Breast Neoplasms
Conditions
Brief summary
The purpose of this trial is to evaluate the efficacy, safety and pharmacokinetics of BIBW 2992, a dual, irreversible EGFR- and HER2-inhibitor, in two cohorts of patients with HER2-negative breast cancer after failure of no more than three regimen of prior chemotherapy.
Interventions
DRUGBIBW 2992
high dose once daily
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion Criteria: * Female patients age 18 years or older * Histologically proven breast cancer after failure or relapse of no more than three lines of chemotherapy including adjuvant, irrespective of prior hormone therapy metastatic disease (stage IV); * HER2-negative patients (HER2 1+ or negative, or HER2 2+ and FISH negative) * At least one measurable tumour lesion (RECIST); * Availability of tumour samples * Written informed consent that is consistent with ICH-GCP guidelines and local law * Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0 - 2.
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 (CR) and partial response (PR) and was assessed according to the Response Evaluation Criteria in Solid Tumours version 1.0 (RECIST). OR was primary endpoint only for Cohort B. |
| Clinical Benefit (CB) | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | CB was defined as CR, PR or stable disease (SD) for a minimum of 4 months (modified CB) and was assessed according to RECIST 1.0 criteria. CB was primary endpoint only for Cohort A. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of OR | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | Duration of OR was measured from the time the criteria for CR or PR (whichever was documented first) were first met until the first date that progressive disease or death was objectively documented. |
| 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 RECIST 1.0 criteria as well as by the investigators assessment. Median time results from unstratified Kaplan-Meier estimates. |
| Overall Survival (OS) | From randomisation to end of follow-up. | OS is defined as time from randomisation to death. |
| Clinical Benefit (CB) | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | CB was defined as CR, PR or stable disease (SD) for a minimum of 4 months (modified CB) and was assessed according to RECIST 1.0 criteria. CB was secondary endpoint only for Cohort B as it was primary endpoint for Cohort A. |
| Best Change From Baseline in ECOG Performance Status | baseline till end of treatment | Best change from baseline in ECOG (Eastern Cooperative Oncology Group) performance status. ECOG is measured as score between 0 (fully active) and 5 (dead). |
| Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 29 (Cpre,ss,29) | day 29 | Cpre,ss,29 represents the pre-dose concentration of afatinib in plasma at steady state on day 29. |
| Significant Change in Cardiac Left Ventricular Ejection Fraction (LVEF) | Baseline and last assessment | LVEF as measured by echocardiography or Multiple Gated Acquisition (MUGA) scan. MUGA scan is an useful noninvasive tool for assessing the function of the heart. Significant change in LVEF values was defined as \>=20 percent decrease from baseline or to below lower limit of normal, which was defined as 50 percent. |
| Time to OR | Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | The time to OR was the duration from the first treatment to the time when the measurement criteria for CR and/or PR were met according to RECIST 1.0 criteria. |
Countries
Belgium, Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A Patients with human epidermal growth factor 2- (HER2-) negative, oestrogen receptor- (ER-) negative, progesterone- (PgR-) negative tumours (triple negative tumours) receiving oral dose of Afatinib 50 mg once daily (qd) | 29 |
| Cohort B Patients with HER2-negative, ER-positive and/or PgR-positive tumours receiving oral dose of Afatinib 50 mg qd | 21 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Dose reduction toxicity AE | 8 | 7 |
| Overall Study | Other Adverse Event | 2 | 2 |
| Overall Study | Progressive Disease | 19 | 12 |
Baseline characteristics
| Characteristic | Cohort A | Cohort B | Total |
|---|---|---|---|
| Age, Continuous | 54.3 years STANDARD_DEVIATION 11.5 | 61.0 years STANDARD_DEVIATION 14.3 | 57.1 years STANDARD_DEVIATION 13 |
| Sex: Female, Male Female | 29 Participants | 21 Participants | 50 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 28 / 29 | 20 / 21 |
| serious Total, serious adverse events | 13 / 29 | 7 / 21 |
Outcome results
Primary
Clinical Benefit (CB)
CB was defined as CR, PR or stable disease (SD) for a minimum of 4 months (modified CB) and was assessed according to RECIST 1.0 criteria. CB was primary endpoint only for Cohort A.
Time frame: Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: TS. No data for Cohort B as CB was primary endpoint only for Cohort A.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort B | Clinical Benefit (CB) | With CB | 3 Participants |
| Cohort B | Clinical Benefit (CB) | Without CB | 24 Participants |
| Cohort B | Clinical Benefit (CB) | missing | 2 Participants |
95% CI: [0.02, 0.27]Maxium Likelihood
Primary
Objective Response (OR)
OR is defined as complete response (CR) and partial response (PR) and was assessed according to the Response Evaluation Criteria in Solid Tumours version 1.0 (RECIST). OR was primary endpoint only for Cohort B.
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. No data for Cohort A as OR was primary endpoint only for Cohort B.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort B | Objective Response (OR) | 0 Participants with OR |
Secondary
Best Change From Baseline in ECOG Performance Status
Best change from baseline in ECOG (Eastern Cooperative Oncology Group) performance status. ECOG is measured as score between 0 (fully active) and 5 (dead).
Time frame: baseline till end of treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort B | Best Change From Baseline in ECOG Performance Status | improved | 1 participants |
| Cohort B | Best Change From Baseline in ECOG Performance Status | deteriorated | 15 participants |
| Cohort B | Best Change From Baseline in ECOG Performance Status | improved | 0 participants |
| Cohort B | Best Change From Baseline in ECOG Performance Status | deteriorated | 13 participants |
Secondary
Clinical Benefit (CB)
CB was defined as CR, PR or stable disease (SD) for a minimum of 4 months (modified CB) and was assessed according to RECIST 1.0 criteria. CB was secondary endpoint only for Cohort B as it was primary endpoint for Cohort A.
Time frame: Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: TS. No data for Cohort A as CB was secondary endpoint only for Cohort B.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort B | Clinical Benefit (CB) | With CB | 1 Participants with CB |
| Cohort B | Clinical Benefit (CB) | Without CB | 17 Participants with CB |
| Cohort B | Clinical Benefit (CB) | missing | 3 Participants with CB |
95% CI: [0.001, 0.238]
Secondary
Duration of OR
Duration of OR was measured from the time the criteria for CR or PR (whichever was documented first) were first met until the first date that progressive disease or death was objectively documented.
Time frame: Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: TS. Median duration of OR was not calcuable as there was no OR observed.
Secondary
Overall Survival (OS)
OS is defined as time from randomisation to death.
Time frame: From randomisation to end of follow-up.
Population: TS. As only 9 patient (31 percent) of Cohort A had died the median OS time was not estimable for Cohort A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort B | Overall Survival (OS) | NA days |
| Cohort B | Overall Survival (OS) | 448 days |
Secondary
Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 29 (Cpre,ss,29)
Cpre,ss,29 represents the pre-dose concentration of afatinib in plasma at steady state on day 29.
Time frame: day 29
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort B | Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 29 (Cpre,ss,29) | 33.1 ng/mL | Geometric Coefficient of Variation 110 |
| Cohort B | Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 29 (Cpre,ss,29) | 22.9 ng/mL | Geometric Coefficient of Variation 64.7 |
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 RECIST 1.0 criteria 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: TS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort B | Progression-free Survival (PFS) | 52 days |
| Cohort B | Progression-free Survival (PFS) | 54 days |
Secondary
Significant Change in Cardiac Left Ventricular Ejection Fraction (LVEF)
LVEF as measured by echocardiography or Multiple Gated Acquisition (MUGA) scan. MUGA scan is an useful noninvasive tool for assessing the function of the heart. Significant change in LVEF values was defined as \>=20 percent decrease from baseline or to below lower limit of normal, which was defined as 50 percent.
Time frame: Baseline and last assessment
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort B | Significant Change in Cardiac Left Ventricular Ejection Fraction (LVEF) | 1 Participants |
| Cohort B | Significant Change in Cardiac Left Ventricular Ejection Fraction (LVEF) | 2 Participants |
Secondary
Time to OR
The time to OR was the duration from the first treatment to the time when the measurement criteria for CR and/or PR were met according to RECIST 1.0 criteria.
Time frame: Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: TS. Median time to OR was not calcuable as there was no OR observed.