| Eligibility |
Inclusion Criteria:
- Be willing and able to provide written informed consent for the trial.
- Postmenopausal status and =75 years of age on day of signing the informed consent with
postmenopausal status defined as one of the following: prior bilateral surgical
oophorectomy; age = 56 years and natural amenorrhea with =1 year since last menses;
age <56 years with amenorrhea =1 year and serum oestradiol levels and
follicle-stimulating hormone (FSH) levels in the postmenopausal range without the use
of luteinizing hormone releasing hormone agonists; or age <56 years after hysterectomy
with one or both ovaries left in place and serum oestradiol levels and FSH levels in
the postmenopausal range.
- Be willing to provide tissue from a newly obtained core or excisional biopsy of the
tumour that should be evaluable for central histological characterization and future
molecular testing.
- Have a performance status of 0 or 1 on the ECOG Performance Scale.
- Have a newly diagnosed non-metastatic previously untreated and operable primary
invasive carcinoma of the breast that meets the following criteria: (1) histologically
confirmed invasive carcinoma of the breast; (2) invasive carcinoma of no special type
(commonly referred to as invasive ductal histology); (3) ER positive/HER2-negative
status; (4) proliferation marker Ki67 level of =20%; and (5) tumour size on imaging
larger than or equal to 1.5 cm (largest diameter). Multifocal, multicentric unilateral
or bilateral breast tumours are allowed provided that all routinely collected/analysed
foci correspond to all criteria above.
- Any clinical nodal status.
- Be willing to provide plasma/blood and tumour samples for translational research.
- Demonstrate adequate organ function as defined in Table 2.
- Have a negative hepatitis B surface antigen (HBsAg) test at screening.
- Have a negative total hepatitis B core antibody (HBcAb) test at screening, or positive
total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening.
The HBV DNA test will be performed only for patients who have a positive total HBcAb
test.
- Have a negative hepatitis C virus (HCV) antibody test at screening, or positive HCV
antibody test followed by a negative HCV RNA test at screening. The HCV RNA test will
be performed only for patients who have a positive HCV antibody test.
- Completion of all necessary screening procedures within 28 days prior to
randomisation.
Exclusion Criteria:
- Having received any previous systemic anti-cancer treatment (i.e. neoadjuvant)
including, but not limited to, chemotherapy, targeted therapy, immunotherapy, hormonal
therapy, or having received radiotherapy for the currently diagnosed breast cancer.
- Having received hormone replacement therapy or hormonal contraception less than 1
month prior to inclusion.
- Currently participating in an interventional study and receiving study therapy or
having participated in a study of an investigational agent and having received study
therapy or to have used an investigational device within 4 weeks of receiving the
treatment dose.
- Having a diagnosis of immunodeficiency or having received high-dose systemic steroid
therapy or any other form of immunosuppressive therapy within 14 days prior to
receiving the trial treatment. Please note the following exceptions: acute, low-dose
systemic immunosuppressant medication or a one-time pulse dose of systemic
immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast
allergy) is allowed; patients who received mineralocorticoids (e.g., fludrocortisone),
or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are
eligible for the study; and patients who are on treatment with inhalation
corticosteroids are eligible for the study.
- Known history of TB (Bacillus Tuberculosis) infection.
- Known hypersensitivity to atezolizumab or any of its excipients.
- History of severe anaphylactic reaction to chimeric or humanized antibodies or fusion
proteins.
- Known allergy or hypersensitivity to any component of the letrozole formulation.
- History of invasive breast cancer prior to this diagnosis (relapse/second primary).
- Personal history of any other malignancy within 5 years prior to inclusion. Exceptions
include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that
have undergone potentially curative therapy, and in situ cervical carcinoma.
- Personal history of autoimmune disease that has required systemic treatment as
follows: treatment with systemic immunostimulatory agents (including, but not limited
to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug-elimination
half-lives (whichever is longer) prior to study inclusion; or treatment with systemic
immunosuppressive medication (including, but not limited to, corticosteroids,
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-a agents)
within 2 weeks prior to study inclusion, or anticipation of need for systemic
immunosuppressive medication during study treatment. Patients with a history of
autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible
for the study. Patients with controlled type 1 diabetes mellitus who are on an insulin
regimen are eligible for the study.
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are met:
rash must cover <10% of body surface area, disease must be well controlled at baseline
and may require only low-potency topical corticosteroids, no occurrence of acute
exacerbations of the underlying condition requiring psoralen and ultraviolet A (PUVA)
therapy or ultraviolet B (UVB) therapy, radiation, methotrexate, retinoids, biologic
agents, oral calcineurin inhibitors, or high potency oral corticosteroids within the
previous 12 months.
- To have a history of pulmonary fibrosis, bronchiolitis obliterans, drug-induced
pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis. History of
radiation induced lung injury such as radiation pneumonitis or radiation fibrosis is
permitted.
- To have a recent or active infection that requires or has required systemic therapy,
being either: a severe infection within 4 weeks prior to initiation of study
treatment, including, but not limited to bacteremia, or severe pneumonia; a severe
infection within 4 weeks prior to initiation of study treatment that has required
hospitalization because of its complications, or an infection that has been treated
with oral or IV antibiotics, antiviral treatment, systemic antimycotics or systemic
antiparasitic drugs within 1 week prior to initiation of study treatment. Patients
receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or
chronic obstructive pulmonary disease exacerbation) are eligible for the study.
- To have a known psychiatric or substance abuse disorder that would interfere with
cooperation with the requirements of the trial.
- To have received prior treatment with CD137 agonists or immune checkpoint blockade
therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.
- To have a known history of Human Immunodeficiency Virus (HIV) infection.
- To have received a live vaccine within 30 days of planned start of study therapy.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed.
- Uncontrolled or symptomatic hypercalcemia.
- Significant cardiovascular disease (such as New York Heart Association Class II or
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3
months prior to initiation of study treatment, unstable arrhythmia, or unstable
angina.
- Major surgical procedure within 4 weeks prior to initiation of study treatment, or
anticipation of need for a major surgical procedure other than for the breast during
the study.
- Prior allogeneic stem cell or solid organ transplantation.
- To have a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
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