BIBW 2992 (Afatinib) With or Without Daily Temozolomide in the Treatment of Patients With Recurrent Malignant Glioma
- Registration Number
- NCT00727506
- Lead Sponsor
- Boehringer Ingelheim
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 151
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description BIBW 2992 BIBW 2992 BIBW 2992 once daily BIBW 2992 plus TMZ BIBW 2992 plus TMZ BIBW 2992 once daily plus TMZ 21/28 days TMZ TMZ TMZ 21/28 days
- Primary Outcome Measures
Name Time Method 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
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
Name Time Method 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.
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.
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.
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.
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.
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).
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.
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
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.
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).
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).
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).
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
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).
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.
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).
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.
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
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.
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
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).
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.
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
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.
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).
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.
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.
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.
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).
Trial Locations
- Locations (28)
1200.36.0007 Boehringer Ingelheim Investigational Site
🇺🇸Charleston, South Carolina, United States
1200.36.1011 Boehringer Ingelheim Investigational Site
🇨🇦Halifax, Nova Scotia, Canada
1200.36.1010 Boehringer Ingelheim Investigational Site
🇨🇦Winnipeg, Manitoba, Canada
1200.36.1005 Boehringer Ingelheim Investigational Site
🇨🇦Calgary, Alberta, Canada
1200.36.1007 Boehringer Ingelheim Investigational Site
🇨🇦Fleurimont, Quebec, Canada
1200.36.1006 Boehringer Ingelheim Investigational Site
🇨🇦Quebec, Canada
1200.36.0019 Boehringer Ingelheim Investigational Site
🇺🇸Orlando, Florida, United States
1200.36.0011 Boehringer Ingelheim Investigational Site
🇺🇸Charlottesville, Virginia, United States
1200.36.0009 Boehringer Ingelheim Investigational Site
🇺🇸New York, New York, United States
1200.36.0014 Boehringer Ingelheim Investigational Site
🇺🇸Los Angeles, California, United States
1200.36.0012 Boehringer Ingelheim Investigational Site
🇺🇸Phoenix, Arizona, United States
1200.36.0023 Boehringer Ingelheim Investigational Site
🇺🇸Atlanta, Georgia, United States
1200.36.0002 Boehringer Ingelheim Investigational Site
🇺🇸Boston, Massachusetts, United States
1200.36.1009 Boehringer Ingelheim Investigational Site
🇨🇦Moncton, New Brunswick, Canada
1200.36.0003 Boehringer Ingelheim Investigational Site
🇺🇸Detroit, Michigan, United States
1200.36.1001 Boehringer Ingelheim Investigational Site
🇨🇦Kingston, Ontario, Canada
1200.36.0001 Boehringer Ingelheim Investigational Site
🇺🇸Durham, North Carolina, United States
1200.36.1003 Boehringer Ingelheim Investigational Site
🇨🇦Toronto, Ontario, Canada
1200.36.1004 Boehringer Ingelheim Investigational Site
🇨🇦Toronto, Ontario, Canada
1200.36.0016 Boehringer Ingelheim Investigational Site
🇺🇸Birmingham, Alabama, United States
1200.36.0008 Boehringer Ingelheim Investigational Site
🇺🇸Louisville, Kentucky, United States
1200.36.0017 Boehringer Ingelheim Investigational Site
🇺🇸Dallas, Texas, United States
1200.36.0010 Boehringer Ingelheim Investigational Site
🇺🇸Houston, Texas, United States
1200.36.0020 Boehringer Ingelheim Investigational Site
🇺🇸Memphis, Tennessee, United States
1200.36.1008 Boehringer Ingelheim Investigational Site
🇨🇦Hamilton, Ontario, Canada
1200.36.1002 Boehringer Ingelheim Investigational Site
🇨🇦Montreal, Quebec, Canada
1200.36.0022 Boehringer Ingelheim Investigational Site
🇺🇸Seattle, Washington, United States
1200.36.0005 Boehringer Ingelheim Investigational Site
🇺🇸Duarte, California, United States