Breast Neoplasms
Conditions
Brief summary
Progression-free rate after 16 weeks of BIBW 2992 administration in association with letrozole
Interventions
DRUGBIBW 2992
BIBW 2992 at high and medium dosages
DRUGLetrozole
Letrozole at standard dosage
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female patients with histologically proven breast adenocarcinoma * Presence of metastatic disease No more than 2 prior chemotherapy regimens for metastatic disease, which could include trastuzumab Patients must currently be on letrozole and developed acquired resistance as defined by disease progression on letrozole following previous response (partial response or better, stable disease superior or equal to 24 weeks) Diagnosis of disease progression inferior or equal to 6 weeks prior to trial entrydefined as: 1. Increase in the number of bone lesions on bone scan or on MRI AND/OR 2. Increased pain in an area of known bony metastasis AND superior or equal to 2 serial elevations in CA 15.3 AND/OR 3. Progression according to RECIST criteria on CT scan, MRI, or x-ray Patients must have documented menopause confirmed by estradiol level inferior to 11 pg/ml
Exclusion criteria
* Premenopausal patients * Rapidly progressive disease in major organs (i.e. lymphangitic spread in the lung and/or bulky liver metastasis) Patient with brain metastasis Significant cardiovascular diseases Previous treatment with an EGFR and/or HER-2 inhibiting drug(patients who received trastuzumab with chemotherapy but not with letrozole can be enrolled)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Progression Free Participants After 16 Weeks of Treatment | 16 weeks | Progression was defined according to 1 of the following criteria: New bone lesion(s) on bone scan or on magnetic resonance imaging; Progression or occurrence of new lesion(s) according to the Response Evaluation Criteria In Solid Tumours version 1.0 (RECIST); an increase in tumour marker CA 15.3 of more than 20 percent,compared with baseline, at 2 consecutive examinations; occurrence of disease-related skeletal events. If a patient did not fulfil any criteria and was withdrawn because of clinical deterioration amounting to PD according to the Investigator, they were considered as having PD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Benefit (CB) | 16 weeks and 24 weeks | CB was defined as CR, PR or stable disease (SD) and was assessed according to RECIST criteria regardless of treatment status. |
| Time to RECIST Tumour Reponse | Baseline till progression | 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 criteria. |
| Duration of Confirmed OR | First occurence or OR till progression or death | Duration of confirmed OR is measured from the time of first OR to the time of progression or death (or date of censoring for progression free survival). |
| Progression-free Survival (PFS) | Baseline till progression, death or data cut-off (04 Jan 2010) | PFS was defined as the time from the first treatment to the occurrence of tumour progression or death, whichever came first. Progression was assessed according to RECIST criteria. |
| Overall Survival (OS) | Baseline till progression, death or data cut-off | OS was defined as the time from first treatment to death. |
| Area Under Curve of Afatinib Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss) | 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing | AUCtau,ss represents the area under the concentration curve of afatinib in plasma over a uniform dosing interval tau at steady state. |
| Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing | Cmax,ss represents the maximum measured concentration of afatinib in plasma at steady state. |
| Number of Participants With Confirmed Objective Response (OR) | Baseline till progression | OR was defined as complete response (CR) or partial response (PR) and was assessed according to RECIST criteria regardless of treatment status. |
| Pre-dose Concentration of Afatinib in Plasma at Steady Stateon Day 85 (Cpre,ss,85) | Day 85 | Cpre,ss,85 represents the pre-dose concentration of afatinib in plasma at steady state on day 85. |
| Time From Dosing to the Maximum Concentration of Afatinib in Plasma at Steady State (Tmax,ss) | 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing | tmax,ss represents the time from dosing to the maximum concentration of afatinib in plasma at steady state |
| Area Under Curve of Letrozole Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss) | 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing | AUC0-tau,ss represents the area under the concentration curve of letrozole in plasma over a uniform dosing interval tau at steady state. |
| Maximum Concentration of Letrozole in Plasma at Steady State (Cmax,ss) | 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing | Cmax,ss represents the maximum measured concentration of letrozole in plasma at steady state. |
| Time From Dosing to the Maximum Concentration of Letrozole in Plasma at Steady State (Tmax,ss) | 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing | tmax,ss represents the time from dosing to the maximum concentration of letrozole in plasma at steady state. |
| Change From Baseline in Ca15.3 | baseline and day 29 | Change from baseline in Ca15.3 tumor marker levels |
| 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). Improvement is a decrease in ECOG score from baseline of at least 1. Deterioration is an increase in ECOG score from baseline of at least 1 |
| Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 57 (Cpre,ss,57) | Day 57 | Cpre,ss,57 represents the pre-dose concentration of afatinib in plasma at steady state on day 57. |
Countries
France
Participant flow
Pre-assignment details
According to the protocol the starting dose of Afatinib was 50mg/day. This dose was reduced according to the protocol to first 40mg/day and then to 30mg/day due to skin toxicity.
Participants by arm
| Arm | Count |
|---|---|
| Afatinib 50 mg With Letrozole Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression. | 7 |
| Afatinib 40 mg With Letrozole Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression. | 13 |
| Afatinib 30 mg With Letrozole Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression. | 8 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Other | 0 | 1 | 1 |
| Overall Study | Other Adverse Event | 3 | 6 | 2 |
| Overall Study | Progressive Disease | 4 | 6 | 5 |
Baseline characteristics
| Characteristic | Afatinib 50 mg With Letrozole | Afatinib 40 mg With Letrozole | Afatinib 30 mg With Letrozole | Total |
|---|---|---|---|---|
| Age, Continuous | 63.0 years STANDARD_DEVIATION 14.7 | 64.8 years STANDARD_DEVIATION 7.2 | 58.5 years STANDARD_DEVIATION 9 | 62.5 years STANDARD_DEVIATION 10 |
| Sex: Female, Male Female | 7 Participants | 13 Participants | 8 Participants | 28 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 7 | 13 / 13 | 8 / 8 |
| serious Total, serious adverse events | 1 / 7 | 3 / 13 | 5 / 8 |
Outcome results
Primary
Percentage of Progression Free Participants After 16 Weeks of Treatment
Progression was defined according to 1 of the following criteria: New bone lesion(s) on bone scan or on magnetic resonance imaging; Progression or occurrence of new lesion(s) according to the Response Evaluation Criteria In Solid Tumours version 1.0 (RECIST); an increase in tumour marker CA 15.3 of more than 20 percent,compared with baseline, at 2 consecutive examinations; occurrence of disease-related skeletal events. If a patient did not fulfil any criteria and was withdrawn because of clinical deterioration amounting to PD according to the Investigator, they were considered as having PD.
Time frame: 16 weeks
Population: Treated set (TS). TS consisted of all patients who were dispensed study medication and have taken at least 1 dose of Afatinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 50 mg With Letrozole | Percentage of Progression Free Participants After 16 Weeks of Treatment | 28.57 Percentage of participants |
| Afatinib 40 mg With Letrozole | Percentage of Progression Free Participants After 16 Weeks of Treatment | 0.00 Percentage of participants |
| Afatinib 30 mg With Letrozole | Percentage of Progression Free Participants After 16 Weeks of Treatment | 25.00 Percentage of participants |
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 at steady state.
Time frame: 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing
Population: Data were particularly sparse for the 50 mg starting dose group and were not summarised.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50 mg With Letrozole | Area Under Curve of Afatinib Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss) | 660 ng*h/mL | Geometric Coefficient of Variation 41.3 |
| Afatinib 40 mg With Letrozole | Area Under Curve of Afatinib Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss) | 579 ng*h/mL | Geometric Coefficient of Variation 62.8 |
Secondary
Area Under Curve of Letrozole Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss)
AUC0-tau,ss represents the area under the concentration curve of letrozole in plasma over a uniform dosing interval tau at steady state.
Time frame: 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing
Population: Analysis of all treatment arms combined, as Letrozole dose was the same in all arms.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50 mg With Letrozole | Area Under Curve of Letrozole Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss) | 2420 ng*h/mL | Geometric Coefficient of Variation 76.2 |
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). Improvement is a decrease in ECOG score from baseline of at least 1. Deterioration is an increase in ECOG score from baseline of at least 1
Time frame: baseline till end of treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50 mg With Letrozole | Best Change From Baseline in ECOG Performance Status | Improved | 4 participants |
| Afatinib 50 mg With Letrozole | Best Change From Baseline in ECOG Performance Status | Deteriorated | 6 participants |
| Afatinib 50 mg With Letrozole | Best Change From Baseline in ECOG Performance Status | Unchanged | 16 participants |
| Afatinib 50 mg With Letrozole | Best Change From Baseline in ECOG Performance Status | Not done | 2 participants |
Secondary
Change From Baseline in Ca15.3
Change from baseline in Ca15.3 tumor marker levels
Time frame: baseline and day 29
Population: Analysis of all treatment arms combined for tumor marker analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 50 mg With Letrozole | Change From Baseline in Ca15.3 | -4.35 percentage of baseline level |
Secondary
Duration of Confirmed OR
Duration of confirmed OR is measured from the time of first OR to the time of progression or death (or date of censoring for progression free survival).
Time frame: First occurence or OR till progression or death
Population: TS. Median duration of RECIST tumour response was not calculable as there was no OR observed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 50 mg With Letrozole | Duration of Confirmed OR | NA days |
| Afatinib 40 mg With Letrozole | Duration of Confirmed OR | NA days |
| Afatinib 30 mg With Letrozole | Duration of Confirmed OR | NA days |
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.
Time frame: 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing
Population: Data were particularly sparse for the 50 mg starting dose group and were not summarised.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50 mg With Letrozole | Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 43.8 ng/mL | Geometric Coefficient of Variation 42 |
| Afatinib 40 mg With Letrozole | Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | 33.9 ng/mL | Geometric Coefficient of Variation 79.4 |
Secondary
Maximum Concentration of Letrozole in Plasma at Steady State (Cmax,ss)
Cmax,ss represents the maximum measured concentration of letrozole in plasma at steady state.
Time frame: 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing
Population: Analysis of all treatment arms combined, as Letrozole dose was the same in all arms.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50 mg With Letrozole | Maximum Concentration of Letrozole in Plasma at Steady State (Cmax,ss) | 135 ng/mL | Geometric Coefficient of Variation 70 |
Secondary
Number of Participants With Clinical Benefit (CB)
CB was defined as CR, PR or stable disease (SD) and was assessed according to RECIST criteria regardless of treatment status.
Time frame: 16 weeks and 24 weeks
Population: TS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 50 mg With Letrozole | Number of Participants With Clinical Benefit (CB) | Participants with CB at 16 weeks | 2 Participants |
| Afatinib 50 mg With Letrozole | Number of Participants With Clinical Benefit (CB) | Participants with CB at 24 weeks | 2 Participants |
| Afatinib 40 mg With Letrozole | Number of Participants With Clinical Benefit (CB) | Participants with CB at 16 weeks | 2 Participants |
| Afatinib 40 mg With Letrozole | Number of Participants With Clinical Benefit (CB) | Participants with CB at 24 weeks | 0 Participants |
| Afatinib 30 mg With Letrozole | Number of Participants With Clinical Benefit (CB) | Participants with CB at 16 weeks | 2 Participants |
| Afatinib 30 mg With Letrozole | Number of Participants With Clinical Benefit (CB) | Participants with CB at 24 weeks | 2 Participants |
Secondary
Number of Participants With Confirmed Objective Response (OR)
OR was defined as complete response (CR) or partial response (PR) and was assessed according to RECIST criteria regardless of treatment status.
Time frame: Baseline till progression
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 50 mg With Letrozole | Number of Participants With Confirmed Objective Response (OR) | 0 Participants |
| Afatinib 40 mg With Letrozole | Number of Participants With Confirmed Objective Response (OR) | 0 Participants |
| Afatinib 30 mg With Letrozole | Number of Participants With Confirmed Objective Response (OR) | 0 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from first treatment to death.
Time frame: Baseline till progression, death or data cut-off
Population: TS. Estimation of median time to death was not feasible, due to the small number of patients who died during the trial.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 50 mg With Letrozole | Overall Survival (OS) | NA days |
| Afatinib 40 mg With Letrozole | Overall Survival (OS) | NA days |
| Afatinib 30 mg With Letrozole | Overall Survival (OS) | NA days |
Secondary
Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 57 (Cpre,ss,57)
Cpre,ss,57 represents the pre-dose concentration of afatinib in plasma at steady state on day 57.
Time frame: Day 57
Population: Data were particularly sparse for the 50 mg starting dose group and were not summarised.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50 mg With Letrozole | Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 57 (Cpre,ss,57) | 21.4 ng/mL | Geometric Coefficient of Variation 42.3 |
| Afatinib 40 mg With Letrozole | Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 57 (Cpre,ss,57) | 15.8 ng/mL | Geometric Coefficient of Variation 42.1 |
Secondary
Pre-dose Concentration of Afatinib in Plasma at Steady Stateon Day 85 (Cpre,ss,85)
Cpre,ss,85 represents the pre-dose concentration of afatinib in plasma at steady state on day 85.
Time frame: Day 85
Population: Data were particularly sparse for the 50 mg starting dose group and were not summarised.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50 mg With Letrozole | Pre-dose Concentration of Afatinib in Plasma at Steady Stateon Day 85 (Cpre,ss,85) | 16.9 ng/mL | Geometric Coefficient of Variation 55.7 |
| Afatinib 40 mg With Letrozole | Pre-dose Concentration of Afatinib in Plasma at Steady Stateon Day 85 (Cpre,ss,85) | 17.3 ng/mL | Geometric Coefficient of Variation 46.5 |
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. Progression was assessed according to RECIST criteria.
Time frame: Baseline till progression, death or data cut-off (04 Jan 2010)
Population: TS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 50 mg With Letrozole | Progression-free Survival (PFS) | 60.0 days |
| Afatinib 40 mg With Letrozole | Progression-free Survival (PFS) | 107.0 days |
| Afatinib 30 mg With Letrozole | Progression-free Survival (PFS) | 79.0 days |
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
Time frame: 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing
Population: Data were particularly sparse for the 50 mg starting dose group and were not summarised.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 50 mg With Letrozole | Time From Dosing to the Maximum Concentration of Afatinib in Plasma at Steady State (Tmax,ss) | 2.00 hours |
| Afatinib 40 mg With Letrozole | Time From Dosing to the Maximum Concentration of Afatinib in Plasma at Steady State (Tmax,ss) | 4.00 hours |
Secondary
Time From Dosing to the Maximum Concentration of Letrozole in Plasma at Steady State (Tmax,ss)
tmax,ss represents the time from dosing to the maximum concentration of letrozole in plasma at steady state.
Time frame: 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing
Population: Analysis of all treatment arms combined, as Letrozole dose was the same in all arms.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 50 mg With Letrozole | Time From Dosing to the Maximum Concentration of Letrozole in Plasma at Steady State (Tmax,ss) | 1.00 hours |
Secondary
Time to RECIST Tumour Reponse
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 criteria.
Time frame: Baseline till progression
Population: TS. Median time to RECIST tumour response was not calculable as there was no OR observed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 50 mg With Letrozole | Time to RECIST Tumour Reponse | NA days |
| Afatinib 40 mg With Letrozole | Time to RECIST Tumour Reponse | NA days |
| Afatinib 30 mg With Letrozole | Time to RECIST Tumour Reponse | NA days |