Study to Compare a Mono Atezolizumab Window Followed by a Atezolizumab - CTX Therapy With Atezolizumab - CTX Therapy

An Adaptive Randomized Neoadjuvant Two Arm Trial in Triple-negative Breast Cancer Comparing a Mono Atezolizumab Window Followed by a Atezolizumab - CTX Therapy With Atezolizumab - CTX Therapy (neoMono)

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

This is a randomized, open-label, adaptive, two arm, multicenter phase II trial that enrolled female and male patients with primary TNBC (defined as ER/PR < 10% and HER2-negative) with tumor stages cT1c - cT4d (cN0 and cN+). Patients are randomized to Arm A and B. Randomization is stratified by PD-L1 expression on immune cells (IC-status) and anatomic tumor stage (according to the AJCC 8th edition Anatomic Stage Groups I, II andIII). PD-L1 status is determined by central pathology using the VENTANA PD-L1 (SP142) assay and is defined by PD-L1 IC expression.

Patients in Arm A receive a 2-week monotherapy of Atezolizumab 840 mg q2w prior to initiation of a 12-week neoadjuvant CTX therapy with Paclitaxel 80 mg/m2 i.v. q1w x 12 doses + Carboplatin AUC of 2 i.v. q1w x 12 doses + Atezolizumab 1200 mg day 1 every 3 weeks for 4 doses followed by Epirubicin 90 mg/m2 + Cyclophosphamide 600 mg/m2, both q3w for 4 cycles + Atezolizumab 1200 mg day 1 every 3 weeks for 4 doses.

Patients in Arm B are treated with a neoadjuvant 12-week regimen of Paclitaxel 80 mg/m² i.v. q1w x 12 doses + Carboplatin AUC of 2 i.v. q1w x 12 doses + Atezolizumab 1200 mg day 1 every 3 weeks for 4 doses without a monotherapy window. This is followed by Epirubicin 90 mg/m² + Cyclophosphamide 600 mg/m2, both q3w for 4 cycles + Atezolizumab 1200 mg day 1 every 3 weeks for 4 doses.

Patients in both arms undergo surgery after 29 - 30 weeks therapy in total for Arm A and 27 - 28 weeks therapy in total for Arm B (3 - 4 weeks after last dose of neoadjuvant therapy).

Safety and toxicities under therapy are supervised via regular DSMB meetings. After surgery, patients are treated according to the local SoC therapy for TNBC and followed-up for 24 months.

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 Eastern Cooperative Oncology Group (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
  • vasectomized partner
  • sexual abstinence

• The patient must be accessible for treatment and follow-up

• Normal cardiac function:

  • Normal electrocardiogram (ECG) (within 6 weeks prior to screening)
  • Normal left ventricular ejection fraction (LVEF) on echocardiorgraphy

• Normal thyroid function

  o Normal TSH and FT4

• Blood counts within 14 days prior screening:

  • absolute neutrophile count (ANC) must be ≥ 1,500/mm3
  • Platelet count must be ≥ 100,000 / mm3
  • Hemoglobin must be ≥ 10 g/dl

• Hepatic functions:

  • Total bilirubin must be ≤ 1 upper limit of normal (ULN) for the lab unless the patient has a bilirubin elevation > 1 x 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 x ULN for the lab.
  • Patients with AST and ALT or alkaline phosphatase > 1 x ULN are eligible for inclusion if liver imaging (computerized tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET-CT, or PET scan) performed within 3 months prior to randomization (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 > 1 x 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 (except registry study) 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%, congestive heart failure (CHF) New York Heart Association (NYHA) classes II-IV),
  • unstable arrhythmias requiring treatment i.e., atrial tachycardia with a heart rate ≥ 100/bpm at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher grade 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 mmHg or diastolic > 100 mmHg).

• Inadequate organ function including but not confined to:

  • hepatic impairment as defined by bilirubin > 1.5 x ULN
  • pulmonary disease (severe dyspnea at rest requiring oxygen therapy)

• Abnormal blood values:

  • Platelet count below 100,000/mm3
  • AST/ALT > 1.5 x 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