This is a randomized, open-label, adaptive, two arm, multicentre, Phase II trial comparing a
neoadjuvant chemotherapy with PDL1-inhibition (Atezolizumab) and Atezolizumab two-week window
to chemotherapy with PDL1-inhibition (Atezolizumab) and identify biomarkers predicting
(early) response to or resistance against Atezolizumab (alone and with CTX) allowing patients
stratification in future clinical trials
Inclusion Criteria:
- Female and male patients, age at diagnosis 18 years and above
- Written informed consent prior to admission to this study
- Histologically confirmed unilateral primary invasive carcinoma of the breast
- Clinical T1c - T4d
- Stage N0-N3 until 21 patients (5%) with stage N3 are randomized, thereafter N0-N2
- Triple negative breast cancer defined by and confirmed by central pathology:
- ER negative (<10% positive cells in IHC) and PR negative (<10% positive cells on
IHC)
- HER2 negative breast cancer:
- Either defined by IHC: ICH scores of 0-1 or an ICH score of 2 in combination
with a negative in-situ-hybridization (ISH)
- Or defined by ISH: negative ISH
- Identifiable PD-L1 IC-status by central pathology (positive or negative) by means of
VENTANA PD-L1 (SP142) Assay; positive status is defined by PD-L1 expression on IC on ≥
1% of the tumor area, negative status is defined by PD-L1 expression on IC on < 1% of
the tumor area
- No clinical evidence for distant metastasis (cM0)
- Tumor block available for translational research
- Performance Status ECOG ≤ 1 or KI ≥ 80 %
- Negative pregnancy test (urine or serum) within 7 days prior to screening in
premenopausal patients
- Women of childbearing potential and male patients with partners of childbearing
potential must accept to implement a highly effective (less than 1% failure rate
according to Pearl index) including at least one non-hormonal contraceptive measures
during the study treatment and for 5 months following the last dose of study treatment
such as:
- Intrauterine device (IUD)
- bilateral tubal occlusion
- vasectomised partner
- sexual abstinence
- The patient must be accessible for treatment and follow-up
- Normal cardiac function:
- Normal ECG (within 6 weeks prior to screening)
- Normal LVEF on Echocardiorgaphy
- Normal thyroid function
o Normal TSH and FT4
- Blood counts within 14 days prior screening:
- ANC must be ≥ 1500/mm3
- Platelet count must be ≥ 100,000 / mm3
- Hemoglobin must be ≥ 10g/dl
- Hepatic functions:
- Total bilirubin must be ≤ ULN for the lab unless the patient has a bilirubin
elevation > ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome
involving slow conjugation of bilirubin
- Alkaline phosphatase must be ≤2,5 X ULN for the lab
- AST and ALT must be ≤1, 5 ULN for the lab.
- Patients with AST and ALT or alkaline phosphatase > ULN are eligible for
inclusion if liver Imaging (CT, MRI, PET-CT, or PET scan) performed within 3
months prior to screening (and part of standard of care) does not demonstrate
metastatic disease and the requirements in criterion (just above) are met
- Patients with alkaline phosphatase that is > ULN but less than or equal to 2, 5 X
ULN or with unexplained bone pain are eligible if bone imaging does not
demonstrate metastatic disease.
- Creatinine clearance ≥ 40 ml/min performed 28 days prior to screening
Exclusion Criteria:
- Previous history of malign diseases, non-melanoma skin cancer and carcinoma of the
cervix are allowed if treated with curative intent
- Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that, in the investigator's opinion, gives reasonable suspicion of
a disease or condition that contraindicates the use of paclitaxel, carboplatin,
epirubicin, cyclophosphamide or Atezolizumab
- Psychological, familial, sociological or geographical conditions that do not permit
compliance with the study protocol
- Concurrent treatment with other drugs that are contraindicating the use of the study
drugs
- Existing pregnancy
- Breastfeeding
- Sequential breast cancer
- Concurrent treatment with other experimental drugs and participation in another
clinical trial or clinical research project within 30 days prior to study entry
- Severe and relevant co-morbidity that would interact with the application of cytotoxic
agents or the participation in the study including but not confined to:
- Uncompensated chronic heart failure or systolic dysfunction (LVEF < 55%, CHF NYHA
classes II-IV),
- unstable arrhythmias requiring treatment i.e., atrial tachycardia with a heart
rate ≥ 100/min at rest, significant ventricular arrhythmia (ventricular
tachycardia) or highergrade AV-block,
- Angina pectoris within the last 6 months requiring anti-anginal medication,
- Clinically significant valvular heart disease,
- Evidence of myocardial infarction on electrocardiogram (ECG),
- Poorly controlled hypertension (e.g., systolic > 180 mm Hg or diastolic > 100 mm
Hg).
- Inadequate organ function including but not confined to:
- hepatic impairment as defined by bilirubin > ULN x 1,5
- pulmonary disease (severe dyspnea at rest requiring oxygen therapy)
- Abnormal blood values:
- Platelet count below 100,000/mm3
- AST/ALT > 1, 5 ULN
- Hypokalaemia > CTCAE grade 1
- Neutropenia > CTCAE grade 1
- Anaemia > CTCAE grade 1
- Administration of a live, attenuated vaccine within 4 weeks before cycle 1 day 1 or
anticipation that such a vaccine will be required during the study
- Treatment with systemic immunosuppressive medications (including but not limited to
interferons, IL-2) within 28 days or 5 half-lives of the drug, whichever is longer,
prior to randomization.
- Treatment with systemic immunosuppressive medications (including but not limited to
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis [anti-TNF] factor agents) within 14 days prior to screening or anticipation
of need for systemic immunosuppressive medications during the study
- Patients with prior allogeneic stem cell or solid organ transplantation
- Active or history of autoimmune disease or immune deficiency, including but not
limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or
multiple sclerosis with the following exceptions:
- Patients with a history of autoimmune-related hypothyroidism on a stable dose of
thyroid replacement hormone may be eligible for this study.
- Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin
regimen may be eligible for this study.
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are permitted provided all of following conditions are met: Rash must
cover < 10% of body surface area; Disease is well controlled at baseline and
requires only low-potency topical corticosteroids; No occurrence of acute
exacerbations of the underlying condition requiring psoralen plus ultraviolet A
radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors,
or high-potency or oral corticosteroids within the previous 12 months.
- 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.
- History of HIV infection, hepatitis B or hepatitis C infection.
- Patients with significant cardiovascular disease
- Patients with inadequate hematological and end-organ function
- Patients receiving therapeutic anti-coagulants
- Stage N3, as soon as 21 patients with stage N3 are randomized
