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

Boehringer Ingelheim151 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

151

Conditions

Glioma

Interventions

BIBW 2992DRUG

BIBW 2992 once daily

TMZDRUG

TMZ 21/28

BIBW 2992 plus TMZDRUG

BIBW 2992 once daily plus TMZ 21/28 days

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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).

Locations (28)

Outcomes

Primary Outcomes

Number of Participants With DLT- Phase I

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

Progression-free Survival (PFS-6) at Six Months - Phase II

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

Secondary Outcomes

Objective Tumor Response in Phase I

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.

Objective Tumor Response in Phase II

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

Progression-free Survival (PFS)- Phase II Part

Progression-free survival was defined as the duration between randomization and the date of the first of the two following events: progression or death.

Data from ClinicalTrials.gov

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1200.36.0016 Boehringer Ingelheim Investigational Site

Birmingham, Alabama, United States

1200.36.0012 Boehringer Ingelheim Investigational Site

Phoenix, Arizona, United States

1200.36.0005 Boehringer Ingelheim Investigational Site

Duarte, California, United States

1200.36.0014 Boehringer Ingelheim Investigational Site

Los Angeles, California, United States

1200.36.0019 Boehringer Ingelheim Investigational Site

Orlando, Florida, United States

1200.36.0023 Boehringer Ingelheim Investigational Site

Atlanta, Georgia, United States

1200.36.0008 Boehringer Ingelheim Investigational Site

Louisville, Kentucky, United States

1200.36.0002 Boehringer Ingelheim Investigational Site

Boston, Massachusetts, United States

1200.36.0003 Boehringer Ingelheim Investigational Site

Detroit, Michigan, United States

1200.36.0009 Boehringer Ingelheim Investigational Site

New York, New York, United States

...and 18 more locations

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.

AUCτ,ss for Afatinib

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).

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

Cmax,ss for Afatinib

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

Tmax,ss for Afatinib

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

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

AUC (0-8) for Temozolomide

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

Cmax for Temozolomide

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 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

terminal half-life (t1/2) of temozolomide in presence and absence of afatinib

Phase II - Trough Plasma Concentration of Afatinib

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

Number of Participants With EGFRvIII Assessed by IHC Test.

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.