Clinical trial NCT00727506: BIBW 2992 (Afatinib) With or Without Daily Temozolomide in the Treatment of Patients With Recurrent Malignant Glioma
Official title: Phase I/II Trial of BIBW 2992 (Afatinib) in Treating Patients With Recurrent Glioblastoma Multiforme
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Glioma
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2008-08-04
Enrollment: 151
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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).

Primary outcomes:
measure: Number of Participants With DLT- Phase I
timeFrame: From randomization till data cut-off (10 Jun 2009), with a mean treatment duration of 51 days
measure: Progression-free Survival (PFS-6) at Six Months - Phase II
timeFrame: At six months after randomization
Secondary outcomes:
measure: Objective Tumor Response in Phase I
timeFrame: 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.
measure: Objective Tumor Response in Phase II
timeFrame: 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
measure: Progression-free Survival (PFS)- Phase II Part
timeFrame: from date of randomization until the date of first documented progression or death by any cause, whichever came first, assessed up to 9 Months.
measure: AUCτ,ss for Afatinib
timeFrame: 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
measure: Cmax,ss for Afatinib
timeFrame: 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
measure: Tmax,ss for Afatinib
timeFrame: 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
measure: AUC (0-8) for Temozolomide
timeFrame: 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
measure: Cmax for Temozolomide
timeFrame: 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
measure: Tmax for Temozolomide
timeFrame: 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
measure: t1/2 for Temozolomide
timeFrame: 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
measure: Phase II - Trough Plasma Concentration of Afatinib
timeFrame: Before (-0.05 h) the drug administration of afatinib on Day 15 of Cycle 2 & 3
measure: Number of Participants With EGFRvIII Assessed by IHC Test.
timeFrame: Baseline (during screening)
measure: Number of Participants With MGMT Marker Assessed by IHC Test.
timeFrame: Baseline (during screening)
measure: Number of Participants With EGFR Marker Assessed by IHC Test.
timeFrame: Baseline (during screening)
measure: Number of Participants With PTEN Marker Assessed by IHC Test.
timeFrame: Baseline (during screening)
measure: Number of Participants With PAKT Marker Assessed by IHC Test.
timeFrame: Baseline (during screening)
measure: Number of Participants With EGFR Assessed by FISH
timeFrame: Baseline (during screening)
measure: Number of Participants With PTEN Assessed by FISH
timeFrame: Baseline (during screening)
measure: Number of Participants With Chromosomes (CEP7) Assessed by FISH
timeFrame: Baseline (during screening)
measure: Number of Participants With Chromosomes (CEP10) Assessed by FISH
timeFrame: Baseline (during screening)
measure: 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
timeFrame: From first administration of treatment until 28 days after last drug administration, up to 491 days.
measure: Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I
timeFrame: From first administration of treatment until 28 days after last drug administration, up to 491 days.
measure: Number of Participants With Adverse Events, Graded According CTCAE - Phase I
timeFrame: From first administration of treatment until 28 days after last drug administration, up to 491 days.
measure: Causes of Death - Phase I
timeFrame: From first administration of treatment until 28 days after last drug administration, up to 491 days.
measure: 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
timeFrame: From first administration of treatment until 28 days after last drug administration, up to 518 days.
measure: Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II
timeFrame: From first administration of treatment until 28 days after last drug administration, up to 518 days.
measure: Number of Participants With Adverse Events, Graded According CTCAE - Phase II
timeFrame: From first administration of treatment until 28 days after last drug administration, up to 518 days.
measure: Causes of Death - Phase II
timeFrame: From first administration of treatment until 28 days after last drug administration, up to 518 days.
measure: Number of Participants With Clinically Relevant Abnormalities for Decreased Cardiac Left Ventricular Function - Phase II
timeFrame: From first administration of treatment until 28 days after last drug administration, up to 518 days.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: 1200.36.0016 Boehringer Ingelheim Investigational Site
state: Alabama
city: Phoenix
country: United States
facility: 1200.36.0012 Boehringer Ingelheim Investigational Site
state: Arizona
city: Duarte
country: United States
facility: 1200.36.0005 Boehringer Ingelheim Investigational Site
state: California
city: Los Angeles
country: United States
facility: 1200.36.0014 Boehringer Ingelheim Investigational Site
state: California
city: Orlando
country: United States
facility: 1200.36.0019 Boehringer Ingelheim Investigational Site
state: Florida
city: Atlanta
country: United States
facility: 1200.36.0023 Boehringer Ingelheim Investigational Site
state: Georgia
city: Louisville
country: United States
facility: 1200.36.0008 Boehringer Ingelheim Investigational Site
state: Kentucky
city: Boston
country: United States
facility: 1200.36.0002 Boehringer Ingelheim Investigational Site
state: Massachusetts
city: Detroit
country: United States
facility: 1200.36.0003 Boehringer Ingelheim Investigational Site
state: Michigan
city: New York
country: United States
facility: 1200.36.0009 Boehringer Ingelheim Investigational Site
state: New York
city: Durham
country: United States
facility: 1200.36.0001 Boehringer Ingelheim Investigational Site
state: North Carolina
city: Charleston
country: United States
facility: 1200.36.0007 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Memphis
country: United States
facility: 1200.36.0020 Boehringer Ingelheim Investigational Site
state: Tennessee
city: Dallas
country: United States
facility: 1200.36.0017 Boehringer Ingelheim Investigational Site
state: Texas
city: Houston
country: United States
facility: 1200.36.0010 Boehringer Ingelheim Investigational Site
state: Texas
city: Charlottesville
country: United States
facility: 1200.36.0011 Boehringer Ingelheim Investigational Site
state: Virginia
city: Seattle
country: United States
facility: 1200.36.0022 Boehringer Ingelheim Investigational Site
state: Washington
city: Calgary
country: Canada
facility: 1200.36.1005 Boehringer Ingelheim Investigational Site
state: Alberta
city: Winnipeg
country: Canada
facility: 1200.36.1010 Boehringer Ingelheim Investigational Site
state: Manitoba
city: Moncton
country: Canada
facility: 1200.36.1009 Boehringer Ingelheim Investigational Site
state: New Brunswick
city: Halifax
country: Canada
facility: 1200.36.1011 Boehringer Ingelheim Investigational Site
state: Nova Scotia
city: Hamilton
country: Canada
facility: 1200.36.1008 Boehringer Ingelheim Investigational Site
state: Ontario
city: Kingston
country: Canada
facility: 1200.36.1001 Boehringer Ingelheim Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: 1200.36.1003 Boehringer Ingelheim Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: 1200.36.1004 Boehringer Ingelheim Investigational Site
state: Ontario
city: Fleurimont
country: Canada
facility: 1200.36.1007 Boehringer Ingelheim Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: 1200.36.1002 Boehringer Ingelheim Investigational Site
state: Quebec
city: Quebec
country: Canada
facility: 1200.36.1006 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References: