Neoplasms
Conditions
Brief summary
A phase II trial to assess the impact of afatinib (BIBW 2992) on the heart (QTcF) and the effectiveness of afatinib (BIBW 2992) in treating certain cancers. Cancers studied will include glioblastoma and cancers which have spread to the brain (metastases).
Interventions
DRUGBIBW 2992
patients to receive continuous oral daily dosing of BIBW 2992
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female patients aged at least 18 years old. 2. Histologically or cytologically confirmed diagnosis of a solid malignant tumour, known to express EGFR/HER2 that is either refractory to standard therapies, or for which no standard treatment is available (including patients with brain metastases). 3. At least one tumor lesion that can accurately be measured by computed tomography (CT) or magnetic resonance imaging (MRI) in at least one dimension with longest diameter to be recorded as greater than or equal to 20 mm using conventional techniques or greater than or equal to 10 mm with spiral CT scan. 4. Life expectancy of at least 3 months. 5. Written informed consent that is consistent with ICH-GCP guidelines. 6. Eastern Cooperative Oncology Group (ECOG) performance score 0,1 or 2. 7. Patients must have recovered from any previous surgery. 8. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) for the duration of trial participation. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days of trial enrolment. Breast feeding mothers will be excluded since these agents may be toxic to infants. For patients with Glioma and brain metastases the following additional inclusion criteria should apply: 1. Histologically-confirmed WHO Grade IV malignant glioma at first episode of recurrence after prior combined chemo-radiotherapy. Patients with prior low-grade glioma are eligible if histological assessment demonstrates transformation to WHO Grade IV malignant glioma. 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).
Exclusion criteria
Major
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response (OR) | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | OR is defined as complete response and partial response (PR) and was assessed according to the Macdonald criteria for glioblastomas and brain metastases and according to Response Evaluation Criteria in Solid Tumours version 1.0 (RECIST) for solid tumours (excluding glioblastomas). |
| Average Time-matched QT Corrected by the Fridericia Formula (QTcF) Change From Baseline to Day 14 | The day before the first drug dose (baseline) and the day 14. Electrocardiograms (ECG) were performed at time point 0 and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 10 h, 24 h thereafter. | Average time-matched QT corrected by the Fridericia formula (QTcF) change from baseline to day 14 over 1 to 24 hours following administration of afatinib. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | Overall survival (OS) is defined as time from start of treatment to death. |
| Disease Control | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | Disease control was defined as CR, PR or stable disease (SD) and was assessed according to the Macdonald criteria for glioblastomas and brain metastases and according to RECIST for solid tumours (excluding glioblastomas). |
| Duration of Disease Control (DC) | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | Duration of Disease control (DC). DC was defined as CR, PR or stable disease (SD) and was assessed according to the Macdonald criteria for glioblastomas and brain metastases and according to RECIST for solid tumours (excluding glioblastomas). |
| Patients With Notable Findings in QTcF on Day 14 | Day 14 | Notable findings are defined as a QTcF\>500 ms or an increase in QTcF of \>60ms. |
| Patients With Clinically Relevant Findings in ECG on Day 14 | Day 14 | Patients with clinically relevant findings in Electrocardiogram data (ECG) on day 14. |
| Time-matched QTcF Changes From Baseline to Day 14 at Each Time-point | Baseline and day 14 (at 1, 2, 3, 4, 5, 6, 7, 10, 24 hours post-dose ) | Individual QTcF measurements at each time-point. Response was defined as the change from baseline. Analysis adjusted for baseline using a mixed model. |
| Average Time-matched QT Change From Baseline to Day 14 | The day before the first drug dose (baseline) and the day 14. Electrocardiograms (ECG) were performed at time point 0 and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 10 h, 24 h thereafter. | Average time-matched QT change from baseline to day 14 over 1 to 24 hours following administration of afatinib. |
| Average Time-matched Heart Rate Change From Baseline to Day 14. | The day before the first drug dose (baseline) and the day 14. | Average time-matched heart rate change from baseline to day 14. |
| Highest CTC Grade for Adverse Events | First administration of trial medication until 28 days after last administration of trial medication | Highest Common Terminology Criteria (CTC) grade for adverse events |
| Patients With Notable Findings in QT on Day 14 | Day 14 | Number of Patients with notable findings in QT on day 14. Notable findings are defined as a QT\>500 ms. |
| Maximum Concentration (Cmax) | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 | Cmax represents the maximum measured concentration of afatinib in plasma on Day 1. |
| Time From Dosing to the Maximum Concentration (Tmax) | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 | tmax represents the time from dosing to the maximum concentration of afatinib in plasma on Day 1. |
| Area Under Curve of Afatinib Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss) | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14 | AUCtau,ss represents the area under the concentration curve of afatinib in plasma over a uniform dosing interval tau (24h) at steady state (Day14). |
| Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14 | Cmax,ss represents the maximum measured concentration of afatinib in plasma at steady state (Day 14). |
| Time From Dosing to the Maximum Concentration of Afatinib in Plasma at Steady State (Tmax,ss) | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14 | tmax,ss represents the time from dosing to the maximum concentration of afatinib in plasma at steady state (Day 14). |
| Accumulation Ratio of AUC Values (R_A,AUC) | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 and 14 | R\_A,AUC represents the accumulation ratio of AUC values after multiple dose administration over a uniform dosing interval t between days 1 and 14 |
| Accumulation Ratio of AUC Values (R_A,Cmax) | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 and 14 | R\_A,Cmax represents the accumulation ratio of Cmax values after multiple dose administration over a uniform dosing interval t between days 1 and 14 |
| Percentage Peak Trough Fluctuation (PTF) | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14 | PTF represents the percentage peak trough fluctuation. PTF is defined as difference between maximum and minimum concentration at steady state divided by the average concentration multiplied with 100 to report as percentage. |
| Area Under Curve 0-24 Hours (AUC0-24) on Day 1 | 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 | AUC0-24 represents the area under the concentration curve of afatinib in plasma from 0 to 24 hours on Day 1. |
| Progression-free Survival (PFS) | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | PFS was defined as the time from the first treatment to the occurrence of tumour progression or death, whichever came first. It was assessed according to the Macdonald criteria for glioblastomas and brain metastases and according to RECIST for solid tumours (excluding glioblastomas) as well as by the investigators assessment. Median time results from unstratified Kaplan-Meier estimates. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Patients Patients with tumours known to historically (over)express epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor (HER) 2 with and without brain metastases, and patients with recurrent glioblastoma receiving an oral dose of Afatinib 50 mg once daily (qd) | 60 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Other | 3 |
| Overall Study | Other Adverse Event | 14 |
| Overall Study | Progressive disease | 41 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Continuous | 58.7 years STANDARD_DEVIATION 11.9 |
| Sex: Female, Male Female | 30 Participants |
| Sex: Female, Male Male | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 58 / 60 |
| serious Total, serious adverse events | 34 / 60 |
Outcome results
Primary
Average Time-matched QT Corrected by the Fridericia Formula (QTcF) Change From Baseline to Day 14
Average time-matched QT corrected by the Fridericia formula (QTcF) change from baseline to day 14 over 1 to 24 hours following administration of afatinib.
Time frame: The day before the first drug dose (baseline) and the day 14. Electrocardiograms (ECG) were performed at time point 0 and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 10 h, 24 h thereafter.
Population: All patients in TS who had at least 1 time-matched pair of QT measurements available from baseline and from Day 14 of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Patients | Average Time-matched QT Corrected by the Fridericia Formula (QTcF) Change From Baseline to Day 14 | -0.3 ms | Standard Error 1.5 |
Primary
Objective Response (OR)
OR is defined as complete response and partial response (PR) and was assessed according to the Macdonald criteria for glioblastomas and brain metastases and according to Response Evaluation Criteria in Solid Tumours version 1.0 (RECIST) for solid tumours (excluding glioblastomas).
Time frame: Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: Treated Set (TS). TS consisted of all patients who received at least one dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | Objective Response (OR) | 1 Participants with OR |
Secondary
Accumulation Ratio of AUC Values (R_A,AUC)
R\_A,AUC represents the accumulation ratio of AUC values after multiple dose administration over a uniform dosing interval t between days 1 and 14
Time frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 and 14
Population: Subset of TS, restricted to patients with adequate protocol compliance, i.e. patients without important protocol violations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| All Patients | Accumulation Ratio of AUC Values (R_A,AUC) | 2.67 ratio | Geometric Coefficient of Variation 53.4 |
Secondary
Accumulation Ratio of AUC Values (R_A,Cmax)
R\_A,Cmax represents the accumulation ratio of Cmax values after multiple dose administration over a uniform dosing interval t between days 1 and 14
Time frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1 and 14
Population: Subset of TS, restricted to patients with adequate protocol compliance, i.e. patients without important protocol violations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| All Patients | Accumulation Ratio of AUC Values (R_A,Cmax) | 2.05 ratio | Geometric Coefficient of Variation 58.5 |
Secondary
Area Under Curve 0-24 Hours (AUC0-24) on Day 1
AUC0-24 represents the area under the concentration curve of afatinib in plasma from 0 to 24 hours on Day 1.
Time frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1
Population: TS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| All Patients | Area Under Curve 0-24 Hours (AUC0-24) on Day 1 | 482 ng*h/mL | Geometric Coefficient of Variation 55.6 |
Secondary
Area Under Curve of Afatinib Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss)
AUCtau,ss represents the area under the concentration curve of afatinib in plasma over a uniform dosing interval tau (24h) at steady state (Day14).
Time frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14
Population: TS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| All Patients | Area Under Curve of Afatinib Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss) | 1250 ng*h/mL | Geometric Coefficient of Variation 53.3 |
Secondary
Average Time-matched Heart Rate Change From Baseline to Day 14.
Average time-matched heart rate change from baseline to day 14.
Time frame: The day before the first drug dose (baseline) and the day 14.
Population: All patients in TS who had at least 1 time-matched pair of QT measurements available from baseline and from Day 14 of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Patients | Average Time-matched Heart Rate Change From Baseline to Day 14. | 0.1 bpm | Standard Error 1.2 |
Secondary
Average Time-matched QT Change From Baseline to Day 14
Average time-matched QT change from baseline to day 14 over 1 to 24 hours following administration of afatinib.
Time frame: The day before the first drug dose (baseline) and the day 14. Electrocardiograms (ECG) were performed at time point 0 and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 10 h, 24 h thereafter.
Population: All patients in TS who had at least 1 time-matched pair of QT measurements available from baseline and from Day 14 of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Patients | Average Time-matched QT Change From Baseline to Day 14 | -0.4 ms | Standard Error 2.6 |
Secondary
Disease Control
Disease control was defined as CR, PR or stable disease (SD) and was assessed according to the Macdonald criteria for glioblastomas and brain metastases and according to RECIST for solid tumours (excluding glioblastomas).
Time frame: Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: TS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | Disease Control | 32 Participants |
Secondary
Duration of Disease Control (DC)
Duration of Disease control (DC). DC was defined as CR, PR or stable disease (SD) and was assessed according to the Macdonald criteria for glioblastomas and brain metastases and according to RECIST for solid tumours (excluding glioblastomas).
Time frame: Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: TS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Patients | Duration of Disease Control (DC) | 15.3 weeks |
Secondary
Highest CTC Grade for Adverse Events
Highest Common Terminology Criteria (CTC) grade for adverse events
Time frame: First administration of trial medication until 28 days after last administration of trial medication
Population: All patients from TS with adverse events
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Patients | Highest CTC Grade for Adverse Events | Grade 1 | 1 Participants |
| All Patients | Highest CTC Grade for Adverse Events | Grade 2 | 19 Participants |
| All Patients | Highest CTC Grade for Adverse Events | Grade 4 | 4 Participants |
| All Patients | Highest CTC Grade for Adverse Events | Grade 5 | 9 Participants |
| All Patients | Highest CTC Grade for Adverse Events | Grade 3 | 27 Participants |
Secondary
Maximum Concentration (Cmax)
Cmax represents the maximum measured concentration of afatinib in plasma on Day 1.
Time frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1
Population: TS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| All Patients | Maximum Concentration (Cmax) | 44.7 ng/mL | Geometric Coefficient of Variation 58.9 |
Secondary
Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss)
Cmax,ss represents the maximum measured concentration of afatinib in plasma at steady state (Day 14).
Time frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14
Population: TS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| All Patients | Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 86.6 ng/mL | Geometric Coefficient of Variation 55.2 |
Secondary
Overall Survival (OS)
Overall survival (OS) is defined as time from start of treatment to death.
Time frame: Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: TS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Patients | Overall Survival (OS) | 39.6 weeks |
Secondary
Patients With Clinically Relevant Findings in ECG on Day 14
Patients with clinically relevant findings in Electrocardiogram data (ECG) on day 14.
Time frame: Day 14
Population: All patients from TS with data for ECG on day 14
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | Patients With Clinically Relevant Findings in ECG on Day 14 | 1 Participants |
Secondary
Patients With Notable Findings in QTcF on Day 14
Notable findings are defined as a QTcF\>500 ms or an increase in QTcF of \>60ms.
Time frame: Day 14
Population: All patients from TS with data for QTcF on day 14
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | Patients With Notable Findings in QTcF on Day 14 | 1 Participants |
Secondary
Patients With Notable Findings in QT on Day 14
Number of Patients with notable findings in QT on day 14. Notable findings are defined as a QT\>500 ms.
Time frame: Day 14
Population: All patients from TS with data for QTcF on day 14
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | Patients With Notable Findings in QT on Day 14 | 0 Participants |
Secondary
Percentage Peak Trough Fluctuation (PTF)
PTF represents the percentage peak trough fluctuation. PTF is defined as difference between maximum and minimum concentration at steady state divided by the average concentration multiplied with 100 to report as percentage.
Time frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14
Population: Subset of TS, restricted to patients with adequate protocol compliance, i.e. patients without important protocol violations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| All Patients | Percentage Peak Trough Fluctuation (PTF) | 97.6 percentage of peak trough fluctuation | Geometric Coefficient of Variation 37.8 |
Secondary
Progression-free Survival (PFS)
PFS was defined as the time from the first treatment to the occurrence of tumour progression or death, whichever came first. It was assessed according to the Macdonald criteria for glioblastomas and brain metastases and according to RECIST for solid tumours (excluding glioblastomas) as well as by the investigators assessment. Median time results from unstratified Kaplan-Meier estimates.
Time frame: Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: All patients from TS who progressed or died.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Patients | Progression-free Survival (PFS) | 10.6 weeks |
Secondary
Time From Dosing to the Maximum Concentration of Afatinib in Plasma at Steady State (Tmax,ss)
tmax,ss represents the time from dosing to the maximum concentration of afatinib in plasma at steady state (Day 14).
Time frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 14
Population: Subset of TS, restricted to patients with adequate protocol compliance, i.e. patients without important protocol violations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Patients | Time From Dosing to the Maximum Concentration of Afatinib in Plasma at Steady State (Tmax,ss) | 3.07 hours |
Secondary
Time From Dosing to the Maximum Concentration (Tmax)
tmax represents the time from dosing to the maximum concentration of afatinib in plasma on Day 1.
Time frame: 0.05 hours (h) before dosing and 1h, 2h, 3h, 4h, 5h, 6h,7h, 10h and 24h after dosing on Day 1
Population: TS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Patients | Time From Dosing to the Maximum Concentration (Tmax) | 3.06 hours |
Secondary
Time-matched QTcF Changes From Baseline to Day 14 at Each Time-point
Individual QTcF measurements at each time-point. Response was defined as the change from baseline. Analysis adjusted for baseline using a mixed model.
Time frame: Baseline and day 14 (at 1, 2, 3, 4, 5, 6, 7, 10, 24 hours post-dose )
Population: All patients in TS who had at least 1 time-matched pair of QT measurements available from either Day1 or Day 14 of treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | Time-matched QTcF Changes From Baseline to Day 14 at Each Time-point | Time-point 1:00 h (N=48) | 1.6 ms | Standard Error 2.2 |
| All Patients | Time-matched QTcF Changes From Baseline to Day 14 at Each Time-point | Time-point 2:00 h (N=48) | 1.2 ms | Standard Error 2.2 |
| All Patients | Time-matched QTcF Changes From Baseline to Day 14 at Each Time-point | Time-point 3:00 h (N=49) | -2.1 ms | Standard Error 2.2 |
| All Patients | Time-matched QTcF Changes From Baseline to Day 14 at Each Time-point | Time-point 4:00 h (N=49) | -2.5 ms | Standard Error 2.2 |
| All Patients | Time-matched QTcF Changes From Baseline to Day 14 at Each Time-point | Time-point 5:00 h (N=49) | -2.3 ms | Standard Error 2.2 |
| All Patients | Time-matched QTcF Changes From Baseline to Day 14 at Each Time-point | Time-point 6:00 h (N=49) | -0.4 ms | Standard Error 2.2 |
| All Patients | Time-matched QTcF Changes From Baseline to Day 14 at Each Time-point | Time-point 7:00 h (N=48) | 0.2 ms | Standard Error 2.2 |
| All Patients | Time-matched QTcF Changes From Baseline to Day 14 at Each Time-point | Time-point 10:00 h (N=49) | 0.2 ms | Standard Error 2.2 |
| All Patients | Time-matched QTcF Changes From Baseline to Day 14 at Each Time-point | Time-point 24:00 h (N=48) | 0.6 ms | Standard Error 2.2 |