Early-staged triple-negative 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 10061020 Term: Breast cancer male 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 stag
Conditions
Interventions
Product Code: MEDI4736
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: DURVALUMAB
CAS Number: 1428935-60-7
Current Sponsor code: MEDI4736
Concentration unit: mg/ml mill
Sponsors
GBG Forschungs GmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures. - Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration alone is not sufficient. Incisional biopsy or lumpectomy prior to randomisation is not allowed. In case of bilateral cancer, the investigator has to decide prospectively which side will be evaluated for the primary endpoint pCR. In case of bilateral breast cancer, all lesions have to be histologically proven TNBC. - 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. - Patients must be in the following stages of disease: • IIA: T2 N0 M0, T1 N1 M0 • IIB: T2 N1 M0, T3 N0 M0 • IIIA: T0–2 N2 M0, T3 N1–2 M0 • IIIB: T4 N0–2 M0 • IIIC: T1-4 N3 M0 In patients with multifocal or multicentric breast cancer, the largest lesion should be measured. - Triple negative disease with centrally confirmed ER negative/PR negative/HER2 negative, and centrally confirmed Ki-67 value. ER negative is defined as <10%, 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 centrally evaluated in three groups: low immune infiltrate (0-10% stromal TILs), intermediate immune infiltrate (11-59% stromal TILs) and lymphocyte-predominant breast cancer (60-100% stromal TILs). - PD-L1 status will be evaluated centrally by IHC. - Male and female subjects = 18 years. - ECOG Performance status 0-1. - Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or shortening fraction) within 3 months prior to randomization. Results for LVEF must be above the normal limit of the institution. - Laboratory requirements: • Hematology: - Absolute neutrophil count (ANC) = 1,5 x 10^9/ L - Platelets = 100 x 10^9 / L - Hemoglobin = 10 g/dL (= 6.2 mmol/L) • Hepatic function: - Total bilirubin < 1.5x UNL - AST and ALT = 1.5x UNL - Alkaline phosphatase = 2.5x UNL. • Renal Function: - < 1.25x ULN creatinine • Thyroid function: - Serum TSH within normal limits prior to randomisation. - In case of abnormal serum TSH additional fT3 and fT4 must be performed. Initiation or adjustment of thyroid medication is allowed to improve TSH value to meet entry criteria. - Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential. A woman is considered to be of childbearing potential if she is not postmenopausal. Postmenopausal is defined as: - Age =60 years. - Age <60 years and =12 continuous months of amenorrhea with no identified cause other than menopause. - Surgical sterilization (bilateral oophorectomy and/or hysterectomy). - For women of childbearing potential and males with partners of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of durvalumab and/or 6 months after the last dose of chemotherapy. Examples of non hormonal contraceptive
Exclusion criteria
Exclusion criteria: - Known hypersensitivity reaction to one of the compounds or substances used in this protocol. - Sentinel node biopsy or axillary dissection prior to start of neoadjuvant therapy. - Patients with definitive clinical or radiologic evidence of Stage IV cancer (metastatic disease) are not eligible. - Patients with a history of any malignancy are ineligible with the following exeptions: - disease-free for at least 5 years and low risk for recurrence of that malignancy (at the investigator’s discretion). - CIS of the cervix, basal cell and squamous cell carcinomas of the skin. - All previous chemotherapies for any malignancy. - Treatment (including radiation therapy, chemotherapy or targeted therapy) for the currently diagnosed breast cancer prior to randomization. - Sex hormones prior treatment must be stopped before study entry. Concurrent treatment with GnRH-analogues allowed. - Any previous treatment with a PD1 or PD-L1 inhibitor, including but not limited to durvalumab. - Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry. - Female patients: pregnancy or lactation at the time of randomization or intention to become pregnant during the study and up to 3 months after treatment with durvalumab and/or up to 6 months after chemotherapy. - Inadequate general condition (not fit for anthracycline-taxane-based chemotherapy). - Body weight =30kg. - Major surgery within 28 days of initiation of study treatment. - 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 prior infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP >150 / 90 mm Hg under treatment with at maximum three antihypertensive drugs), rhythm abnormalities requiring permanent treatment (excluding chronic artrial fibrillation not requiring a pacemaker), clinically significant valvular heart disease, supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication; conduction abnormality requiring a pacemaker. - History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. - Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis). - History of primary immunodeficiency or allogeneic organ transplant. - Uncontrolled intercurrent illness including, but not limited to serious chronic gastrointestinal conditions associated with diarrhea, active peptic ulcer disease or gastritis, active bleeding diatheses, or active interstitial lung disease. - Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab. - Active or history of autoimmune disease or immune deficiency. - History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent. - Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results. - Pre-existing motor or sensory neuropathy of a severity = grade 2 by NCI-CTCAE criteria v5.0. - Known currently active infection including tuberculosis (clinical evaluation
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. Pathologic complete response in the breast and axillary lymph nodes (ypT0/ypN0): To compare pathological complete response (pCR=ypT0/ypN0) rates between TNBC patients treated with durvalumab concurrently given to chemotherapy (weekly paclitaxel +/- carboplatin followed by EC or AC) vs. chemotherapy alone. 2. Event-Free Survival (EFS): To compare EFS rates between TNBC patients treated with durvalumab concurrently given to chemotherapy (weekly paclitaxel +/- carboplatin followed by EC or AC) followed by adjuvant treatment with durvalumab vs. no study treatment (observation). ;Secondary Objective: - To determine and compare overall survival (OS) in both treatment groups. - To evaluate the predictive role of PD-L1 expression at baseline. - To evaluate the prognostic and predictive role of PD-L1 expression at baseline. - To determine and compare in both treatment groups: - the pCR rates in the breast, - the pCR rates in the breast and lymph nodes evaluated histologically, - the rates of breast conserving surgery, - the conversion rate from node-positive to node-negative, - Disease Free Survival (DFS) - Locoregional recurrence-free interval (LRRFI), - Distant disease-free survival (DDFS), - Brain metastases free survival (BMFS). - To assess and compare the impact of study treatment on QoL in both treatment groups. - To assess and compare the compliance with study therapy in both treatment groups. - To assess and compare toxicity associated with study therapy in both treatment groups. ;Primary end point(s): 1. Pathological complete response (ypT0/ypN0) 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. 2. EFS is defined as time from randomization until first EFS event, which are progression on protocol therapy resulting in administration of non-protocol therapy or inoperability, local invasive recurrence following mastectomy, | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Overall Survival is defined as time from randomization until death from any cause. - pCR (ypT0/Tis/ypN0/+) is defined as no microscopic evidence of residual invasive viable tumor cells in all resected specimens of the breast, irrespective of lymph node status. - pCR (ypT0/ypN0/+) is defined as no microscopic evidence of residual invasive and no non-invasive viable tumor cells in all resected specimens of the breast, irrespective of lymph node status. - pCR (ypT0/Tis/ypN0) is defined as no microscopic evidence of residual invasive viable tumor cells in all resected specimens of the breast and axilla. - Breast conservation rate: Percentage of patients undergoing breast conserving surgery (defined as tumorectomy, segmentectomy or quadrantectomy as a most radical surgery) following neoadjuvant therapy. - Positive nodal status conversion rate: Percentage of patients node-positive by palpation or ultrasound that convert to pathologically node-negative following completion of neoadjuvant chemotherapy. - Disease free survival: defined as time from randomization until first DFS event: local invasive and non-invasive recurrence following mastectomy, local invasive and non-invasive recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, contralateral invasive breast cancer, second non-breast primary malignancies (excluding squamous or basal cell carcinoma of the skin), or death from any cause prior to recurrence or second primary cancer. - Locoregional recurrence-free interval: defined as time from randomization until any loco-regional (ipsilateral breast (invasive), chest wall, local/regional lymph nodes) recurrence of disease or any invasive contralateral breast cancer whichever occurs first. Progression under therapy is not considered as an event for LRRFI. Distant recurrence, secondary malignancy and death are considered competing events. - Distant disease-free survival: defined as time from randomizati | — |
Countries
Australia, Brazil, Canada, China, France, Germany, India, Japan, Korea, Republic of, South Africa, Spain, United States
Contacts
Public ContactGeparTREIZE
GBG Forschungs GmbH
Outcome results
None listed