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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:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00727506
First received: July 31, 2008
Last updated: July 10, 2017
Last verified: July 2017
July 31, 2008
July 10, 2017
July 14, 2008
May 12, 2011   (Final data collection date for primary outcome measure)
  • 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 ]
    Number of Participants With Dose Limiting Toxicities (DLT) - Phase I Part
  • Progression-free Survival (PFS-6) at Six Months - Phase II [ Time Frame: 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.
Phase I Part: Occurrence of Dose limiting toxicity (DLT). Phase II Part: 6 month progression free survival rate. [ Time Frame: Undue toxicity or progression. ]
Complete list of historical versions of study NCT00727506 on ClinicalTrials.gov Archive Site
  • 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. ]
    Objective Tumor Response is defined as complete response (CR) and partial response (PR) according to the MacDonald criteria assessed by central independent review.
  • 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 ]
    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 [ 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. ]
    Progression-free survival was defined as the duration between randomization and the date of the first of the two following events: progression or death.
  • 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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.
  • 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 ]
    maximum measured plasma concentration following the first dose of uniform intervals τ (Cmax) of temozolomide in presence and absence of afatinib.
  • 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 ]
    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.
  • 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 ]
    terminal half-life (t1/2) of temozolomide in presence and absence of afatinib
  • 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 ]
    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. [ Time Frame: 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.
  • Number of Participants With MGMT Marker Assessed by IHC Test. [ Time Frame: 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. [ Time Frame: 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 PTEN Marker Assessed by IHC Test. [ Time Frame: 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.
  • Number of Participants With PAKT Marker Assessed by IHC Test. [ Time Frame: 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 [ Time Frame: 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).
  • Number of Participants With PTEN Assessed by FISH [ Time Frame: 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 Chromosomes (CEP7) Assessed by FISH [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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).
  • 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. ]
    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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
Pharmacokinetis Safety Objective tumor response PFS Molecular determinants [ Time Frame: Undue toxicity or progression. ]
Not Provided
Not Provided
 
BIBW 2992 (Afatinib) With or Without Daily Temozolomide in the Treatment of Patients With Recurrent Malignant Glioma
Phase I/II Trial of BIBW 2992 (Afatinib) in Treating Patients With Recurrent Glioblastoma Multiforme

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.

Not Provided
Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Glioma
  • Drug: BIBW 2992
    BIBW 2992 once daily
  • Drug: TMZ
    TMZ 21/28
  • Drug: BIBW 2992 plus TMZ
    BIBW 2992 once daily plus TMZ 21/28 days
  • Experimental: BIBW 2992
    BIBW 2992 once daily
    Intervention: Drug: BIBW 2992
  • Active Comparator: TMZ
    TMZ 21/28 days
    Intervention: Drug: TMZ
  • Experimental: BIBW 2992 plus TMZ
    BIBW 2992 once daily plus TMZ 21/28 days
    Intervention: Drug: BIBW 2992 plus TMZ
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
151
May 25, 2016
May 12, 2011   (Final data collection date for primary outcome measure)

Inclusion criteria:

Phase I Part:

  1. Histologically-confirmed WHO Grade III or IV malignant glioma that is recurrent after prior chemoradiotherapy. Patients with prior low-grade glioma are eligible if histologic assessment demonstrates transformation to WHO Grade III or IV malignant glioma.
  2. Age at least 18 years at entry
  3. KPS at least 60%
  4. Patients must have recovered from previous surgery and chemotherapy.
  5. Written informed consent that is consistent with local law and ICH-GCP guidelines.

Phase II Part:

  1. Histologically-confirmed WHO Grade IV malignant glioma at first episode of recurrence after prior combined chemoradiotherapy. Patients with prior low-grade glioma are eligible if histologic assessment demonstrates transformation to WHO Grade IV malignant glioma and if prior treatment included temozolomide chemotherapy and radiotherapy.
  2. Bi-dimensionally measurable disease with a minimum measurement of 1 cm (10 mm) in one diameter on Gd MRI performed within 14 days prior to first treatment (Day 1).
  3. Age at least 18 years at entry
  4. KPS at least 70%
  5. Patients must have recovered from previous surgery and chemotherapy.
  6. Written informed consent that is consistent with local law and ICH-GCP guidelines.
  7. Patients receiving corticosteroids have to receive a stable or decreasing dose for at least 14 days before start of study treatment.

Exclusion criteria:

Phase I and Phase II Parts:

  1. Less than 12 weeks between radiotherapy and start of study treatment, unless new enhancing lesion outside of radiation field or radiologically progressive on two consecutive MRI scans at least four weeks apart or biopsy-proven recurrence.
  2. Less than two weeks from surgical resection (one week from prior stereotactic biopsy) or major surgical procedure.
  3. Less than two weeks after previous chemotherapy (6 weeks from nitrosureas).
  4. Treatment with other investigational drugs; participation in another clinical study within the past 2 weeks before start of therapy or concomitantly with this study.
  5. Progressive disease or toxicity =CTCAEv3 Grade 3 to protracted temozolomide dosing (defined as temozolomide administered more than 5 days/28 day cycle).
  6. Active infectious disease requiring intravenous therapy.
  7. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
  8. Gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhea.
  9. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol.
  10. Patient is <3 years free of another primary malignancy except: if the other primary malignancy is either not currently clinically significant or does not require active intervention (such as a basal cell skin cancer or a cervical carcinoma in situ). Existence of any other malignant disease is not allowed.
  11. Cardiac left ventricular function with resting ejection fraction <50%.
  12. Absolute neutrophil count (ANC) less than 1500/mm3.
  13. Platelet count less than 100,000/mm3.
  14. Bilirubin greater than 1.5 x upper limit of institutional norm.
  15. Aspartate amino transferase (AST) greater than 3 x upper limit of institutional norm.
  16. Serum creatinine greater than 1.5 x upper limit of institutional norm.
  17. Patients who are sexually active and unwilling to use a medically acceptable method of contraception.
  18. Pregnancy or breast-feeding.
  19. Patients unable to comply with the protocol.
  20. Known pre-existing interstitial lung disease (ILD).

Phase I part only:

1. Less than four weeks from prior treatment with bevacizumab.

Phase II Part only:

  1. Prior EGFR-directed therapy.
  2. Prior bevacizumab therapy.
  3. Patients presenting with second or higher number of episodes of recurrence.
  4. Requirement of treatment with any of the prohibited concomitant medications listed in Section 4.2.2 (Restrictions regarding concomitant treatment).
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Canada,   United States
 
 
NCT00727506
1200.36
Not Provided
Not Provided
Not Provided
Boehringer Ingelheim
Boehringer Ingelheim
Not Provided
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
Boehringer Ingelheim
July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP