Phase II Neoadjuvant Study Evaluating Capivasertib Plus Fulvestrant vs Fulvestrant in Patients With Primary High-risk Lobular Breast Cancer- LOBSTER
This is a multicenter, prospective, open-label, randomized phase II study to evaluate the CCCA assessed by Ki67 drop below \<2.7% from baseline to week 2 (window of opportunity) and to week 10 with capivasertib plus fulvestrant compared with fulvestrant alone as neoadjuvant treatment for primary high-risk lobular breast cancer patients. 120 patients will be randomized to receive: \- Capivasertib (400 mg po twice daily d1-4 followed by 3 days off) for 2 weeks followed by capivasertib (400 mg po twice daily d1-4 followed by 3 days off) and fulvestrant (500 mg i.m. q28d, with an additional 500 mg dose given two weeks after the initial dose) for additional 8 weeks (overall 4 administrations of fulvestrant) or \- Fulvestrant (500mg i.m. q28d, with an additional 500 mg dose given two weeks after the core biopsy and the initial dose) for 10 weeks (overall 4 administrations) Treatment will be given until surgery/core-biopsy, disease progression, unacceptable toxicity, or withdrawal of consent of the patient. All patients will undergo core-biopsies, under treatment and after completing study therapy in order to assess Ki67%. Further treatment including surgery, (neo)adjuvant chemotherapy, radiotherapy, and (neo)adjuvant endocrine therapy will be administered at the discretion of the investigator and according to standard of care outside the clinical trial.
• Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and followup, and documented according to the local regulatory requirements.
• Postmenopausal women with age at diagnosis ≥ 18 years.
• Postmenopausal status is defined as:
⁃ Age ≥60 years
⁃ Age \<60 years and amenorrhea for at least 12 continuous months with no identified cause other than menopause
⁃ Bilateral oophorectomy Negative pregnancy test (urine or serum) within 14 days prior to randomization for all postmenopausal women 50 years of age or younger without bilateral oophorectomy
• Unilateral or bilateral primary untreated lobular invasive carcinoma of the breast. In case of bilateral breast cancer, both sides must be lobular; the lead tumor has to be defined by the investigator based on the inclusion criteria for the respective subtype and the risk status. Lobular histology has to be centrally confirmed.
• Willingness and ability to provide archived formalin fixed paraffin embedded (FFPE) tissue block from core biopsy before the start of neoadjuvant therapy.
• Centrally confirmed HER2-negative (IHC score 0-1+ or ISH negative according to ASCO/CAP guideline) and HR-positive (≥10% positive stained cells) disease, assessed on the core of diagnostic biopsy. Ki67% \>10% is required. In case of bilateral breast cancer, HER2-negative, HR-positive and lobular histology status has to be confirmed for both sides.
• Patients with invasive lobular breast cancer at high risk for recurrence defined as cT1c and clinical nodal involvement (cN+) or ≥ cT2 disease (irrespective of nodal involvement).
• No clinical evidence of distant metastases.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
• Estimated life expectancy of at least 5 years irrespective of the diagnosis of breast cancer.
⁃ The patient must be accessible for scheduled visits, treatment, and followup.
⁃ Normal cardiac function must be confirmed according to local guidelines.
⁃ Laboratory requirements:
⁃ Hematology
‣ Absolute neutrophil count (ANC) ≥1.5 x 109 / L
‣ Platelets ≥100 x 109 / L
‣ Hemoglobin ≥10 g/dL (≥6.2 mmol/L) Hepatic function
‣ Total bilirubin \<1.25x ULN
‣ AST and ALT \<=1.5x ULN
‣ Alkaline phosphatase \<=2.5x ULN Glucose Metabolism
‣ HbA1c \<8.0% (63.9 mmol/mol) Renal Function
‣ Creatinine \<1.25x ULN or creatinine clearance ≥50 ml/min (if creatinine is above ULN according to Cockroft-Gault)
⁃ Complete staging work-up prior to the initiation of neoadjuvant therapy as per standard recommendations.