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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00727506
Recruitment Status : Completed
First Posted : August 4, 2008
Results First Posted : January 24, 2014
Last Update Posted : August 15, 2017
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Glioma
Interventions Drug: BIBW 2992
Drug: TMZ
Drug: BIBW 2992 plus TMZ
Enrollment 151
Recruitment Details  
Pre-assignment Details 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
Hide 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 [1] 8 [1] 18 [1] 39 [2] 41 [2] 39 [2]
Completed 0 0 0 0 0 0
Not Completed 6 8 18 39 41 39
Reason Not Completed
Adverse Event             0             0             4             4             1             8
Dose Limiting Toxicity (DLT)             2             0             2             0             0             0
Progressive disease             4             7             9             28             38             28
Refused to continue medication             0             1             2             3             1             2
Other reason not described above             0             0             1             4             1             1
[1]
Entered
[2]
Randomized
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
Hide 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 Number of Baseline Participants 6 8 18 39 41 39 151
Hide Baseline Analysis Population Description
For Phase I part, all patients who were treated with at least one dose of the study medication. For Phase II part, all patients who were randomized and have taken at least one dose of the study medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6 participants 8 participants 18 participants 39 participants 41 participants 39 participants 151 participants
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  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 8 participants 18 participants 39 participants 41 participants 39 participants 151 participants
Female
2
  33.3%
2
  25.0%
8
  44.4%
14
  35.9%
14
  34.1%
18
  46.2%
58
  38.4%
Male
4
  66.7%
6
  75.0%
10
  55.6%
25
  64.1%
27
  65.9%
21
  53.8%
93
  61.6%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Number of participants
Number Analyzed 6 participants 8 participants 18 participants 39 participants 41 participants 39 participants 151 participants
Asian 0 1 0 0 1 1 3
Black/African American 0 0 2 2 0 2 6
Hawaiian/Pacific Isle 0 0 0 0 0 1 1
White 6 7 16 37 40 35 141
Karnofsky performance score   [1] 
Measure Type: Number
Unit of measure:  Number of participants
Number Analyzed 6 participants 8 participants 18 participants 39 participants 41 participants 39 participants 151 participants
70 1 1 1 9 9 12 33
80 1 1 2 13 12 9 38
90 2 4 11 12 17 15 61
100 2 2 4 5 3 3 19
[1]
Measure Description: The scale range is from 100 (Normal no complaints) to 0 (dead). This score was used in Phase II randomization stratification and in some efficacy analyses.
1.Primary Outcome
Title Number of Participants With DLT- Phase I
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 6 8 18
Measure Type: Number
Unit of Measure: participants
2 0 4
2.Primary Outcome
Title Progression-free Survival (PFS-6) at Six Months - Phase II
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probablity of survival
0.230
(0.09 to 0.37)
0.030
(0.00 to 0.09)
0.103
(0.00 to 0.21)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase II - Temozolomide 75mg/m^2, Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Phase II - Temozolomide 75mg/m^2, Phase II - Afatinib 40mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 [Not Specified]
3.Secondary Outcome
Title Objective Tumor Response in Phase I
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 6 8 18
Measure Type: Number
Unit of Measure: participants
0 1 0
4.Secondary Outcome
Title Objective Tumor Response in Phase II
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: participants
4 1 3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase II - Temozolomide 75mg/m^2, Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Phase II - Temozolomide 75mg/m^2, Phase II - Afatinib 40mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1954
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
5.Secondary Outcome
Title Progression-free Survival (PFS)- Phase II Part
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 39 41 39
Median (Full Range)
Unit of Measure: Months
1.87
(1.15 to 3.68)
0.99
(0.95 to 1.84)
1.53
(0.99 to 1.87)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase II - Temozolomide 75mg/m^2, Phase II - Afatinib 40mg
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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.0320
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.780
Confidence Interval (2-Sided) 95%
1.088 to 2.912
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Phase II - Temozolomide 75mg/m^2, Phase II - Afatinib 40mg Plus Temozolomide 75 mg/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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.2044
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.392
Confidence Interval (2-Sided) 95%
0.841 to 2.301
Estimation Comments [Not Specified]
6.Secondary Outcome
Title AUCτ,ss for Afatinib
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
Hide Outcome Measure Data
Hide 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)
Hide 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).
Overall Number of Participants Analyzed 15 5
Geometric Mean (Standard Deviation)
Unit of Measure: ng·h/mL
1070  (63.7) 918  (65.3)
7.Secondary Outcome
Title Cmax,ss for Afatinib
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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).
Overall Number of Participants Analyzed 15 6
Geometric Mean (Standard Deviation)
Unit of Measure: ng/mL
63.2  (62.1) 50.5  (58.0)
8.Secondary Outcome
Title Tmax,ss for Afatinib
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
Hide Outcome Measure Data
Hide 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)
Hide 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).
Overall Number of Participants Analyzed 15 6
Median (Full Range)
Unit of Measure: hour
4.00
(1.50 to 8.00)
3.50
(1.00 to 7.92)
9.Secondary Outcome
Title AUC (0-8) for Temozolomide
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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).
Overall Number of Participants Analyzed 14 17
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng·h/mL
8380
(24.1%)
8160
(27.8%)
10.Secondary Outcome
Title Cmax for Temozolomide
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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).
Overall Number of Participants Analyzed 15 17
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
2520
(33.3%)
2690
(39.7%)
11.Secondary Outcome
Title Tmax for Temozolomide
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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).
Overall Number of Participants Analyzed 15 17
Median (Full Range)
Unit of Measure: h
1.22
(1.00 to 3.25)
1.00
(0.500 to 2.00)
12.Secondary Outcome
Title t1/2 for Temozolomide
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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).
Overall Number of Participants Analyzed 14 17
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
2.17
(34.3%)
2.08
(58.4%)
13.Secondary Outcome
Title Phase II - Trough Plasma Concentration of Afatinib
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
PKS
Arm/Group Title Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Hide 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
Overall Number of Participants Analyzed 41 39
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
predose at Day 15 of Cycle 2 (n=17; 15)
19.8
(0.1% to 12.9%)
29.7
(1.6% to 20.9%)
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.
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: Participants
Sample tested: Negative 6 8 5
Sample tested: + 5 3 4
Sample tested: +/++ 0 3 2
Sample tested: ++ 1 4 4
Sample tested: ++/+++ 1 3 3
Sample tested: +++ 3 5 10
No Sample for test 23 15 11
15.Secondary Outcome
Title Number of Participants With MGMT Marker Assessed by IHC Test.
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: Participants
MGMT+ 9 8 12
MGMT- 7 15 15
No Sample for test 23 18 12
16.Secondary Outcome
Title Number of Participants With EGFR Marker Assessed by IHC Test.
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: Participants
EGFR wt+ 14 23 24
EGFR wt- 2 0 4
No Sample for test 23 18 11
17.Secondary Outcome
Title Number of Participants With PTEN Marker Assessed by IHC Test.
Hide 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)
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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
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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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: Participants
PTEN intact 5 4 7
PTEN loss 11 19 21
No Sample for test 23 18 11
18.Secondary Outcome
Title Number of Participants With PAKT Marker Assessed by IHC Test.
Hide 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)
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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
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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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: Participants
PAKT+ 5 11 11
PAKT- 11 13 16
No Sample for test 23 17 12
19.Secondary Outcome
Title Number of Participants With EGFR Assessed by FISH
Hide 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)
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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
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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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: Participants
EGFR abnormal (Amplification) 5 14 11
EGFR normal (Intact) 1 0 1
EGFR abnormal (Gain) 10 9 16
No Sample for test 23 18 11
20.Secondary Outcome
Title Number of Participants With PTEN Assessed by FISH
Hide 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)
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Hide 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
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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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: Participants
PTEN abnormal (Loss) 11 20 25
PTEN normal (Gain) 1 2 1
PTEN normal (Intact) 4 1 2
No Sample for test 23 18 11
21.Secondary Outcome
Title Number of Participants With Chromosomes (CEP7) Assessed by FISH
Hide 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)
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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
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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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: Participants
CEP7 abnormal (Gain) 15 24 27
CEP7 normal (Intact) 1 0 1
No Sample for test 23 17 11
22.Secondary Outcome
Title Number of Participants With Chromosomes (CEP10) Assessed by FISH
Hide 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)
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Hide 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
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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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: Participants
CEP10 abnormal (Loss) 10 19 24
CEP10 normal (Gain) 2 3 1
CEP10 normal (Intact) 4 1 2
No Sample for test 23 18 11
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
Hide 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.
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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
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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
Overall Number of Participants Analyzed 6 8 18
Measure Type: Number
Unit of Measure: Participants
drug−related AEs 4 8 17
AEs leading to discontinuation of trial drug 2 1 10
Serious AE's 2 1 10
other significant AEs 1 0 5
24.Secondary Outcome
Title Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I
Hide 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.
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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
Hide 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
Overall Number of Participants Analyzed 6 8 18
Measure Type: Number
Unit of Measure: Participants
Rash 0 0 1
Vomiting 0 0 2
Nausea 0 1 0
Diarrhoea 0 1 2
acne 0 0 0
Haemorrhage intracranial 1 0 0
Convulsion 0 1 1
Syncope 0 1 0
Hemiparesis 0 0 2
Aphasia 0 0 1
Brain oedema 0 0 1
Cerebrovascular accident 0 0 1
Headache 0 0 1
Paralysis 0 0 1
Peroneal nerve palsy 0 0 1
Vasogenic cerebral oedema 0 0 1
25.Secondary Outcome
Title Number of Participants With Adverse Events, Graded According CTCAE - Phase I
Hide 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.
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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
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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
Overall Number of Participants Analyzed 6 8 18
Measure Type: Number
Unit of Measure: Participants
Grade 1 1 2 0
Grade 2 3 4 7
Grade 3 0 1 7
Grade 4 2 1 3
Grade 5 0 0 1
26.Secondary Outcome
Title Causes of Death - Phase I
Hide 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.
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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
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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
Overall Number of Participants Analyzed 6 8 18
Measure Type: Number
Unit of Measure: 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
Hide 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.
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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
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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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: Participants
drug−related AEs 22 35 36
AE leading to dose reduction 2 4 7
AEs leading to discontinuation of trial drug 9 8 14
Serious AE's 6 10 13
28.Secondary Outcome
Title Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II
Hide 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.
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Hide 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
Hide 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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: Participants
Rash 3 19 22
Acne 0 0 4
Vomiting 8 4 10
Nausea 7 6 13
Diarrhoea 4 29 32
Neurological decompensation 0 2 0
Cerebral haemorrhage 0 0 1
Dysgeusia 0 0 1
Hemiparesis 1 0 1
Ataxia 0 1 0
Headache 0 1 0
Memory impairment 0 1 0
Speech disorder 0 1 0
29.Secondary Outcome
Title Number of Participants With Adverse Events, Graded According CTCAE - Phase II
Hide 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.
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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
Hide 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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: Participants
Grade 1 3 5 2
Grade 2 14 18 10
Grade 3 13 15 19
Grade 4 5 2 5
Grade 5 2 1 2
30.Secondary Outcome
Title Causes of Death - Phase II
Hide 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.
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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
Hide 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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: deaths
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
Hide 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.
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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
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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
Overall Number of Participants Analyzed 39 41 39
Measure Type: Number
Unit of Measure: Participants
0.0 0.0 0.0
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 [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 Phase II - Temozolomide 75mg/m^2 Phase II - Afatinib 40mg Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/-- 
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/6 (33.33%)   1/8 (12.50%)   10/18 (55.56%)   6/39 (15.38%)   10/41 (24.39%)   13/39 (33.33%) 
Blood and lymphatic system disorders             
Anaemia  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/41 (2.44%)  0/39 (0.00%) 
Febrile neutropenia  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Spontaneous haematoma  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/41 (2.44%)  0/39 (0.00%) 
Thrombocytopenia  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  2/39 (5.13%) 
Cardiac disorders             
Palpitations  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/41 (2.44%)  0/39 (0.00%) 
Gastrointestinal disorders             
Abdominal pain  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Diarrhoea  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  2/39 (5.13%) 
Dysphagia  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/41 (2.44%)  0/39 (0.00%) 
Vomiting  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  2/39 (5.13%) 
General disorders             
Asthenia  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
General physical health deterioration  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Pyrexia  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/41 (0.00%)  0/39 (0.00%) 
Disease progression  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Fatigue  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Influenza like illness  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Hepatobiliary disorders             
Cholecystitis  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Infections and infestations             
Cellulitis  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  1/41 (2.44%)  1/39 (2.56%) 
Necrotising fasciitis  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/41 (2.44%)  0/39 (0.00%) 
Sepsis  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/41 (0.00%)  0/39 (0.00%) 
Bacteraemia  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Pneumonia  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Pyelonephritis  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Urinary tract infection  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Injury, poisoning and procedural complications             
Femoral neck fracture  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Metabolism and nutrition disorders             
Dehydration  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  2/39 (5.13%) 
Hyponatraemia  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/41 (2.44%)  0/39 (0.00%) 
Musculoskeletal and connective tissue disorders             
Muscular weakness  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  1/41 (2.44%)  0/39 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Malignant neoplasm progression  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  2/41 (4.88%)  1/39 (2.56%) 
Nervous system disorders             
Altered state of consciousness  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/41 (0.00%)  0/39 (0.00%) 
Cerebral haemorrhage  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Cerebrovascular accident  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Headache  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  1/41 (2.44%)  0/39 (0.00%) 
Hemiparesis  1  0/6 (0.00%)  0/8 (0.00%)  2/18 (11.11%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Hydrocephalus  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/41 (0.00%)  0/39 (0.00%) 
Neurological decompensation  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/41 (2.44%)  0/39 (0.00%) 
Peripheral motor neuropathy  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/41 (0.00%)  0/39 (0.00%) 
Somnolence  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Seizure  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  3/41 (7.32%)  1/39 (2.56%) 
Aphasia  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Brain oedema  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Convulsion  1  0/6 (0.00%)  1/8 (12.50%)  2/18 (11.11%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Grand mal convulsion  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Haemorrhage intracranial  1  1/6 (16.67%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Paralysis  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Psychiatric disorders             
Confusional state  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  2/39 (5.13%) 
Mental status changes  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  2/41 (4.88%)  0/39 (0.00%) 
Delirium  1  1/6 (16.67%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Renal and urinary disorders             
Acute prerenal failure  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Nephrolithiasis  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Respiratory failure  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Respiratory distress  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Skin and subcutaneous tissue disorders             
Rash  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/41 (2.44%)  0/39 (0.00%) 
Vascular disorders             
Deep vein thrombosis  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Thrombosis  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.0 and 19.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   6/6 (100.00%)   8/8 (100.00%)   18/18 (100.00%)   36/39 (92.31%)   40/41 (97.56%)   37/39 (94.87%) 
Blood and lymphatic system disorders             
Lymphopenia  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  5/39 (12.82%)  0/41 (0.00%)  0/39 (0.00%) 
Thrombocytopenia  1  1/6 (16.67%)  0/8 (0.00%)  0/18 (0.00%)  3/39 (7.69%)  0/41 (0.00%)  4/39 (10.26%) 
Leukopenia  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Cardiac disorders             
Sinus bradycardia  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  0/41 (0.00%)  0/39 (0.00%) 
Ear and labyrinth disorders             
Deafness bilateral  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  0/41 (0.00%)  0/39 (0.00%) 
Endocrine disorders             
Hypothyroidism  1  1/6 (16.67%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Eye disorders             
Dry eye  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/41 (2.44%)  2/39 (5.13%) 
Eye pain  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  2/39 (5.13%) 
Vision blurred  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  3/39 (7.69%)  1/41 (2.44%)  0/39 (0.00%) 
Visual acuity reduced  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/41 (2.44%)  2/39 (5.13%) 
Gastrointestinal disorders             
Constipation  1  2/6 (33.33%)  0/8 (0.00%)  4/18 (22.22%)  7/39 (17.95%)  2/41 (4.88%)  3/39 (7.69%) 
Diarrhoea  1  1/6 (16.67%)  4/8 (50.00%)  13/18 (72.22%)  4/39 (10.26%)  29/41 (70.73%)  31/39 (79.49%) 
Dry mouth  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  3/41 (7.32%)  3/39 (7.69%) 
Dyspepsia  1  0/6 (0.00%)  0/8 (0.00%)  2/18 (11.11%)  1/39 (2.56%)  2/41 (4.88%)  3/39 (7.69%) 
Haematochezia  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  3/39 (7.69%) 
Haemorrhoids  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  3/39 (7.69%) 
Nausea  1  0/6 (0.00%)  2/8 (25.00%)  2/18 (11.11%)  8/39 (20.51%)  6/41 (14.63%)  13/39 (33.33%) 
Stomatitis  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  2/41 (4.88%)  2/39 (5.13%) 
Vomiting  1  0/6 (0.00%)  2/8 (25.00%)  7/18 (38.89%)  8/39 (20.51%)  4/41 (9.76%)  8/39 (20.51%) 
Abdominal pain  1  0/6 (0.00%)  0/8 (0.00%)  2/18 (11.11%)  1/39 (2.56%)  2/41 (4.88%)  1/39 (2.56%) 
Abdominal pain upper  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Colitis  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Dyschezia  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Flatulence  1  1/6 (16.67%)  0/8 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/41 (0.00%)  0/39 (0.00%) 
Ileus  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Oesophagitis  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  1/41 (2.44%)  1/39 (2.56%) 
Oral discomfort  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Oral pain  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Pancreatitis  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Tongue discolouration  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
General disorders             
Asthenia  1  0/6 (0.00%)  0/8 (0.00%)  3/18 (16.67%)  2/39 (5.13%)  1/41 (2.44%)  4/39 (10.26%) 
Chills  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  2/41 (4.88%)  0/39 (0.00%) 
Fatigue  1  1/6 (16.67%)  2/8 (25.00%)  9/18 (50.00%)  10/39 (25.64%)  9/41 (21.95%)  11/39 (28.21%) 
Gait disturbance  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  4/39 (10.26%)  3/41 (7.32%)  0/39 (0.00%) 
Mucosal inflammation  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  4/41 (9.76%)  4/39 (10.26%) 
Oedema peripheral  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  4/39 (10.26%)  3/41 (7.32%)  4/39 (10.26%) 
Temperature intolerance  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  2/41 (4.88%)  0/39 (0.00%) 
Feeling cold  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Irritability  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Malaise  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  1/39 (2.56%)  0/41 (0.00%)  1/39 (2.56%) 
Oedema  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Pain  1  0/6 (0.00%)  0/8 (0.00%)  2/18 (11.11%)  1/39 (2.56%)  0/41 (0.00%)  1/39 (2.56%) 
Pyrexia  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Thirst  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Infections and infestations             
Infection  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  2/39 (5.13%) 
Localised infection  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  2/41 (4.88%)  2/39 (5.13%) 
Nasopharyngitis  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  4/39 (10.26%) 
Oral candidiasis  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  4/39 (10.26%)  1/41 (2.44%)  0/39 (0.00%) 
Paronychia  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  3/39 (7.69%) 
Rash pustular  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/41 (2.44%)  2/39 (5.13%) 
Sinusitis  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  0/41 (0.00%)  0/39 (0.00%) 
Urinary tract infection  1  1/6 (16.67%)  2/8 (25.00%)  0/18 (0.00%)  3/39 (7.69%)  2/41 (4.88%)  3/39 (7.69%) 
Herpes zoster  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/41 (0.00%)  2/39 (5.13%) 
Influenza  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  2/39 (5.13%) 
Upper respiratory tract infection  1  1/6 (16.67%)  0/8 (0.00%)  1/18 (5.56%)  1/39 (2.56%)  0/41 (0.00%)  2/39 (5.13%) 
Bronchitis  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Candidiasis  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Cellulitis  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  0/39 (0.00%)  1/41 (2.44%)  1/39 (2.56%) 
Rhinovirus infection  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  1/39 (2.56%)  0/41 (0.00%)  1/39 (2.56%) 
Vaginal infection  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Injury, poisoning and procedural complications             
Contusion  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/41 (2.44%)  6/39 (15.38%) 
Fall  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  3/41 (7.32%)  1/39 (2.56%) 
Procedural pain  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Toxicity to various agents  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Investigations             
Weight decreased  1  0/6 (0.00%)  0/8 (0.00%)  2/18 (11.11%)  2/39 (5.13%)  0/41 (0.00%)  7/39 (17.95%) 
Weight increased  1  1/6 (16.67%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  0/41 (0.00%)  0/39 (0.00%) 
Alanine aminotransferase increased  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Aspartate aminotransferase increased  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Electrocardiogram abnormal  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  1/39 (2.56%)  0/41 (0.00%)  0/39 (0.00%) 
Lipase increased  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Liver function test abnormal  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
White blood cells urine  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Metabolism and nutrition disorders             
Decreased appetite  1  0/6 (0.00%)  1/8 (12.50%)  3/18 (16.67%)  1/39 (2.56%)  3/41 (7.32%)  11/39 (28.21%) 
Dehydration  1  0/6 (0.00%)  1/8 (12.50%)  5/18 (27.78%)  0/39 (0.00%)  0/41 (0.00%)  3/39 (7.69%) 
Hyperglycaemia  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  4/39 (10.26%)  2/41 (4.88%)  0/39 (0.00%) 
Hypokalaemia  1  0/6 (0.00%)  2/8 (25.00%)  7/18 (38.89%)  2/39 (5.13%)  1/41 (2.44%)  2/39 (5.13%) 
Increased appetite  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  3/39 (7.69%)  1/41 (2.44%)  0/39 (0.00%) 
Hypocalcaemia  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Hypoglycaemia  1  1/6 (16.67%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Hypophagia  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Musculoskeletal and connective tissue disorders             
Arthralgia  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  4/39 (10.26%)  1/41 (2.44%)  2/39 (5.13%) 
Back pain  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  1/39 (2.56%)  2/41 (4.88%)  4/39 (10.26%) 
Muscle spasms  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  4/41 (9.76%)  3/39 (7.69%) 
Muscular weakness  1  0/6 (0.00%)  0/8 (0.00%)  3/18 (16.67%)  3/39 (7.69%)  3/41 (7.32%)  7/39 (17.95%) 
Pain in extremity  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  1/39 (2.56%)  0/41 (0.00%)  4/39 (10.26%) 
Muscle twitching  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Myopathy  1  1/6 (16.67%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Malignant neoplasm progression  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  1/41 (2.44%)  0/39 (0.00%) 
Nervous system disorders             
Amnesia  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  3/39 (7.69%)  3/41 (7.32%)  1/39 (2.56%) 
Aphasia  1  1/6 (16.67%)  1/8 (12.50%)  0/18 (0.00%)  6/39 (15.38%)  2/41 (4.88%)  4/39 (10.26%) 
Balance disorder  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  3/39 (7.69%)  0/41 (0.00%)  1/39 (2.56%) 
Brain oedema  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  4/39 (10.26%)  3/41 (7.32%)  0/39 (0.00%) 
Cognitive disorder  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  2/39 (5.13%)  0/41 (0.00%)  0/39 (0.00%) 
Dizziness  1  0/6 (0.00%)  0/8 (0.00%)  3/18 (16.67%)  5/39 (12.82%)  2/41 (4.88%)  2/39 (5.13%) 
Dysarthria  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  1/41 (2.44%)  0/39 (0.00%) 
Dysgeusia  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  1/39 (2.56%)  0/41 (0.00%)  4/39 (10.26%) 
Headache  1  2/6 (33.33%)  0/8 (0.00%)  2/18 (11.11%)  10/39 (25.64%)  6/41 (14.63%)  10/39 (25.64%) 
Hemiparesis  1  1/6 (16.67%)  0/8 (0.00%)  0/18 (0.00%)  4/39 (10.26%)  3/41 (7.32%)  1/39 (2.56%) 
Hypoaesthesia  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  6/39 (15.38%)  2/41 (4.88%)  0/39 (0.00%) 
Memory impairment  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  1/39 (2.56%)  4/41 (9.76%)  3/39 (7.69%) 
Motor dysfunction  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  0/41 (0.00%)  0/39 (0.00%) 
Paraesthesia  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  4/39 (10.26%)  2/41 (4.88%)  1/39 (2.56%) 
Peripheral motor neuropathy  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  2/39 (5.13%) 
Somnolence  1  1/6 (16.67%)  0/8 (0.00%)  1/18 (5.56%)  3/39 (7.69%)  2/41 (4.88%)  0/39 (0.00%) 
Speech disorder  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  1/39 (2.56%)  4/41 (9.76%)  0/39 (0.00%) 
Tremor  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  3/39 (7.69%)  2/41 (4.88%)  3/39 (7.69%) 
Seizure  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  9/41 (21.95%)  3/39 (7.69%) 
Sensory disturbance  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  1/41 (2.44%)  0/39 (0.00%) 
Ataxia  1  0/6 (0.00%)  1/8 (12.50%)  1/18 (5.56%)  1/39 (2.56%)  1/41 (2.44%)  0/39 (0.00%) 
Convulsion  1  2/6 (33.33%)  1/8 (12.50%)  3/18 (16.67%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Hemianopia  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Lethargy  1  1/6 (16.67%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Mental impairment  1  1/6 (16.67%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Partial seizures  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  1/39 (2.56%)  0/41 (0.00%)  0/39 (0.00%) 
Peroneal nerve palsy  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Sedation  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Syncope  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  1/39 (2.56%)  0/41 (0.00%)  1/39 (2.56%) 
Vasogenic cerebral oedema  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Psychiatric disorders             
Anxiety  1  0/6 (0.00%)  1/8 (12.50%)  1/18 (5.56%)  2/39 (5.13%)  3/41 (7.32%)  1/39 (2.56%) 
Confusional state  1  0/6 (0.00%)  2/8 (25.00%)  2/18 (11.11%)  3/39 (7.69%)  3/41 (7.32%)  3/39 (7.69%) 
Depression  1  0/6 (0.00%)  1/8 (12.50%)  2/18 (11.11%)  1/39 (2.56%)  2/41 (4.88%)  5/39 (12.82%) 
Insomnia  1  0/6 (0.00%)  1/8 (12.50%)  0/18 (0.00%)  3/39 (7.69%)  4/41 (9.76%)  2/39 (5.13%) 
Panic attack  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  0/41 (0.00%)  0/39 (0.00%) 
Affect lability  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Mental status changes  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Renal and urinary disorders             
Urinary incontinence  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  3/41 (7.32%)  4/39 (10.26%) 
Dysuria  1  0/6 (0.00%)  0/8 (0.00%)  2/18 (11.11%)  0/39 (0.00%)  1/41 (2.44%)  0/39 (0.00%) 
Reproductive system and breast disorders             
Genital discomfort  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Vulvovaginal discomfort  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Cough  1  1/6 (16.67%)  0/8 (0.00%)  0/18 (0.00%)  4/39 (10.26%)  2/41 (4.88%)  7/39 (17.95%) 
Dyspnoea  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  1/41 (2.44%)  2/39 (5.13%) 
Epistaxis  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  4/41 (9.76%)  6/39 (15.38%) 
Nasal congestion  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  1/41 (2.44%)  1/39 (2.56%) 
Dyspnoea exertional  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  1/39 (2.56%)  0/41 (0.00%)  0/39 (0.00%) 
Oropharyngeal pain  1  0/6 (0.00%)  0/8 (0.00%)  2/18 (11.11%)  0/39 (0.00%)  1/41 (2.44%)  1/39 (2.56%) 
Skin and subcutaneous tissue disorders             
Acne  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  5/39 (12.82%) 
Dermatitis acneiform  1  0/6 (0.00%)  2/8 (25.00%)  3/18 (16.67%)  0/39 (0.00%)  6/41 (14.63%)  3/39 (7.69%) 
Dry skin  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  3/41 (7.32%)  9/39 (23.08%) 
Erythema  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/41 (2.44%)  3/39 (7.69%) 
Pruritus  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  5/39 (12.82%)  3/41 (7.32%)  4/39 (10.26%) 
Rash  1  1/6 (16.67%)  7/8 (87.50%)  13/18 (72.22%)  3/39 (7.69%)  18/41 (43.90%)  22/39 (56.41%) 
Urticaria  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  2/39 (5.13%) 
Ingrowing nail  1  0/6 (0.00%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  2/39 (5.13%) 
Hyperhidrosis  1  1/6 (16.67%)  0/8 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Pruritus generalised  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Rash generalised  1  0/6 (0.00%)  0/8 (0.00%)  2/18 (11.11%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Rash macular  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  1/41 (2.44%)  0/39 (0.00%) 
Rash pruritic  1  0/6 (0.00%)  0/8 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  0/39 (0.00%) 
Vascular disorders             
Hypotension  1  0/6 (0.00%)  1/8 (12.50%)  1/18 (5.56%)  0/39 (0.00%)  0/41 (0.00%)  1/39 (2.56%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.0 and 19.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim, Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00727506    
Other Study ID Numbers: 1200.36
First Submitted: July 31, 2008
First Posted: August 4, 2008
Results First Submitted: August 8, 2013
Results First Posted: January 24, 2014
Last Update Posted: August 15, 2017