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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00727506
First Posted: August 4, 2008
Last Update Posted: August 15, 2017
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.
Information provided by (Responsible Party):
Boehringer Ingelheim
Results First Submitted: August 8, 2013  
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

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
This study consists of 2 parts (phase I and phase II) with separate participants.

Reporting Groups
  Description
Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 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
Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 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
Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 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
Phase II - Temozolomide 75mg/m^2 Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Phase II - Afatinib 40mg Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part
Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2 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

Participant Flow:   Overall Study
    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
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 
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



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 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
Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 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
Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 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
Phase II - Temozolomide 75mg/m^2 Patients receiving Temozolomide monotherapy 75 mg/m^2 for 21 days followed by 7 days off - Phase II part
Phase II - Afatinib 40mg Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part
Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2 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 Total of all reporting groups

Baseline Measures
   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 
Overall Participants Analyzed 
[Units: Participants]
 6   8   18   39   41   39   151 
Age 
[Units: Years]
Mean (Standard Deviation)
 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 
[Units: Participants]
Count of 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 
[Units: Number of 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] 
[Units: Number of 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] 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.


  Outcome Measures
  Show All Outcome Measures

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

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

3.  Secondary:   Objective Tumor Response in Phase I   [ 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. ]

4.  Secondary:   Objective Tumor Response in Phase II   [ 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 ]

5.  Secondary:   Progression-free Survival (PFS)- Phase II Part   [ 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. ]

6.  Secondary:   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 ]

7.  Secondary:   Cmax,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 ]

8.  Secondary:   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 ]

9.  Secondary:   AUC (0-8) for Temozolomide   [ 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 ]

10.  Secondary:   Cmax for Temozolomide   [ 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 ]

11.  Secondary:   Tmax for Temozolomide   [ 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 ]

12.  Secondary:   t1/2 for Temozolomide   [ 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 ]

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

14.  Secondary:   Number of Participants With EGFRvIII Assessed by IHC Test.   [ Time Frame: Baseline (during screening) ]

15.  Secondary:   Number of Participants With MGMT Marker Assessed by IHC Test.   [ Time Frame: Baseline (during screening) ]

16.  Secondary:   Number of Participants With EGFR Marker Assessed by IHC Test.   [ Time Frame: Baseline (during screening) ]

17.  Secondary:   Number of Participants With PTEN Marker Assessed by IHC Test.   [ Time Frame: Baseline (during screening) ]

18.  Secondary:   Number of Participants With PAKT Marker Assessed by IHC Test.   [ Time Frame: Baseline (during screening) ]

19.  Secondary:   Number of Participants With EGFR Assessed by FISH   [ Time Frame: Baseline (during screening) ]

20.  Secondary:   Number of Participants With PTEN Assessed by FISH   [ Time Frame: Baseline (during screening) ]

21.  Secondary:   Number of Participants With Chromosomes (CEP7) Assessed by FISH   [ Time Frame: Baseline (during screening) ]

22.  Secondary:   Number of Participants With Chromosomes (CEP10) Assessed by FISH   [ Time Frame: Baseline (during screening) ]

23.  Secondary:   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   [ Time Frame: From first administration of treatment until 28 days after last drug administration, up to 491 days. ]

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

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

26.  Secondary:   Causes of Death - Phase I   [ Time Frame: From first administration of treatment until 28 days after last drug administration, up to 491 days. ]

27.  Secondary:   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   [ Time Frame: From first administration of treatment until 28 days after last drug administration, up to 518 days. ]

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

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

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

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


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information
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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.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Boehringer Ingelheim, Call Center
Organization: Boehringer Ingelheim
phone: 1-800-243-0127
e-mail: clintriage.rdg@boehringer-ingelheim.com



Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00727506     History of Changes
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