A Randomized, Phase II Study for Premenopausal Metastatic or Locally Advanced Breast Cancer Patients: Capivasertib, Goserelin, Fulvestrant With/Without Durvalumab, Versus Goserelin, Fulvestrant, and Durvalumab, Versus Goserelin/ Fulvestrant.
This is an open-label randomized phase II study in estrogen receptor positive locally advanced or metastatic breast cancer patients. The main inclusion population are either luminal subtype B by PAM50 analysis or failed less than 2 lines of hormonal therapy for locally advanced or metastatic breast cancer. The subjects have to be premenopausal or perimenopausal and are not allowed to receive any systemic chemotherapy for their locally advanced or metastatic breast cancer. Eligible subjects will be randomized into goserelin/ fulvestrant/ durvalumab (Arm A), goserelin/ fulvestrant/ capivasertib/ durvalumab (Arm B), or goserelin/ fulvestrant/ capivasertib (Arm C) at a 1:1:1 ratio. The primary endpoint is objective response rate (ORR) of the whole other three arm compared to historical goserelin/ fulvestrantcontrol arm. The major secondary endpoint will be progression-free survival or ORR compared among different treatment arms.
• A histological confirmed ER positive (\>1%) invasive breast cancer.
• Locally advanced or metastatic disease with at least one measurable target lesion
• Patients who had not received chemotherapy for locally advanced or metastatic disease
• Patients have to be (i) either primary resistant to hormonal therapy defined as recurrence developed within 2 years of adjuvant hormonal therapy (ii) or resistant to prior hormonal therapy (failed ≤ 2lines of hormonal therapy for locally advanced or metastatic breast cancer)
• Patients must be premenopausal or perimenopausal women according the clinical menstrual history or E2 / FSH level based on local hospital guidance. Patient with menopausal status cannot be determined due to ongoing LHRH agonist treatment is allowed if evidence of premenopausal status prior to patients' LHRH agonist usage can be provided.
• ECOG 0-1
• Patients must have adequate organ and marrow reserve measured within 14 days(within screening period ) prior to randomization as defined below:
‣ Hemoglobin ≥ 9.0 g/dL;
⁃ Absolute neutrophil count ≥ 1,500 /L;
⁃ Platelets ≥ 100,000/L;
⁃ Total bilirubin ≤ 1.5 x upper normal limit;
⁃ AST(SGOT)/ALT(SGPT) ≤ 2.5 x upper normal limit; for patients with liver metastases AST(SGOT)/ALT(SGPT) ≤ 5 x upper normal limit is allowed;
⁃ Serum creatinine ≤ 1.5mg/dL or creatinine clearance ≧50ml/min;
⁃ aPTT \< 1.5 x upper normal limit (unless on therapeutic anti-coagulation);
⁃ Proteinuria ≤ 1+ with urine dipstick, if \> 1+, 24-hour urine protein must be ≤ 1 g.
• Age older than 20-year-old.
• All women of childbearing potential must have a negative pregnancy test obtained within 7 days before starting therapy. Patients must not be breastfeeding.
⁃ Patients with reproductive potential must use effective contraception (hormone or barrier method of birth control) prior to study entry, for the duration of study participation, and for 6 months after the completion of therapy.
⁃ Patients (or a surrogate) must be able to comply with study procedures and to give signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the clinical study protocol (CSP). The patients (or a surrogate) must be able to provide of signed and dated written ICF prior to any mandatory study specific procedures, sampling, and analyses.
⁃ Body weight \>30 kg