Breast Neoplasms, Neoplasm Metastasis
Conditions
Brief summary
The aim of this study is to investigate the efficacy and safety of afatinib alone or in combination with vinorelbine, as treatment in patients with HER2-overexpressing metastatic breast cancer, who have progressive brain lesions after trastuzumab and/or lapatinib based therapy
Interventions
DRUGVinorelbine
Vinorelbine 25 mg/m² on days 1, 8, 15 in a 3-weekly course
Patients will receive, at the investigator's discretion, the most appropriate medical treatment consisting of single agent or combination regimen approved for the treatment of metastatic breast cancer, and according to patient status and local guidelines.
DRUGafatinib
Afatinib monotherapy:once daily, continuous treatment in a 3-weekly course. If well tolerated, the dose may be escalated to 50 mg.
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. patients with HER2 positive breast cancer with a documented central nervous system (CNS) recurrence/progression (by imaging) during or after a HER2 inhibitor (Trastuzumab and/or Lapatinib) based therapy (no leptomeningeal carcinomatosis as the only site of CNS metastases) 2. at least one measurable and progressive lesion in the brain (=10 mm on T1-weighted, gadolinium-enhanced Magnetic Resonance Imaging). Measurable or non measurable extracranial metastases allowed. 3. previous treatment with HER2 inhibitors to be discontinued prior to first study treatment administration (at least 14 days for trastuzumab and other antibodies, at least 7 days for lapatinib). 4. previous chemotherapy and hormonal therapy (adjuvant and metastatic regimens) allowed, but chemotherapy must have been discontinued at least 14 days and hormonal therapy at least 7 days prior to first study treatment administration. 5. Patients must have recovered to baseline condition or to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 grade = 1 from any acute CTCAE v. 3.0 grade =2 side effects of previous treatments. 6. prior surgery, whole brain radiotherapy or stereotactic radiosurgery allowed provided that there is unequivocal evidence of one or more new and/or progressive brain metastases after completion of whole brain radiotherapy or stereotactic radiosurgery.
Exclusion criteria
1. Prior treatment with HER2- tyrosine kinase inhibitor other than lapatinib 2. Any other current malignancy or malignancy diagnosed within the past five (5) years (other than bilateral primary breast cancer, metastases to the contralateral breast, non-melanomatous skin cancer and in situ cervical cancer). 3. Significant chronic or recent acute gastrointestinal disorders with diarrhoea as a major symptom e.g. Crohn's disease, malabsorption or Common Terminology Criteria (CTC) grade =2 diarrhoea of any aetiology.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Patient Benefit Rate at 12 Weeks | 12 weeks from randomisation | Percentage of patients with patient benefit at week 12. Patient benefit was defined by the absence of central nervous system (CNS) disease progression according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 in addition to no tumour-related worsening of the neurological signs and symptoms (NSS), no tumour-related increase in corticosteroid dosage and no progression of extra CNS disease according to RECIST 1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival | From first drug administration until 28 days after end of treatment, up to 805 days | Progression-Free Survival is defined as the time from the date of randomisation to the date of disease progression or death whichever came first. Disease progression was defined as either disease progression in CNS lesions (including worsening in NSS and use of corticosteroid) or disease progression in extra-CNS lesions according to RECIST 1.1. |
| Overall Survival | From first drug administration until 28 days after end of treatment, up to 805 days | Overall Survival is defined as time from randomisation to the date of death from any cause. |
Countries
Canada, Finland, France, Germany, Italy, South Korea, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Afatinib Mono Afatinib monotherapy administered orally: starting dose 40 mg per day, continuous treatment in a 3-weekly course. If well tolerated, the dose may be escalated to 50 mg. | 40 |
| Afatinib+Vino Afatinib 40 mg per day administered orally, continuous treatment, in combination with weekly Vinorelbine 25 mg/m² administered intravenously on days 1, 8, 15 in a 3-weekly course. | 38 |
| Investigator's Choice Patients will receive, at the investigator's discretion, the most appropriate medical treatment consisting of single agent or combination regimen approved for the treatment of metastatic breast cancer, and according to patient status and local guidelines. | 43 |
| Total | 121 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Not treated | 0 | 1 | 1 |
| Overall Study | Other reason not defined below | 0 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 0 | 2 |
Baseline characteristics
| Characteristic | Afatinib Mono | Afatinib+Vino | Investigator's Choice | Total |
|---|---|---|---|---|
| Age, Continuous | 51.5 years STANDARD_DEVIATION 10.3 | 51.2 years STANDARD_DEVIATION 10.6 | 52.6 years STANDARD_DEVIATION 10.3 | 51.8 years STANDARD_DEVIATION 10.3 |
| Sex: Female, Male Female | 40 Participants | 38 Participants | 43 Participants | 121 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 | 39 / 40 | 37 / 37 | 40 / 42 |
| serious Total, serious adverse events | 18 / 40 | 24 / 37 | 22 / 42 |
Outcome results
Primary
Patient Benefit Rate at 12 Weeks
Percentage of patients with patient benefit at week 12. Patient benefit was defined by the absence of central nervous system (CNS) disease progression according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 in addition to no tumour-related worsening of the neurological signs and symptoms (NSS), no tumour-related increase in corticosteroid dosage and no progression of extra CNS disease according to RECIST 1.1
Time frame: 12 weeks from randomisation
Population: Randomised Set (RS): includes all randomised patients, whether treated or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib Mono | Patient Benefit Rate at 12 Weeks | 30.0 percentage of participants |
| Afatinib+Vino | Patient Benefit Rate at 12 Weeks | 34.2 percentage of participants |
| Investigator's Choice | Patient Benefit Rate at 12 Weeks | 41.9 percentage of participants |
Secondary
Overall Survival
Overall Survival is defined as time from randomisation to the date of death from any cause.
Time frame: From first drug administration until 28 days after end of treatment, up to 805 days
Population: RS including only patients who died
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib Mono | Overall Survival | 57.7 weeks |
| Afatinib+Vino | Overall Survival | 37.3 weeks |
| Investigator's Choice | Overall Survival | 52.1 weeks |
Secondary
Progression-Free Survival
Progression-Free Survival is defined as the time from the date of randomisation to the date of disease progression or death whichever came first. Disease progression was defined as either disease progression in CNS lesions (including worsening in NSS and use of corticosteroid) or disease progression in extra-CNS lesions according to RECIST 1.1.
Time frame: From first drug administration until 28 days after end of treatment, up to 805 days
Population: RS including only patients who experienced disease progression or death
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib Mono | Progression-Free Survival | 11.9 weeks |
| Afatinib+Vino | Progression-Free Survival | 12.3 weeks |
| Investigator's Choice | Progression-Free Survival | 18.4 weeks |