Patients with triple negative, early breast cancer MedDRA version: 20.0 Level: PT Classification code 10057654 Term: Breast cancer female System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10006200 Term: Breast cancer stage II System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10006202 Term: Breast
Conditions
Interventions
Trade Name: Abraxane
Pharmaceutical Form: Powder for solution for injection/infusion
INN or Proposed INN: Nab-Paclitaxel
CAS Number: 33069-62-4
Current Sponsor code: Abraxane
Other descriptive name: P
Sponsors
GBG Forschungs GmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Written informed consent for all study according to local regulatory requirements prior to beginning specific protocol procedures. 2. Complete baseline documentation must be sent to GBG Forschungs GmbH. 3. Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration alone is not sufficient. Incisional biopsy is not allowed. In case of bilateral cancer, the investigator has to decide prospectively which side will be evaluated for the primary endpoint. 4. Tumor lesion in the breast or the nodes must be measurable in two dimensions, preferably by sonography. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion. 5. Patients must be in the following stages of disease: - cT1b - cT4a-d irrespective of nodal involvement. In patients with multifocal or multicentric breast cancer, the largest lesion should be measured. 6. Triple negative disease with centrally confirmed ER negative/PR negative/HER-2 negative, and centrally confirmed Ki-67 value. ER negative is defined as <1%, PR negative is defined as <10% stained cells and HER2-negative is defined as either IHC 0/1+ or IHC 2+ and in-situ hybridisation (ISH) of either ratio <2.0 or less than 6 copies of HER2 per tumor cell. Stromal TILs will be evaluated in three groups: low immune infiltrate (0-10% stromal TILs), intermediate immune infiltrate (11-59% stromal TILs), LPBC 60-100% stromal TILs. PD-L1 status and other predefined markers will be prospectively assessed during the study. Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the GBG central pathology laboratory prior to randomization. 7. Age ? 18 years. 8. ECOG Performance status 0-1. 9. Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or shortening fraction) within 3 months prior to randomization. Results must be above the normal limit of the institution. 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 < 1.5x UNL and - ASAT (SGOT) and ALAT (SGPT) ? 1.5x UNL and - Alkaline phosphatase ? 2.5x UNL. Renal Function - < 1.25x ULN creatinine Thyroid function - FT3 within local laboratory normal range - FT4 within local laboratory normal range - TSH within local laboratory normal range 11. Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential. Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: =60 years old and no menses for =1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry. 12. Complete staging work-up within 3 months prior to randomization. All patients must have had breast imaging by breast ultrasound plus either bilateral mammography or breast MRI (one of those =21 day). All patients must have had chest X-ray (PA and lateral), abdominal ultrasound or CT scan or MRI, and bone scan (according to guidelines). In case of positive bone scan, bone X-ray is mandatory. Other tests may be performed as clinically indicated. 13. Patients must be available and compliant for central diagnostics, treatment and follow-up. Are
Exclusion criteria
Exclusion criteria: 1. Prior chemotherapy for any malignancy. 2. Prior radiation therapy for breast cancer. 3. Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment. 4. Inadequate general condition (not fit for dose-dense, dose-intensified anthracycline-taxane-targeted agents-based chemotherapy). 5. Previous malignant disease being disease-free for less than 5 years (except CIS of the cervix and non-melanomatous skin cancer). 6. Known or suspected congestive heart failure (>NYHA I) and / 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 >140 / 90 mm Hg under treatment with at maximum two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease. 7. Mean QT interval corrected for heart rate (QTc) =470 ms calculated from 3 electrocardiograms (ECGs) using Bazett’s Correction 8. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis) 9. History of primary immunodeficiency 10. History of allogeneic organ transplant 11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV). 12. Known history of previous clinical diagnosis of tuberculosis 13. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving MEDI4736 14. Autoimmune disease and conditions (i.e. inflammatory bowel disease) 15. History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent 16. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results 17. Pre-existing motor or sensory neuropathy of a severity ? grade 2 by NCI-CTC criteria v 4.0. 18. Currently active infection. 19. Incomplete wound healing or unhealed bone fracture. 20. Definite contraindications for the use of corticosteroids 21. Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol; 22. Concurrent treatment with: - chronic corticosteroids prior to study entry with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or equivalent corticosteroid. - other immunosuppressive medication (e.g. low dose MTX) - sex hormones (including hormonal contraception) prior treatment must be stopped before study entry. - other experimental drugs or any other anti-cancer therapy. 23. Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry. 24. Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736 25. Male patients.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To compare the pathological complete response (pCR= ypT0 ypN0) rates of neoadjuvant treatment of sequential, nab-Paclitaxel followed by EC +/- the PD-L1 antibody MEDI4736 in patients with early triple negative breast cancer;Secondary Objective: To assess pCR rates per arm separately for the stratified subpopulations. To determine rates of ypT0/is ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0;. To determine response rates of the breast tumor and axillary nodes based on physical examination and imaging tests (sonography, mammography, or MRI) after treatment in both arms. To assess clinical response rate after taxane in both groups To determine breast conservation rate after each treatment. To assess toxicity and compliance. To examine and compare pre-specified molecular markers such as tumor infiltrating lymphocytes, PD-1, PD-L1, Ki-67, etc. on core biopsies before chemotherapy, after the window phase and surgical tissue after end of chemotherapy. To determine loco-regional invasive recurrence free survival (LRRFS), distant-disease-free survival, invasive disease-free survival, event free survival and overall survival in both arms and according to stratified subpopulations examine quality of life using FACT-Taxane;Primary end point(s): Pathological complete response of breast and lymph nodes (ypT0 ypN0; primary endpoint) is defined as no microscopic evidence of residual invasive and no non-invasive viable tumor cells in all resected specimens of the breast and axilla. Pathological response will be assessed considering all removed breast and lymphatic tissues from all surgeries. Patients with negative sentinel node biopsy prior to treatment start and no axilla surgery after neoadjuvant chemotherapy will be counted as pCR if no invasive and non-invasive residual tumor is detected in the removed breast tissue. Patients with histologically/cytologically positive nodes prior to treatment start and no axilla surgery after chemotherapy will be counted as | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): ypT0/is ypN0 is defined as no microscopic evidence of residual invasive viable tumor cells in all resected specimens of the breast and axilla; in case of sentinel node biopsy prior to treatment start, the axillary lymph nodes will be evaluated as described for the primary endpoint. ypT0 ypN0/+ is defined as no microscopic evidence of residual invasive or non-invasive viable tumor cells in all resected specimens of the breast; ypT0/is ypN0/+ is defined as no microscopic evidence of residual invasive viable tumor cells in all resected specimens of the breast; patients with a sentinel node biopsy prior to treatment start will be evaluated for ypT(any) ypN0 similarly to the description given for the primary endpoint. Clinical (c) and imaging (i) response will be assessed after part 2 of the study 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, during and after treatment. Breast conservation is defined as tumorectomy, segmentectomy or quadrantectomy as a most radical surgery. Tolerability and Safety: Descriptive statistics for the 2 treatments 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 termination will be categorized according to the main reason and will be presented in frequency tables. Safety by toxicity grades is defined by the NCI-CTCAE version 4.0. Quality of life: the two treatment arms will be compared descriptively conc | — |
Countries
Germany
Contacts
Public ContactDr. Ursula Wolf
GBG Forschungs GmbH
Outcome results
None listed