Tailoring NEOadjuvant Therapy in Hormone Receptor Positive, HER2 Negative, Luminal Breast Cancer.

Tailoring NEOadjuvant Therapy in Hormone Receptor Positive, HER2 Negative, Luminal Breast Cancer.

The aim of this prospective, randomized, multicenter, open-label, phase II study is to test if chemotherapy can be replaced by the combination of ribociclib plus letrozole as a neo-adjuvant therapy for patients with non-metastatic primary luminal breast cancer.

Based on Ki67 levels after two weeks of initial letrozole treatment in postmenopausal patients with hormone receptor positive, HER2 negative, stage II/III breast cancer, patients are either advised to continue letrozole treatment (if Ki67 <1%) or will be randomized between standard chemotherapy (AC-T) or ribociclib in combination with letrozole (if Ki67 ≥1%).

Inclusion Criteria:

• Postmenopausal women presenting with histological proven (core biopsy material) hormone receptor positive (ER≥50%, PR any), HER2 negative, stage II/ III breast cancer.
• Measurable disease (breast and/or lymph nodes)
• WHO 0-2
• Adequate bone marrow function (within 4 weeks prior to registration): WBC≥3.0x109/l, neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l
• Adequate liver function (within 4 weeks prior to registration): bilirubin ≤1.5 x upper limit of normal (UNL) range, ALAT and/or ASAT ≤2.5 x UNL, Alkaline Phosphatase ≤5 x UNL
• Adequate renal function (within 4 weeks prior to registration): the calculated creatinine clearance should be ≥50 ml/min
• Accessible for treatment and follow-up
• Written informed consent

Inclusion criteria randomization specific:

In order to be eligible to be randomized in this study, a subject must meet all of the following criteria:

• Registration in the NEOLBC trial before 2 weeks biopsy
• Use of letrozole
• Outcome central Ki67 determination in two weeks biopsy available.

Exclusion Criteria:

• Evidence of distant metastases (M1)

• Previous invasive breast cancer

• Prior chemotherapy, radiation therapy or hormonal therapy with the exception of patients who received letrozole ≤ 14 days (+ max. 4 days) prior to registration and who are still on letrozole.

• Previous malignancy within 5 years, with exception of a history of a previous basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix.

• Peripheral neuropathy > grade 2, whatever the cause

• Serious other diseases as infections (hepatitis B, C and HIV), recent myocardial infarction, clinical signs of cardiac failure or clinically significant arrhythmias or on screening, any of the following cardiac parameters: bradycardia (heart rate <50 at rest) or QTcF ≥450 msec.

• Known hypersensitivity reaction to any of the components of the treatment (peanuts, soy)

• Currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.

• Currently receiving any of the following substances and cannot be discontinued 7 days prior to randomisation:

  • Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelo's, star-fruit, pomegranate and Seville oranges.
  • That have a known risk to prolong the QT interval or induce Torsades de Pointes.
  • That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
  • Herbal preparations/medications, dietary supplements.

• Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent.