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 < 10%, PR <
10%, HER2 negative) as locally determined.
- - Tumor infiltrating lymphocytes (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.
- - 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.
