheim Investigational Site Louisville Kentucky United States
8 1200.36.0002 Boehringer Ingelheim Investigational Site Boston Massachusetts United States
9 1200.36.0003 Boehringer Ingelheim Investigational Site Detroit Michigan United States
10 1200.36.0009 Boehringer Ingelheim Investigational Site New York New York United States
11 1200.36.0001 Boehringer Ingelheim Investigational Site Durham North Carolina United States
12 1200.36.0007 Boehringer Ingelheim Investigational Site Charleston South Carolina United States
13 1200.36.0020 Boehringer Ingelheim Investigational Site Memphis Tennessee United States
14 1200.36.0017 Boehringer Ingelheim Investigational Site Dallas Texas United States
15 1200.36.0010 Boehringer Ingelheim Investigational Site Houston Texas United States
16 1200.36.0011 Boehringer Ingelheim Investigational Site Charlottesville Virginia United States
17 1200.36.0022 Boehringer Ingelheim Investigational Site Seattle Washington United States
18 1200.36.1005 Boehringer Ingelheim Investigational Site Calgary Alberta Canada
19 1200.36.1010 Boehringer Ingelheim Investigational Site Winnipeg Manitoba Canada
20 1200.36.1009 Boehringer Ingelheim Investigational Site Moncton New Brunswick Canada
21 1200.36.1011 Boehringer Ingelheim Investigational Site Halifax Nova Scotia Canada
22 1200.36.1008 Boehringer Ingelheim Investigational Site Hamilton Ontario Canada
23 1200.36.1001 Boehringer Ingelheim Investigational Site Kingston Ontario Canada
24 1200.36.1003 Boehringer Ingelheim Investigational Site Toronto Ontario Canada
25 1200.36.1004 Boehringer Ingelheim Investigational Site Toronto Ontario Canada
26 1200.36.1007 Boehringer Ingelheim Investigational Site Fleurimont Quebec Canada
27 1200.36.1002 Boehringer Ingelheim Investigational Site Montreal Quebec Canada
28 1200.36.1006 Boehringer Ingelheim Investigational Site Quebec Canada

Sponsors and Collaborators

  • Boehringer Ingelheim

Investigators

  • Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00727506
Other Study ID Numbers:
  • 1200.36
First Posted:
Aug 4, 2008
Last Update Posted:
Aug 15, 2017
Last Verified:
Jul 1, 2017
Additional relevant MeSH terms:
Glioma
Afatinib

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail This study consists of 2 parts (phase I and phase II) with separate participants.
Arm/Group Title Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Afatinib 20mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Period Title: Overall Study
STARTED 6 8 18 39 41 39
COMPLETED 0 0 0 0 0 0
NOT COMPLETED 6 8 18 39 41 39

Baseline Characteristics

Arm/Group Title Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2 Total
Arm/Group Description Patients receiving Afatinib 20mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Total of all reporting groups
Overall Participants 6 8 18 39 41 39 151
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
51.7
(12.4)
51.6
(14.2)
51.0
(9.4)
56.9
(10.62)
56.6
(9.44)
55.4
(11.02)
56.3
(10.3)
Sex: Female, Male (Count of Participants)
Female
2
33.3%
2
25%
8
44.4%
14
35.9%
14
34.1%
18
46.2%
58
38.4%
Male
4
66.7%
6
75%
10
55.6%
25
64.1%
27
65.9%
21
53.8%
93
61.6%
Race/Ethnicity, Customized (Number of participants) [Number]
Asian
0
0%
1
12.5%
0
0%
0
0%
1
2.4%
1
2.6%
3
2%
Black/African American
0
0%
0
0%
2
11.1%
2
5.1%
0
0%
2
5.1%
6
4%
Hawaiian/Pacific Isle
0
0%
0
0%
0
0%
0
0%
0
0%
1
2.6%
1
0.7%
White
6
100%
7
87.5%
16
88.9%
37
94.9%
40
97.6%
35
89.7%
141
93.4%
Karnofsky performance score (Number of participants) [Number]
70
1
16.7%
1
12.5%
1
5.6%
9
23.1%
9
22%
12
30.8%
33
21.9%
80
1
16.7%
1
12.5%
2
11.1%
13
33.3%
12
29.3%
9
23.1%
38
25.2%
90
2
33.3%
4
50%
11
61.1%
12
30.8%
17
41.5%
15
38.5%
61
40.4%
100
2
33.3%
2
25%
4
22.2%
5
12.8%
3
7.3%
3
7.7%
19
12.6%

Outcome Measures

1. Primary Outcome
Title Number of Participants With DLT- Phase I
Description Number of Participants With Dose Limiting Toxicities (DLT) - Phase I Part
Time Frame From randomization till data cut-off (10 Jun 2009), with a mean treatment duration of 51 days

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2
Arm/Group Description Patients receiving Afatinib 20mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part
Measure Participants 6 8 18
Number [participants]
2
33.3%
0
0%
4
22.2%
2. Primary Outcome
Title Progression-free Survival (PFS-6) at Six Months - Phase II
Description PFS-6 is defined as probability of patients surviving to six months after randomization without progression. Disease progression was evaluated by an independent review committee and by the investigators, independently. The evaluation by the independent review committee was used for the primary outcome measure. The measurement "Number" the estimated PFS-6 value from the Kaplan-Meier curve of PFS.
Time Frame At six months after randomization

Outcome Measure Data

Analysis Population Description
Randomised Set (RS). The randomised set includes all patients who were randomised to receive treatment in the Phase II part of the trial.
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
Number (95% Confidence Interval) [probablity of survival]
0.230
0.030
0.103
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2, Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.148
Comments P-value is from an approximate normal test for the 6 month time point.
Method z-test
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2, Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.008
Comments P-value is an approximate normal test for the six month time point.
Method z-test
Comments
3. Secondary Outcome
Title Objective Tumor Response in Phase I
Description Objective Tumor Response is defined as complete response (CR) and partial response (PR) according to the MacDonald criteria assessed by central independent review.
Time Frame From treatment start until the date of first documented progression or data cutoff at May 12, 2011, whichever came first, with a mean treatment duration of 69.7 days.

Outcome Measure Data

Analysis Population Description
Patients treated in Phase I part
Arm/Group Title Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2
Arm/Group Description Patients receiving Afatinib 20mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part
Measure Participants 6 8 18
Number [participants]
0
0%
1
12.5%
0
0%
4. Secondary Outcome
Title Objective Tumor Response in Phase II
Description Objective Tumor Response is defined as complete response (CR) and partial response (PR) according to the MacDonald criteria assessed by central independent review. Only data collected until cut-off date July 15, 2016 were considered.
Time Frame From randomization to until the date of first documented progression or data cutoff on July 15, 2016, whichever came first, with a mean treatment duration of 110.0 days

Outcome Measure Data

Analysis Population Description
RS
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
Number [participants]
4
66.7%
1
12.5%
3
16.7%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2, Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 1.0000
Comments
Method Fisher Exact
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2, Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.1954
Comments
Method Fisher Exact
Comments
5. Secondary Outcome
Title Progression-free Survival (PFS)- Phase II Part
Description Progression-free survival was defined as the duration between randomization and the date of the first of the two following events: progression or death.
Time Frame from date of randomization until the date of first documented progression or death by any cause, whichever came first, assessed up to 9 Months.

Outcome Measure Data

Analysis Population Description
Randomized set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
Median (Full Range) [Months]
1.87
0.99
1.53
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2, Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2
Comments Hazard ratio was calculated from Cox proportional hazard model stratified by age class (<=50 vs. >50 years old) and baseline Karnofsky Performance Scale (KPS) score (70, 80 vs. 90, 100). P-value was two-sided from log-rank test stratified by the same variables.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0320
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.780
Confidence Interval (2-Sided) 95%
1.088 to 2.912
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2, Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2
Comments Hazard ratio was calculated from Cox proportional hazard model stratified by age class (<=50 vs. >50 years old) and baseline KPS score (70, 80 vs. 90, 100). P-value was two-sided from log-rank test stratified by the same variables.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.2044
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.392
Confidence Interval (2-Sided) 95%
0.841 to 2.301
Parameter Dispersion Type:
Value:
Estimation Comments
6. Secondary Outcome
Title AUCτ,ss for Afatinib
Description Area under the plasma concentration-time curve of afatinib after multiple administration (AUCτ,ss) of 50 mg afatinib in presence and absence of 75 mg/m² temozolomide (TMZ).
Time Frame Before (-0.05 h) the drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h and 24 h after drug administration on Day 15 (in presence of temozolomide) and Day 28 (in absence of temozolomide) of treatment Cycle 1

Outcome Measure Data

Analysis Population Description
PKS Set and the patients who had enough PK samples for calculation of AUC. Pharmacokinetic set (PKS) : All patients who provided at least one blood sample were included in the Pharmacokinetic (PK) analysis.
Arm/Group Title Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of TMZ) Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of TMZ)
Arm/Group Description Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part (in presence of temozolomide). Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part (in absence of temozolomide).
Measure Participants 15 5
Geometric Mean (Standard Deviation) [ng·h/mL]
1070
(63.7)
918
(65.3)
7. Secondary Outcome
Title Cmax,ss for Afatinib
Description maximum measured plasma concentration of afatinib after multiple administration of 50 mg afatinib in presence and absence of 75 mg/m² temozolomide.
Time Frame Before (-0.05 h) the drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h and 24h after drug administration on Day 15 (in presence of temozolomide) and Day 28 (in absence of temozolomide) of treatment Cycle 1

Outcome Measure Data

Analysis Population Description
PKS set
Arm/Group Title Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of TMZ) Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of TMZ)
Arm/Group Description Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part (in presence of temozolomide). Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part (in absence of temozolomide).
Measure Participants 15 6
Geometric Mean (Standard Deviation) [ng/mL]
63.2
(62.1)
50.5
(58.0)
8. Secondary Outcome
Title Tmax,ss for Afatinib
Description time from dosing to the maximum plasma concentration of afatinib after multiple administration of 50 mg afatinib in presence and absence of 75 mg/m² temozolomide
Time Frame Before (-0.05 h) the drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h and 24h after drug administration on Day 15 (in presence of temozolomide) and Day 28 (in absence of temozolomide) of treatment Cycle 1

Outcome Measure Data

Analysis Population Description
PKS set
Arm/Group Title Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of TMZ) Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of TMZ)
Arm/Group Description Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part (in presence of temozolomide). Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part (in absence of temozolomide).
Measure Participants 15 6
Median (Full Range) [hour]
4.00
(58.0)
3.50
(62.1)
9. Secondary Outcome
Title AUC (0-8) for Temozolomide
Description Area under the plasma concentration-time curve over the time interval from zero to 08h (AUC (0-8)) of temozolomide in presence and absence of afatinib.
Time Frame Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1

Outcome Measure Data

Analysis Population Description
PKS set
Arm/Group Title Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of Afatinib) Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of Afatinib)
Arm/Group Description Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part (in presence of Afatinib). Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part (in absence of Afatinib).
Measure Participants 14 17
Geometric Mean (Geometric Coefficient of Variation) [ng·h/mL]
8380
(24.1)
8160
(27.8)
10. Secondary Outcome
Title Cmax for Temozolomide
Description maximum measured plasma concentration following the first dose of uniform intervals τ (Cmax) of temozolomide in presence and absence of afatinib.
Time Frame Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1

Outcome Measure Data

Analysis Population Description
PKS set
Arm/Group Title Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of Afatinib) Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of Afatinib)
Arm/Group Description Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part (in presence of Afatinib). Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part (in absence of Afatinib).
Measure Participants 15 17
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
2520
(33.3)
2690
(39.7)
11. Secondary Outcome
Title Tmax for Temozolomide
Description time from dosing to the maximum plasma concentration following the first dose of uniform intervals τ (tmax) of temozolomide in presence and absence of afatinib.
Time Frame Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1

Outcome Measure Data

Analysis Population Description
PKS set
Arm/Group Title Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of Afatinib) Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of Afatinib)
Arm/Group Description Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part (in presence of Afatinib). Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part (in absence of Afatinib).
Measure Participants 15 17
Median (Full Range) [h]
1.22
1.00
12. Secondary Outcome
Title t1/2 for Temozolomide
Description terminal half-life (t1/2) of temozolomide in presence and absence of afatinib
Time Frame Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1

Outcome Measure Data

Analysis Population Description
PKS set
Arm/Group Title Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of Afatinib) Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of Afatinib)
Arm/Group Description Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part (in presence of Afatinib). Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part (in absence of Afatinib).
Measure Participants 14 17
Geometric Mean (Geometric Coefficient of Variation) [hours]
2.17
(34.3)
2.08
(58.4)
13. Secondary Outcome
Title Phase II - Trough Plasma Concentration of Afatinib
Description Trough plasma concentration of afatinib after multiple administration of 40 mg afatinib administered as monotherapy or in combination with 75 mg/m² temozolomide
Time Frame Before (-0.05 h) the drug administration of afatinib on Day 15 of Cycle 2 & 3

Outcome Measure Data

Analysis Population Description
PKS
Arm/Group Title Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 41 39
predose at Day 15 of Cycle 2 (n=17; 15)
19.8
(69.5)
29.7
(72.1)
predose at Day 15 of Cycle 3 (n=10; 10)
19.6
(70.8)
20.2
(79.1)
14. Secondary Outcome
Title Number of Participants With EGFRvIII Assessed by IHC Test.
Description Number of participants with the epidermal growth factor receptor variant III (EGFRvIII) assessed by IHC test for the evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for EGFRvIII by immunohistochemistry (IHC) test.
Time Frame Baseline (during screening)

Outcome Measure Data

Analysis Population Description
Randomized set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
Sample tested: Negative
6
100%
8
100%
5
27.8%
Sample tested: +
5
83.3%
3
37.5%
4
22.2%
Sample tested: +/++
0
0%
3
37.5%
2
11.1%
Sample tested: ++
1
16.7%
4
50%
4
22.2%
Sample tested: ++/+++
1
16.7%
3
37.5%
3
16.7%
Sample tested: +++
3
50%
5
62.5%
10
55.6%
No Sample for test
23
383.3%
15
187.5%
11
61.1%
15. Secondary Outcome
Title Number of Participants With MGMT Marker Assessed by IHC Test.
Description Number of participants with MGMT marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for O6-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry (IHC) test.
Time Frame Baseline (during screening)

Outcome Measure Data

Analysis Population Description
Randomized set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
MGMT+
9
150%
8
100%
12
66.7%
MGMT-
7
116.7%
15
187.5%
15
83.3%
No Sample for test
23
383.3%
18
225%
12
66.7%
16. Secondary Outcome
Title Number of Participants With EGFR Marker Assessed by IHC Test.
Description Number of participants with EGFR marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Epidermal Growth Factor Receptor (EGFR) by immunohistochemistry (IHC) test
Time Frame Baseline (during screening)

Outcome Measure Data

Analysis Population Description
Randomized set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
EGFR wt+
14
233.3%
23
287.5%
24
133.3%
EGFR wt-
2
33.3%
0
0%
4
22.2%
No Sample for test
23
383.3%
18
225%
11
61.1%
17. Secondary Outcome
Title Number of Participants With PTEN Marker Assessed by IHC Test.
Description Number of participants with PTEN marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Phosphatase and Tensin Homologue - a tumor suppressor gene/protein (PTEN) by immunohistochemistry (IHC) test.
Time Frame Baseline (during screening)

Outcome Measure Data

Analysis Population Description
Randomized set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
PTEN intact
5
83.3%
4
50%
7
38.9%
PTEN loss
11
183.3%
19
237.5%
21
116.7%
No Sample for test
23
383.3%
18
225%
11
61.1%
18. Secondary Outcome
Title Number of Participants With PAKT Marker Assessed by IHC Test.
Description Number of participants with PAKT marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Serinethreonine kinase (PAKT) by immunohistochemistry (IHC) test.
Time Frame Baseline (during screening)

Outcome Measure Data

Analysis Population Description
Randomized set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
PAKT+
5
83.3%
11
137.5%
11
61.1%
PAKT-
11
183.3%
13
162.5%
16
88.9%
No Sample for test
23
383.3%
17
212.5%
12
66.7%
19. Secondary Outcome
Title Number of Participants With EGFR Assessed by FISH
Description Number of participants with EGFR assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for EGFR by fluorescent in situ hybridization (FISH).
Time Frame Baseline (during screening)

Outcome Measure Data

Analysis Population Description
Randomized set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
EGFR abnormal (Amplification)
5
83.3%
14
175%
11
61.1%
EGFR normal (Intact)
1
16.7%
0
0%
1
5.6%
EGFR abnormal (Gain)
10
166.7%
9
112.5%
16
88.9%
No Sample for test
23
383.3%
18
225%
11
61.1%
20. Secondary Outcome
Title Number of Participants With PTEN Assessed by FISH
Description Number of participants with PTEN assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for PTEN by fluorescent in situ hybridization (FISH).
Time Frame Baseline (during screening)

Outcome Measure Data

Analysis Population Description
Randomized set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
PTEN abnormal (Loss)
11
183.3%
20
250%
25
138.9%
PTEN normal (Gain)
1
16.7%
2
25%
1
5.6%
PTEN normal (Intact)
4
66.7%
1
12.5%
2
11.1%
No Sample for test
23
383.3%
18
225%
11
61.1%
21. Secondary Outcome
Title Number of Participants With Chromosomes (CEP7) Assessed by FISH
Description Number of participants with Chromosomes (CEP7) assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Chromosomes (CEP7) by fluorescent in situ hybridization (FISH).
Time Frame Baseline (during screening)

Outcome Measure Data

Analysis Population Description
Randomized set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
CEP7 abnormal (Gain)
15
250%
24
300%
27
150%
CEP7 normal (Intact)
1
16.7%
0
0%
1
5.6%
No Sample for test
23
383.3%
17
212.5%
11
61.1%
22. Secondary Outcome
Title Number of Participants With Chromosomes (CEP10) Assessed by FISH
Description Number of participants with Chromosomes (CEP10) assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Chromosomes (CEP10) by fluorescent in situ hybridization (FISH).
Time Frame Baseline (during screening)

Outcome Measure Data

Analysis Population Description
Randomized set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
CEP10 abnormal (Loss)
10
166.7%
19
237.5%
24
133.3%
CEP10 normal (Gain)
2
33.3%
3
37.5%
1
5.6%
CEP10 normal (Intact)
4
66.7%
1
12.5%
2
11.1%
No Sample for test
23
383.3%
18
225%
11
61.1%
23. Secondary Outcome
Title Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I
Description Safety was assessed based on number of participants with investigator defined drug-related AEs, AEs leading to discontinuation of trial drug, All Serious Adverse events (AE) and other significant AEs (according to International Conference on Harmonisation (ICH) E3).
Time Frame From first administration of treatment until 28 days after last drug administration, up to 491 days.

Outcome Measure Data

Analysis Population Description
Treated set
Arm/Group Title Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2
Arm/Group Description Patients receiving Afatinib 20mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part
Measure Participants 6 8 18
drug-related AEs
4
66.7%
8
100%
17
94.4%
AEs leading to discontinuation of trial drug
2
33.3%
1
12.5%
10
55.6%
Serious AE's
2
33.3%
1
12.5%
10
55.6%
other significant AEs
1
16.7%
0
0%
5
27.8%
24. Secondary Outcome
Title Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I
Description Safety of afatinib as indicated by number of participants with adverse events based on intensity and incidence of AE's, especially skin reactions (rash, acne), gastrointestinal (GI) (Vomiting, nausea, diarrhea) and neurological
Time Frame From first administration of treatment until 28 days after last drug administration, up to 491 days.

Outcome Measure Data

Analysis Population Description
Treated set
Arm/Group Title Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2
Arm/Group Description Patients receiving Afatinib 20mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part
Measure Participants 6 8 18
Rash
0
0%
0
0%
1
5.6%
Vomiting
0
0%
0
0%
2
11.1%
Nausea
0
0%
1
12.5%
0
0%
Diarrhoea
0
0%
1
12.5%
2
11.1%
acne
0
0%
0
0%
0
0%
Haemorrhage intracranial
1
16.7%
0
0%
0
0%
Convulsion
0
0%
1
12.5%
1
5.6%
Syncope
0
0%
1
12.5%
0
0%
Hemiparesis
0
0%
0
0%
2
11.1%
Aphasia
0
0%
0
0%
1
5.6%
Brain oedema
0
0%
0
0%
1
5.6%
Cerebrovascular accident
0
0%
0
0%
1
5.6%
Headache
0
0%
0
0%
1
5.6%
Paralysis
0
0%
0
0%
1
5.6%
Peroneal nerve palsy
0
0%
0
0%
1
5.6%
Vasogenic cerebral oedema
0
0%
0
0%
1
5.6%
25. Secondary Outcome
Title Number of Participants With Adverse Events, Graded According CTCAE - Phase I
Description Safety of Afatinib assesed based on Number of participants with adverse events, graded according to United States National Cancer Institute Common terminology Criteria for Adverse Events (US NCI CTCAE) Version 3.0. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).
Time Frame From first administration of treatment until 28 days after last drug administration, up to 491 days.

Outcome Measure Data

Analysis Population Description
Treated set
Arm/Group Title Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2
Arm/Group Description Patients receiving Afatinib 20mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part
Measure Participants 6 8 18
Grade 1
1
16.7%
2
25%
0
0%
Grade 2
3
50%
4
50%
7
38.9%
Grade 3
0
0%
1
12.5%
7
38.9%
Grade 4
2
33.3%
1
12.5%
3
16.7%
Grade 5
0
0%
0
0%
1
5.6%
26. Secondary Outcome
Title Causes of Death - Phase I
Description Cause of the death reported during on treatment was due to disease progression.
Time Frame From first administration of treatment until 28 days after last drug administration, up to 491 days.

Outcome Measure Data

Analysis Population Description
Treated set
Arm/Group Title Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2
Arm/Group Description Patients receiving Afatinib 20mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part
Measure Participants 6 8 18
Number [deaths]
0
0
1
27. Secondary Outcome
Title Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II
Description Safety was assessed based on number of participants with investigator defined drug-related AEs, AE leading to dose reduction, Adverse events (AEs) leading to discontinuation of trial drug and All Serious Adverse events (SAE).
Time Frame From first administration of treatment until 28 days after last drug administration, up to 518 days.

Outcome Measure Data

Analysis Population Description
Treated set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
drug-related AEs
22
366.7%
35
437.5%
36
200%
AE leading to dose reduction
2
33.3%
4
50%
7
38.9%
AEs leading to discontinuation of trial drug
9
150%
8
100%
14
77.8%
Serious AE's
6
100%
10
125%
13
72.2%
28. Secondary Outcome
Title Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II
Description Safety of afatinib as indicated by number of participants with adverse events based on intensity and incidence of AE's, especially skin reactions (rash, acne), gastrointestinal (GI) (Vomiting, nausea, diarrhea) and neurological.
Time Frame From first administration of treatment until 28 days after last drug administration, up to 518 days.

Outcome Measure Data

Analysis Population Description
Treated set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
Rash
3
50%
19
237.5%
22
122.2%
Acne
0
0%
0
0%
4
22.2%
Vomiting
8
133.3%
4
50%
10
55.6%
Nausea
7
116.7%
6
75%
13
72.2%
Diarrhoea
4
66.7%
29
362.5%
32
177.8%
Neurological decompensation
0
0%
2
25%
0
0%
Cerebral haemorrhage
0
0%
0
0%
1
5.6%
Dysgeusia
0
0%
0
0%
1
5.6%
Hemiparesis
1
16.7%
0
0%
1
5.6%
Ataxia
0
0%
1
12.5%
0
0%
Headache
0
0%
1
12.5%
0
0%
Memory impairment
0
0%
1
12.5%
0
0%
Speech disorder
0
0%
1
12.5%
0
0%
29. Secondary Outcome
Title Number of Participants With Adverse Events, Graded According CTCAE - Phase II
Description Safety of Afatinib assessed based on the number of participants with adverse events, graded according to United States National Cancer Institute Common terminology Criteria for Adverse Events (US NCI CTCAE) Version 3.0. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).
Time Frame From first administration of treatment until 28 days after last drug administration, up to 518 days.

Outcome Measure Data

Analysis Population Description
Treated set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
Grade 1
3
50%
5
62.5%
2
11.1%
Grade 2
14
233.3%
18
225%
10
55.6%
Grade 3
13
216.7%
15
187.5%
19
105.6%
Grade 4
5
83.3%
2
25%
5
27.8%
Grade 5
2
33.3%
1
12.5%
2
11.1%
30. Secondary Outcome
Title Causes of Death - Phase II
Description Causes of death during on treatment.
Time Frame From first administration of treatment until 28 days after last drug administration, up to 518 days.

Outcome Measure Data

Analysis Population Description
Treated set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
Malignant Neoplasm Progression
1
0
1
Respiratory failure
0
0
1
Tumor progression
1
1
0
31. Secondary Outcome
Title Number of Participants With Clinically Relevant Abnormalities for Decreased Cardiac Left Ventricular Function - Phase II
Description Number of participants with Clinically Relevant Abnormalities for decreased Cardiac left ventricular function.
Time Frame From first administration of treatment until 28 days after last drug administration, up to 518 days.

Outcome Measure Data

Analysis Population Description
Treated set
Arm/Group Title Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Measure Participants 39 41 39
Number [Participants]
0.0
0%
0.0
0%
0.0
0%

Adverse Events

Time Frame From first administration of treatment until 28 days after last drug administration, up to 491 days (Phase I) and 518 days (Phase II).
Adverse Event Reporting Description
Arm/Group Title Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Arm/Group Description Patients receiving Afatinib 20mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase I part Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m^2 for 21 days followed by 7 days off - Phase II part.
All Cause Mortality
Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
Serious Adverse Events
Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 2/6 (33.3%) 1/8 (12.5%) 10/18 (55.6%) 6/39 (15.4%) 10/41 (24.4%) 13/39 (33.3%)
Blood and lymphatic system disorders
Anaemia 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 1/41 (2.4%) 0/39 (0%)
Febrile neutropenia 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Spontaneous haematoma 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 1/41 (2.4%) 0/39 (0%)
Thrombocytopenia 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 2/39 (5.1%)
Cardiac disorders
Palpitations 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 1/41 (2.4%) 0/39 (0%)
Gastrointestinal disorders
Abdominal pain 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Diarrhoea 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 2/39 (5.1%)
Dysphagia 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 1/41 (2.4%) 0/39 (0%)
Vomiting 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 2/39 (5.1%)
General disorders
Asthenia 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
General physical health deterioration 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Pyrexia 0/6 (0%) 0/8 (0%) 0/18 (0%) 1/39 (2.6%) 0/41 (0%) 0/39 (0%)
Disease progression 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Fatigue 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Influenza like illness 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Hepatobiliary disorders
Cholecystitis 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Infections and infestations
Cellulitis 0/6 (0%) 0/8 (0%) 0/18 (0%) 1/39 (2.6%) 1/41 (2.4%) 1/39 (2.6%)
Necrotising fasciitis 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 1/41 (2.4%) 0/39 (0%)
Sepsis 0/6 (0%) 0/8 (0%) 0/18 (0%) 1/39 (2.6%) 0/41 (0%) 0/39 (0%)
Bacteraemia 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Pneumonia 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Pyelonephritis 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Urinary tract infection 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Injury, poisoning and procedural complications
Femoral neck fracture 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Metabolism and nutrition disorders
Dehydration 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 2/39 (5.1%)
Hyponatraemia 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 1/41 (2.4%) 0/39 (0%)
Musculoskeletal and connective tissue disorders
Muscular weakness 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 1/41 (2.4%) 0/39 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 2/41 (4.9%) 1/39 (2.6%)
Nervous system disorders
Altered state of consciousness 0/6 (0%) 0/8 (0%) 0/18 (0%) 1/39 (2.6%) 0/41 (0%) 0/39 (0%)
Cerebral haemorrhage 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Cerebrovascular accident 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Headache 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 1/41 (2.4%) 0/39 (0%)
Hemiparesis 0/6 (0%) 0/8 (0%) 2/18 (11.1%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Hydrocephalus 0/6 (0%) 0/8 (0%) 0/18 (0%) 1/39 (2.6%) 0/41 (0%) 0/39 (0%)
Neurological decompensation 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 1/41 (2.4%) 0/39 (0%)
Peripheral motor neuropathy 0/6 (0%) 0/8 (0%) 0/18 (0%) 1/39 (2.6%) 0/41 (0%) 0/39 (0%)
Somnolence 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Seizure 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 3/41 (7.3%) 1/39 (2.6%)
Aphasia 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Brain oedema 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Convulsion 0/6 (0%) 1/8 (12.5%) 2/18 (11.1%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Grand mal convulsion 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Haemorrhage intracranial 1/6 (16.7%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Paralysis 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Psychiatric disorders
Confusional state 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 2/39 (5.1%)
Mental status changes 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 2/41 (4.9%) 0/39 (0%)
Delirium 1/6 (16.7%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Renal and urinary disorders
Acute prerenal failure 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Nephrolithiasis 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Respiratory distress 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Skin and subcutaneous tissue disorders
Rash 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 1/41 (2.4%) 0/39 (0%)
Vascular disorders
Deep vein thrombosis 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Thrombosis 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Other (Not Including Serious) Adverse Events
Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 6/6 (100%) 8/8 (100%) 18/18 (100%) 36/39 (92.3%) 40/41 (97.6%) 37/39 (94.9%)
Blood and lymphatic system disorders
Lymphopenia 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 5/39 (12.8%) 0/41 (0%) 0/39 (0%)
Thrombocytopenia 1/6 (16.7%) 0/8 (0%) 0/18 (0%) 3/39 (7.7%) 0/41 (0%) 4/39 (10.3%)
Leukopenia 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Cardiac disorders
Sinus bradycardia 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 0/41 (0%) 0/39 (0%)
Ear and labyrinth disorders
Deafness bilateral 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 0/41 (0%) 0/39 (0%)
Endocrine disorders
Hypothyroidism 1/6 (16.7%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Eye disorders
Dry eye 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 1/41 (2.4%) 2/39 (5.1%)
Eye pain 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 2/39 (5.1%)
Vision blurred 0/6 (0%) 0/8 (0%) 0/18 (0%) 3/39 (7.7%) 1/41 (2.4%) 0/39 (0%)
Visual acuity reduced 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 1/41 (2.4%) 2/39 (5.1%)
Gastrointestinal disorders
Constipation 2/6 (33.3%) 0/8 (0%) 4/18 (22.2%) 7/39 (17.9%) 2/41 (4.9%) 3/39 (7.7%)
Diarrhoea 1/6 (16.7%) 4/8 (50%) 13/18 (72.2%) 4/39 (10.3%) 29/41 (70.7%) 31/39 (79.5%)
Dry mouth 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 3/41 (7.3%) 3/39 (7.7%)
Dyspepsia 0/6 (0%) 0/8 (0%) 2/18 (11.1%) 1/39 (2.6%) 2/41 (4.9%) 3/39 (7.7%)
Haematochezia 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 3/39 (7.7%)
Haemorrhoids 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 3/39 (7.7%)
Nausea 0/6 (0%) 2/8 (25%) 2/18 (11.1%) 8/39 (20.5%) 6/41 (14.6%) 13/39 (33.3%)
Stomatitis 0/6 (0%) 0/8 (0%) 0/18 (0%) 1/39 (2.6%) 2/41 (4.9%) 2/39 (5.1%)
Vomiting 0/6 (0%) 2/8 (25%) 7/18 (38.9%) 8/39 (20.5%) 4/41 (9.8%) 8/39 (20.5%)
Abdominal pain 0/6 (0%) 0/8 (0%) 2/18 (11.1%) 1/39 (2.6%) 2/41 (4.9%) 1/39 (2.6%)
Abdominal pain upper 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Colitis 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Dyschezia 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Flatulence 1/6 (16.7%) 0/8 (0%) 0/18 (0%) 1/39 (2.6%) 0/41 (0%) 0/39 (0%)
Ileus 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Oesophagitis 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 1/41 (2.4%) 1/39 (2.6%)
Oral discomfort 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Oral pain 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Pancreatitis 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Tongue discolouration 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
General disorders
Asthenia 0/6 (0%) 0/8 (0%) 3/18 (16.7%) 2/39 (5.1%) 1/41 (2.4%) 4/39 (10.3%)
Chills 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 2/41 (4.9%) 0/39 (0%)
Fatigue 1/6 (16.7%) 2/8 (25%) 9/18 (50%) 10/39 (25.6%) 9/41 (22%) 11/39 (28.2%)
Gait disturbance 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 4/39 (10.3%) 3/41 (7.3%) 0/39 (0%)
Mucosal inflammation 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 4/41 (9.8%) 4/39 (10.3%)
Oedema peripheral 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 4/39 (10.3%) 3/41 (7.3%) 4/39 (10.3%)
Temperature intolerance 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 2/41 (4.9%) 0/39 (0%)
Feeling cold 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Irritability 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Malaise 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 1/39 (2.6%) 0/41 (0%) 1/39 (2.6%)
Oedema 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Pain 0/6 (0%) 0/8 (0%) 2/18 (11.1%) 1/39 (2.6%) 0/41 (0%) 1/39 (2.6%)
Pyrexia 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Thirst 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Infections and infestations
Infection 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 2/39 (5.1%)
Localised infection 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 2/41 (4.9%) 2/39 (5.1%)
Nasopharyngitis 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 4/39 (10.3%)
Oral candidiasis 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 4/39 (10.3%) 1/41 (2.4%) 0/39 (0%)
Paronychia 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 3/39 (7.7%)
Rash pustular 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 1/41 (2.4%) 2/39 (5.1%)
Sinusitis 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 0/41 (0%) 0/39 (0%)
Urinary tract infection 1/6 (16.7%) 2/8 (25%) 0/18 (0%) 3/39 (7.7%) 2/41 (4.9%) 3/39 (7.7%)
Herpes zoster 0/6 (0%) 0/8 (0%) 0/18 (0%) 1/39 (2.6%) 0/41 (0%) 2/39 (5.1%)
Influenza 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 2/39 (5.1%)
Upper respiratory tract infection 1/6 (16.7%) 0/8 (0%) 1/18 (5.6%) 1/39 (2.6%) 0/41 (0%) 2/39 (5.1%)
Bronchitis 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Candidiasis 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Cellulitis 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 0/39 (0%) 1/41 (2.4%) 1/39 (2.6%)
Rhinovirus infection 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 1/39 (2.6%) 0/41 (0%) 1/39 (2.6%)
Vaginal infection 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Injury, poisoning and procedural complications
Contusion 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 1/41 (2.4%) 6/39 (15.4%)
Fall 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 3/41 (7.3%) 1/39 (2.6%)
Procedural pain 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Toxicity to various agents 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Investigations
Weight decreased 0/6 (0%) 0/8 (0%) 2/18 (11.1%) 2/39 (5.1%) 0/41 (0%) 7/39 (17.9%)
Weight increased 1/6 (16.7%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 0/41 (0%) 0/39 (0%)
Alanine aminotransferase increased 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Aspartate aminotransferase increased 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Electrocardiogram abnormal 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 1/39 (2.6%) 0/41 (0%) 0/39 (0%)
Lipase increased 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Liver function test abnormal 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
White blood cells urine 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Metabolism and nutrition disorders
Decreased appetite 0/6 (0%) 1/8 (12.5%) 3/18 (16.7%) 1/39 (2.6%) 3/41 (7.3%) 11/39 (28.2%)
Dehydration 0/6 (0%) 1/8 (12.5%) 5/18 (27.8%) 0/39 (0%) 0/41 (0%) 3/39 (7.7%)
Hyperglycaemia 0/6 (0%) 0/8 (0%) 0/18 (0%) 4/39 (10.3%) 2/41 (4.9%) 0/39 (0%)
Hypokalaemia 0/6 (0%) 2/8 (25%) 7/18 (38.9%) 2/39 (5.1%) 1/41 (2.4%) 2/39 (5.1%)
Increased appetite 0/6 (0%) 0/8 (0%) 0/18 (0%) 3/39 (7.7%) 1/41 (2.4%) 0/39 (0%)
Hypocalcaemia 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Hypoglycaemia 1/6 (16.7%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Hypophagia 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 4/39 (10.3%) 1/41 (2.4%) 2/39 (5.1%)
Back pain 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 1/39 (2.6%) 2/41 (4.9%) 4/39 (10.3%)
Muscle spasms 0/6 (0%) 0/8 (0%) 0/18 (0%) 1/39 (2.6%) 4/41 (9.8%) 3/39 (7.7%)
Muscular weakness 0/6 (0%) 0/8 (0%) 3/18 (16.7%) 3/39 (7.7%) 3/41 (7.3%) 7/39 (17.9%)
Pain in extremity 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 1/39 (2.6%) 0/41 (0%) 4/39 (10.3%)
Muscle twitching 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Myopathy 1/6 (16.7%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 1/41 (2.4%) 0/39 (0%)
Nervous system disorders
Amnesia 0/6 (0%) 0/8 (0%) 0/18 (0%) 3/39 (7.7%) 3/41 (7.3%) 1/39 (2.6%)
Aphasia 1/6 (16.7%) 1/8 (12.5%) 0/18 (0%) 6/39 (15.4%) 2/41 (4.9%) 4/39 (10.3%)
Balance disorder 0/6 (0%) 0/8 (0%) 0/18 (0%) 3/39 (7.7%) 0/41 (0%) 1/39 (2.6%)
Brain oedema 0/6 (0%) 0/8 (0%) 0/18 (0%) 4/39 (10.3%) 3/41 (7.3%) 0/39 (0%)
Cognitive disorder 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 2/39 (5.1%) 0/41 (0%) 0/39 (0%)
Dizziness 0/6 (0%) 0/8 (0%) 3/18 (16.7%) 5/39 (12.8%) 2/41 (4.9%) 2/39 (5.1%)
Dysarthria 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 1/41 (2.4%) 0/39 (0%)
Dysgeusia 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 1/39 (2.6%) 0/41 (0%) 4/39 (10.3%)
Headache 2/6 (33.3%) 0/8 (0%) 2/18 (11.1%) 10/39 (25.6%) 6/41 (14.6%) 10/39 (25.6%)
Hemiparesis 1/6 (16.7%) 0/8 (0%) 0/18 (0%) 4/39 (10.3%) 3/41 (7.3%) 1/39 (2.6%)
Hypoaesthesia 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 6/39 (15.4%) 2/41 (4.9%) 0/39 (0%)
Memory impairment 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 1/39 (2.6%) 4/41 (9.8%) 3/39 (7.7%)
Motor dysfunction 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 0/41 (0%) 0/39 (0%)
Paraesthesia 0/6 (0%) 0/8 (0%) 0/18 (0%) 4/39 (10.3%) 2/41 (4.9%) 1/39 (2.6%)
Peripheral motor neuropathy 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 2/39 (5.1%)
Somnolence 1/6 (16.7%) 0/8 (0%) 1/18 (5.6%) 3/39 (7.7%) 2/41 (4.9%) 0/39 (0%)
Speech disorder 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 1/39 (2.6%) 4/41 (9.8%) 0/39 (0%)
Tremor 0/6 (0%) 0/8 (0%) 0/18 (0%) 3/39 (7.7%) 2/41 (4.9%) 3/39 (7.7%)
Seizure 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 9/41 (22%) 3/39 (7.7%)
Sensory disturbance 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 1/41 (2.4%) 0/39 (0%)
Ataxia 0/6 (0%) 1/8 (12.5%) 1/18 (5.6%) 1/39 (2.6%) 1/41 (2.4%) 0/39 (0%)
Convulsion 2/6 (33.3%) 1/8 (12.5%) 3/18 (16.7%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Hemianopia 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Lethargy 1/6 (16.7%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Mental impairment 1/6 (16.7%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Partial seizures 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 1/39 (2.6%) 0/41 (0%) 0/39 (0%)
Peroneal nerve palsy 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Sedation 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Syncope 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 1/39 (2.6%) 0/41 (0%) 1/39 (2.6%)
Vasogenic cerebral oedema 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Psychiatric disorders
Anxiety 0/6 (0%) 1/8 (12.5%) 1/18 (5.6%) 2/39 (5.1%) 3/41 (7.3%) 1/39 (2.6%)
Confusional state 0/6 (0%) 2/8 (25%) 2/18 (11.1%) 3/39 (7.7%) 3/41 (7.3%) 3/39 (7.7%)
Depression 0/6 (0%) 1/8 (12.5%) 2/18 (11.1%) 1/39 (2.6%) 2/41 (4.9%) 5/39 (12.8%)
Insomnia 0/6 (0%) 1/8 (12.5%) 0/18 (0%) 3/39 (7.7%) 4/41 (9.8%) 2/39 (5.1%)
Panic attack 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 0/41 (0%) 0/39 (0%)
Affect lability 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Mental status changes 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Renal and urinary disorders
Urinary incontinence 0/6 (0%) 0/8 (0%) 0/18 (0%) 1/39 (2.6%) 3/41 (7.3%) 4/39 (10.3%)
Dysuria 0/6 (0%) 0/8 (0%) 2/18 (11.1%) 0/39 (0%) 1/41 (2.4%) 0/39 (0%)
Reproductive system and breast disorders
Genital discomfort 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Vulvovaginal discomfort 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Respiratory, thoracic and mediastinal disorders
Cough 1/6 (16.7%) 0/8 (0%) 0/18 (0%) 4/39 (10.3%) 2/41 (4.9%) 7/39 (17.9%)
Dyspnoea 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 1/41 (2.4%) 2/39 (5.1%)
Epistaxis 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 4/41 (9.8%) 6/39 (15.4%)
Nasal congestion 0/6 (0%) 0/8 (0%) 0/18 (0%) 2/39 (5.1%) 1/41 (2.4%) 1/39 (2.6%)
Dyspnoea exertional 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 1/39 (2.6%) 0/41 (0%) 0/39 (0%)
Oropharyngeal pain 0/6 (0%) 0/8 (0%) 2/18 (11.1%) 0/39 (0%) 1/41 (2.4%) 1/39 (2.6%)
Skin and subcutaneous tissue disorders
Acne 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 5/39 (12.8%)
Dermatitis acneiform 0/6 (0%) 2/8 (25%) 3/18 (16.7%) 0/39 (0%) 6/41 (14.6%) 3/39 (7.7%)
Dry skin 0/6 (0%) 0/8 (0%) 0/18 (0%) 1/39 (2.6%) 3/41 (7.3%) 9/39 (23.1%)
Erythema 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 1/41 (2.4%) 3/39 (7.7%)
Pruritus 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 5/39 (12.8%) 3/41 (7.3%) 4/39 (10.3%)
Rash 1/6 (16.7%) 7/8 (87.5%) 13/18 (72.2%) 3/39 (7.7%) 18/41 (43.9%) 22/39 (56.4%)
Urticaria 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 2/39 (5.1%)
Ingrowing nail 0/6 (0%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 2/39 (5.1%)
Hyperhidrosis 1/6 (16.7%) 0/8 (0%) 0/18 (0%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Pruritus generalised 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Rash generalised 0/6 (0%) 0/8 (0%) 2/18 (11.1%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)
Rash macular 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 1/41 (2.4%) 0/39 (0%)
Rash pruritic 0/6 (0%) 0/8 (0%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 0/39 (0%)
Vascular disorders
Hypotension 0/6 (0%) 1/8 (12.5%) 1/18 (5.6%) 0/39 (0%) 0/41 (0%) 1/39 (2.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.

Results Point of Contact

Name/Title Boehringer Ingelheim, Call Center
Organization Boehringer Ingelheim
Phone 1-800-243-0127
Email clintriage.rdg@boehringer-ingelheim.com
Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00727506
Other Study ID Numbers:
  • 1200.36
First Posted:
Aug 4, 2008
Last Update Posted:
Aug 15, 2017
Last Verified:
Jul 1, 2017