Patients with HER2-positive early breast cancer. MedDRA version: 14.1 Level: LLT Classification code 10065430 Term: HER-2 positive breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Afatinib
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Afatinib
CAS Number: 850140-72-6
Other descriptive name: AFATINIB
Concentration unit: mg milligram(s)
Concentration
Sponsors
GBG Forschungs GmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Written informed consent for all study procedures according to local regulatory requirements prior to beginning of specific protocol procedures. 2. Complete baseline documentation must be sent to GBG Forschungs GmbH. 3. Unilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration is not sufficient. Incisional biopsy is not allowed. Tumor lesion in the breast with a sonographical size of = 2 cm in maximum diameter. The lesion has to be measurable in two dimensions, preferably by sonography. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion. 4. Operable or locally advanced or inflammatory breast cancer (cT2 - cT4a-d). In patients with multifocal or multicentric breast cancer, the largest lesion should be measured. 5. Centrally confirmed positive HER2 status detected on core biopsy. HER2-positive is defined as IHC 3+ by a validated test method or FISH/SISH ratio > 2.0. Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the Department of Pathology at the Charité, Berlin, prior to randomisation. 6. Centrally confirmed hormone receptor status (ER/PgR). 7. Age = 18 years. 8. Karnofsky Performance status = 80%. 9. Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or shortening fraction) within 3 months prior to randomisation. Results must be above 55%. 10. Laboratory requirements: Hematology - Absolute neutrophil count (ANC) = 2.0 x 109 / L and - Platelets = 100 x 109 / L and - Hemoglobin = 10 g/dL (= 6.2 mmol/L) Hepatic function - Total bilirubin =65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Bilateral breast cancer. 2. Prior chemotherapy for any malignancy. 3. Prior radiation therapy for breast cancer. 4. Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilisation) during study treatment. 5. Inadequate general condition (not fit for anthracycline-taxane based chemotherapy) as per investigator assessment. 6. Previous malignant disease with a disease-free period of less than 5 years (except CIS of the cervix and non-melanomatous skin cancer). 7. Known or pre-existing interstitial lung disease. 8. Known or suspected congestive heart failure (NYHA > I) or coronary heart disease, angina pectoris requiring antianginal medication, previous history of myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP > 160 / 90 mm Hg under treatment with two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease. 9. History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent. 10. Chronic-inflammatory bowel diseases. 11. Pre-existing motor or sensory neuropathy of a severity grade = 2 by NCI criteria. 12. No evidence or history of infection (including hepatitis B, C or HIV). 13. Definite contraindications for the use of corticosteroids except inhalative corticoids. 14. Known hypersensitivity reaction to one of the investigational compounds or incorporated substances used in this protocol. 15. Concurrent treatment with: - chronic corticosteroids unless initiated > 6 months prior to study entry and at low dose (= 10 mg methylprednisolone or equivalent). - sex hormones. Prior treatment must be stopped before study entry. - other experimental drugs or any other anti-cancer therapy. 16. Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry. 17. Male patients.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the pathological complete response (pCR=ypT0/is ypN0) rates of neoadjuvant treatment of afatinib in combination with weekly paclitaxel + trastuzumab followed by epirubicin/cyclophosphamide/trastuzumab in patients with HER2-positive primary breast cancer.;Secondary Objective: - To determine the rates of ypT0 ypN0; ypT0; ypT0/is; ypN0; and regression grades according to Sinn. - To determine the response rates of the breast tumor and axillary nodes by physical examination and imaging tests (sonography, mammography, or MRI) after 6 weeks of the 2 anti-HER2 agents alone and at surgery. - To determine the breast and axilla conservation rate after treatment. - To assess the toxicity and compliance. - To correlate skin toxicity and diarrhoea with pCR. - To examine and compare pre-specified molecular markers such as EGFR, HER2, HER3, HER4, TGFß, EGF, AREG, HBEGF, BTC, EPIGEN, EREG, NRG1, NRG2, neuroglycan, tomoregulin, NRG4 and NRG3K-RAS, MET, IGF1R, IRS1, PTEN, FGFR1, FGFR2, FGFR3, AXL, RET, and PDGFR; EGFR signature, Ki67, p95HER2, and PI3K mutation before start of afatinib+trastuzumab, before and after chemotherapy.;Primary end point(s): Pathological complete response of breast and lymph nodes (ypT0/is ypN0).;Timepoint(s) of evaluation of this end point: Pathological response will be assessed considering all removed breast and lymphatic tissues from all surgeries. Surgery takes place shortly after the 30 weeks treatment. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoints: Other pCR definitions (ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+) ypTany ypN0, regression grade according to Sinn, response by physical examination, imaging response, breast conservation) will also be summarized as rates in the treatment group, two-sided 90% confidence intervals will be calculated according to Pearson and Clopper, these tests are considered explorative. Clinical and imaging response will be assessed in the last week of the 6 weeks treatment period without chemotherapy and before surgery by physical examination and imaging tests. Sonography is the preferred examination, however, if sonography appears not to provide valid results or is not performed, other imaging tests will be considered with the following priority: MRI, mammography, computed tomogram. The same imaging method should be considered for the measurement before and after treatment. For defined categories of efficacy (complete, partial, stable, or progression), the proportion of patients with success will be determined and appropriate confidence intervals will be calculated. Patients in whom success cannot be determined (e.g. patients in whom histology is not evaluable) will be included in the denominator, i.e. these patients will affect the success rate in the same way as treatment failures. The clinical tumor response by palpation prior to surgery will also be presented, if applicable. Breast conservation rate: All breast conserving surgeries (tumorectomies, segmentectomies, quadrantectomies) without reconstruction are summarized as rates. Tolerability and Safety: Descriptive statistics will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped. The reason for termination includes aspects of efficacy (e.g. termination due to tumor progression), safety (e.g. termination due to adverse events) and compliance (e.g. termination due to patient's withdrawal of consent). Reasons for premature terminat | — |
Countries
Germany
Contacts
Public ContactDr. Lorenz Huebner
GBG Forschungs GmbH
Outcome results
None listed