Luminal B Breast Cancer MedDRA version: 20.0 Level: PT Classification code 10006187 Term: Breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: durvalumab
Pharmaceutical Form: Concentrate for solution for injection
INN or Proposed INN: DURVALUMAB
CAS Number: 14289355-60-
Concentration unit: mg/ml milligram(s)/millilitre
Concentr
Sponsors
Institut Jules Bordet
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subjects must meet all of the following criteria in order to be eligible for this study: 1. Age = 18 years old 2. Female 3. ECOG performance status = 1 4. Weight = 35 kg. 5. Histological diagnosis of invasive breast adenocarcinoma that is estrogen receptor-positive (ER-positive) and HER2- negative, as per the updated American Society of Clinical Oncology (ASCO) - College of American Pathologists (CAP) guidelines and performed according to local testing. In addition, only tumours with Proliferation Index Ki67 = 15% or histology grade III are accepted. 6. Agreement to perform new study related biopsies to provide tissue samples 7. MammaPrint genomic high risk score according to centralised testing, except for specific conditions as mentioned below. Mammaprint will only be tested for luminal B breast tumours with either Proliferation Index Ki67 = 15% or histology grade III tumours. (Testing to be done during screening period). 8. Tumour size: ? If subject is cN0: tumour size = 2 cm, as determined by MRI imaging. ? If subject is cN1, cN2 or cN3: tumour size = 1.5 cm, as determined by MRI imaging. The requirement for an MRI is not applicable in the case of medical contraindications to perform MRI (e.g., obesity or claustrophobia). In this situation, tumour evaluations should be performed by ultrasound. 9. Multifocal, multicentric unilateral or bilateral breast adenocarcinoma tumours are allowed provided that all biopsiable foci are ER+/HER2- according to local testing and all foci are able to receive SBRT treatment within the defined dosimetric constraints. In some cases a separate biopsy of every focus is not mandatory, but only if every of the following conditions are present: small focal lesion ? lesion in close proximity to the main primary cancer from which a biopsy was taken ? the investigator and the radiologist consider the lesion to be clearly related to the main primary breast cancer from which a biopsy was taken ? the lesion will be removed during the same lumpectomy than the main primary breast cancer For bilateral, multifocal or multicentric disease, the site selected for pre-treatment biopsy should correspond to the site of largest measurable disease meeting eligibility criteria. The location of tumour biopsy site (laterality, quadrant, position from the nipple and type of imaging modality to guide biopsy) should be collected (see Appendix 2). 10. Serum pregnancy test (for subjects of childbearing potential) negative within 2 weeks prior to first dose of study administration. 11. Women of childbearing potential must agree to use 1 highly effective method of contraception (see protocol section 6.9.1) during the screening period, during the course of the study and at least 12 months after the last administration of study treatment. It is strongly recommended for the male partner of a female subject to also use male condom plus spermicide throughout this period. 12. Adequate bone marrow function as defined below: ? Absolute neutrophil count =1500/µL, i.e. 1.5x109/L ? Hemoglobin = 9.0 g/dL ? Platelets =100000/µL, i.e. 100x109/L 13. Adequate liver function as defined below: ? Serum total bilirubin = 1.5 x ULN. In case of known Gilbert’s syndrome = 3 x UNL is allowed ? AST (SGOT) = 3.0 x ULN ? ALT (SGPT) = 3.0 x ULN Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 112 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for t
Exclusion criteria
Exclusion criteria: Subjects meeting one of the following criteria are not eligible for this study: 1) Pregnant and/or lactating women. 2) Subject with a significant medical, neuro-psychiatric, substance abuse or surgical condition, currently uncontrolled by treatment, which, in the principal investigator’s opinion, may interfere with completion of the study. 3) TNM stage cT4 breast cancer including inflammatory breast cancer. 4) Presence of any distant metastasis. 5) Contra-indication for treatment by paclitaxel, doxorubicin or cyclophosphamide, or known allergy to any tested substances or any excipients (e.g; chemotherapy or immunotherapy formulations). Contra-indication for subjects with known sensitivity to acetaminophen/paracetamol, diphenhydramine or equivalent antihistamine (this is a contra-indication for treatment with oleclumab). 6) Previously known contra-indication for treatment by radiation therapy such as rare genetic disorders associated with DNA repair disorders such as ataxia-telangiectasia (A-T), Nijmegen Breakage Syndrome (NBS) and Fanconi anemia. 7) Active or prior documented autoimmune disease (including inflammatory bowel disease, celiac disease, Wegener’s granulomatosis) within the past 3 years. NOTE: Subjects with childhood atopy or asthma, vitiligo, alopecia, Grave’s disease, Hashimoto’s thyroiditis, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded 8) Prior malignancy active within the previous 5 years, except for localised cancers that are considered to have been cured and in the opinion of the investigator present a low risk for recurrence. Examples include basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast. 9) Known history of, or any evidence of active, non-infectious pneumonitis. 10) Active infection including: ? Tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice) ? Hepatitis B (known positive HBV surface antigen (HBsAg) result). Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. ? Hepatitis C. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 11) Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, transient ischemic attack, or stroke within the previous 3 months, unstable arrhythmias, and/or unstable angina. 12) Medical condition requiring current systemic anticoagulation, or a history of congenital hypercoagulable condition. Subjects taking aspirin at doses < 325 mg per day are eligible provided that prothrombin time is within the institutional range of normal. Use of local anticoagulation for port maintenance is permitted. 13) Subjects with history of venous thrombosis in the past 12 months prior to the scheduled first dose of study treatment (oleclumab). 14) Diabetes mellitus Type 1 or poorly controlled Type 2 diabetes mellitus defined as a screening hemoglobin A1C = 8 % or a fasting plasma glucose = 160 mg/dL (or 8.8 mmol/L) 15) Any live (attenuated) vaccine within 30 days of planned start of study therapy. 16) Prior systemic immunosuppressive medication (excluding corticosteroids) within 30 days of planned start of study therapy. 17) Prior radiation therapy to the ipsila
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Safety Run-in ·To evaluate safety and toxicity of adding SBRT directed to the primary tumour to the combination durvalumab-oleclumab-paclitaxel. ·To evaluate feasibility of performing surgery (breast conserving surgery or mastectomy) within 6 weeks after the end of neo-adjuvant treatment. Phase II Primary objective •To demonstrate improved tumour response of the primary tumour and nodal metastases in arms 2 or 3 versus arm 1. ;Secondary Objective: Phase II Secondary objectives Surgery Evaluate the complete pathological response rate defined as ypT0/Tis ypN0: absence of residual invasive disease, residual insitu carcinoma is accepted. Evaluate the complete pathological response rate defined as ypT0 ypN0: absence of residual invasive disease and insitu carcinoma. Evaluate the response to the primary tumour irrespective of the response to the pathological lymph nodes. Evaluate the response to the pathological lymph nodes irrespective of the response to the primary tumour. Evaluate feasibility to perform breast-sparing surgery of arms 2 and 3 vs. arm 1. Demonstrate an increase in TIL levels of the primary breast cancer between baseline and week 6 biopsy Follow-up Evaluate ability to control invasive disease and survival in arms 2 and 3 vs. arm 1 during year 3 and 5 years after surgery Evaluate severity and duration of AEs of the arms 2 and 3 vs. arm 1 Evaluate cosmetic changes to the breast of arms 2 and 3 vs. arm 1;Primary end point(s): Safety run-in endpoints •Occurrence of immune related or radiation therapy related toxicity of special interest •Feasibility of delivering a sufficient dose of paclitaxel and ddAC •Feasibility of performing surgery within a specified timeframe after the last neo-adjuvant treatment Phase II Primary endpoint ·Residual cancer burden (RCB 0 vs. RCB 1-2-3) at time of surgery. RCB 0 is defined as pathological complete response (pCR) and RCB 1 is defined as minimal residual disease. RCB is calculated as a continuous inde | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase II Secondary endpoints At surgery • Rate of pCR - ypT0/Tis ypN0, defined as the absence of residual invasive cancer at the time of definitive surgery. • Rate of pCR - no DCIS (yp DCIS (ypT0 ypN0), defined as the absence of residual invasive and in situ cancer at time of definitive surgery. · Complete pathologic response rate (pCR) of the primary tumour (ypT0/Tis), irrespective of the response rate of the resected nodal metastases. · Complete pathologic response rate (pCR) of the resected nodal metastases (ypN0), irrespective of the response rate of the primary tumour. · % of breast conservation surgery in arms 2 and 3 versus arm 1 • Change in TIL levels between baseline and the week 6 biopsy. Follow-up Phase Efficacy endpoints at 3 years and 5 years after surgery will be measured, as defined by the Standardized Definitions for Efficacy End Points in Neoadjuvant Breast Cancer Clinical Trials (NeoSTEEP) (88). The following endpoints will be assessed: event-free survival (EFS), breast cancer event-free survival (BC-EFS), overall survival (OS) and distant recurrence-free survival (DRFS). Furthermore, the occurrence of ipsilateral locoregional recurrence (breast, chestwall or locoregional nodal recurrence), ipsilateral local recurrence (breast or chest wall) (laterality of the index lesion), and ipsilateral locoregional nodal recurrence (laterality of the index lesion) will be assessed. The endpoints will be measured using regular follow-up investigations: lab work, clinical examination and annual breast ultrasound and mammography. Radiologic imaging will not be routinely performed, unless directed by abnormal blood results or clinical examination. · Duration and severity of AEs based on CTCAE 5.0. · Changes in breast appearance: breast fibrosis in whole breast, breast fibrosis in boost area, breast size, breast shape, nipple position, shape of the areola and nipple, skin color, appearance of surgical scar, evaluation of teleangiectasia an | — |
Countries
Belgium, France
Contacts
Public ContactCTSU - 7eme etage
Institut Jules Bordet
Outcome results
None listed