Overview

This study aims to evaluate the efficacy and safety of preoperative Durvalumab in patients with early small (cT1N0) triple negative breast cancer tumors. This study will recruit patients with early HR-negative breast cancer all invasive types (ER < 1%, PR < 1%, HER2 negative) and TILs >=5%, eligible for a short-term treatment with Durvalumab. A total of 200 patients are planned to be enrolled in the study and which will receive 2 administrations of durvalumab 10mg/kg.

After study treatment, patients:

• In whom surgery is the first standard treatment strategy (i.e. after study treatment) no biopsy is required at the end-of-treatment visit.
• In whom neo adjuvant therapy is the first standard treatment strategy (i.e. after study treatment) a breast ultrasound guided biopsy is mandatory at the EoT visit. If the biopsy-proven residual disease is demonstrated, patients will have the option to receive standard neoadjuvant therapy at the discretion of the treating investigator. Those with a complete response may proceed directly to surgery.

Eligibility

Inclusion Criteria:

• Patient should understand, sign, and date the written informed consent form (including the consent to collect tissue, blood and stool samples, as specified by the protocol) prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol.
• Female patients aged 18 years or older
• Histologically confirmed untreated invasive carcinoma of the breast (ER < 1%, PR < 1%, HER2 negative) as locally determined
• Tumor infiltrating lymphocites (TILs) ≥ 5% in breast tumor biopsy as locally determined
• Breast cancer clinical TNM stage I (cT1N0 as measured by radiological imaging). Bilateral, multicentric and multifocal tumors are allowed, assuming tumor evaluations and pre- and post-treatment biopsies are performed in the same target lesion. Only the largest tumor will be measured to determine the study eligibility.
• No evidence of metastatic disease or confirmed lymph node involvement
• Eastern Cooperative Oncology Group (ECOG) performance status 0/1
• Patients of child-bearing potential are eligible, provided they have a negative serum β-hCG pregnancy test within 2 weeks or urine pregnancy test within 48 hours prior to the first dose of study treatment, and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 3 months after the last dose of durvalumab Note: A woman is considered of childbearing potential following menarche and until becoming post-menopausal (≥ 12 months of non-therapy-induced amenorrhea) unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral oophorectomy and bilateral salpingectomy.
• Sexually active women of childbearing potential must agree to use a highly effective method of contraception supplemented by a barrier method, or to abstain from sexual activity during the study and for at least 3 months after the last study treatment administration. Female subjects should also refrain from breastfeeding throughout this period.

        Note: A highly effective birth control method is a one, which can achieve a failure rate of
        less than 1% per year when used consistently and correctly. Such methods include: combined
        (estrogen and progestogen containing) hormonal contraception; progestogen-only hormonal
        contraception associated with inhibition of ovulation; intrauterine device (IUD);
        intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized
        partner (on the understanding that this is the only one partner during the whole study
        duration), and sexual abstinence during the entire period of risk associated with study
        treatment. To prevent the risk of interaction between the study drug and hormonal
        contraceptives, hormonal contraceptives should be supplemented with a barrier method
        (preferably male condom). Following methods are considered as unacceptable methods
        (non-exhaustive list): periodic abstinence (calendar, symptothermal, post-ovulation
        methods) and withdrawal (coitus interruptus).
        - Blood tests demonstrating: Creatinine ≤ 1.5 x ULN Bilirubin ≤ 1.5 x ULN, AST or ALT < 3 x
        ULN, ALP < 2.5 x ULN (patients with known Gilbert disease who have serum bilirubin level ≤
        3 × the institutional ULN may be enrolled) For patients not receiving therapeutic
        anticoagulation: INR or aPTT ≤ 1.5 x ULN. For patients receiving therapeutic
        anticoagulation: stable anticoagulant regimen Adequate bone marrow function as shown by:
        ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb > 9 g/dL, Serum albumin > 2.5 g/dL Fasting
        Serum amylase ≤ 2 × ULN Fasting Serum lipase ≤ ULN
        - Patients must be affiliated to a social security system or beneficiary of the same.
        Exclusion Criteria:
          -  Patients with triple negative breast cancer and TILs <5%
          -  Any systemic therapy (e.g, chemotherapy, targeted therapy, immune-therapy) or
             radiotherapy for current breast cancer disease before study entry
          -  Known hypersensibility to durvalumab or any of its components
          -  Patients with prior allogeneic stem cell or solid organ transplantation
          -  Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or
             anticipation that such a live, attenuated vaccine will be required during the study or
             within 5 months after the last dose of durvalumab
          -  Treatment with systemic immunostimulatory agents (including but not limited to
             interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever
             is shorter, prior to enrolment
          -  Treatment with systemic immunosuppressive medication (including, but not limited to,
             corticosteroids, cyclophosphamide, azathioprine, methotrexate and thalidomide) within
             2 weeks prior to initiation of study treatment, or anticipation of need for systemic
             immunosuppressive medication during study treatment, with the following exceptions:
               1. Patients who received acute, low-dose systemic immunosuppressant medication, or
                  systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of
                  prednisone or its equivalent, or a one-time pulse dose of systemic
                  immunosuppressant medication (e.g., 48 hours of corticosteroids as premedication
                  for hypersensitivity reaction (e.g., CT scan premedication)) are eligible for the
                  study
               2. Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids
                  for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose
                  corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible
                  for the study
               3. Patients who received intranasal, inhaled, topical or local steroid injections
                  (e.g., intra articular injection)
          -  Active or history of autoimmune disease or immune deficiency, with the exception of
             history of treated autoimmune-related hypothyroidism and Type 1 diabetes mellitus on
             insulin regimen
          -  History of idiopathic pulmonary fibrosis, organizing pneumonia or interstitial lung
             disease
          -  History of HIV infection
          -  Patients with active hepatitis infection (defined as having a positive hepatitis B
             surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past
             hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a
             negative HBsAg test and a positive to hepatitis B core antigen [anti-HBc] antibody
             test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are
             eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
          -  Active tuberculosis
          -  Current treatment with anti-viral therapy for HBV
          -  Participation in another clinical study with an investigational product during the
             last 28 days and while on study treatment
          -  Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including
             antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies
          -  Psychological, familial, sociological or geographical conditions that do not permit
             compliance with the study protocol
          -  Serious uncontrolled concomitant disease that would put the patient at high risk of
             treatment-related complications
          -  Patient has clinically significant, uncontrolled heart disease and/or recent cardiac
             events including any of the following:
          -  History of angina pectoris, coronary artery bypass graft (CABG), symptomatic
             pericarditis, or myocardial infarction within 12 months prior to the start of study
             treatment
               1. History of documented congestive heart failure (New York Heart Association
                  functional classification III-IV)
               2. Documented cardiomyopathy
               3. Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by
                  Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
               4. History of any cardiac arrhythmias (e.g., ventricular tachycardia), complete left
                  bundle branch block, high grade AV block (e.g., bifascicular block, Mobitz type
                  II and third degree AV block), supraventricular, nodal arrhythmias, or conduction
                  abnormality in the previous 12 months
               5. Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mmHg
                  and/or Diastolic Blood Pressure (DBP) ≥ 100 mmHg, with or without
                  antihypertensive medication. Initiation or adjustment of antihypertensive
                  medication(s) is allowed prior to screening.
               6. Long QT syndrome, family history of idiopathic sudden death or congenital long QT
                  syndrome, or any of the following:
        Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or
        hypomagnesemia, history of cardiac failure, or history of clinically
        significant/symptomatic bradycardia Concomitant medication(s) with a known risk to prolong
        the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or
        replaced by safe alternative medication Bradycardia (heart rate < 50 at rest), by ECG or
        pulse.
          -  Female patients who are pregnant or breastfeeding, or adults of reproductive potential
             who are not using effective birth control methods. If barrier contraceptives are being
             used, these must be continued throughout the trial by both sexes
          -  Patients unwilling to or unable (as assessed by the investigator) to comply with the
             protocol
          -  Patients under guardianship or deprived of her liberty by a judicial or administrative
             decision or incapable of giving its consent.