Study Evaluating Efficacy & Safety of Afuresertib Plus Fulvestrant in Patients w/ Locally Advanced or Metastatic HR+/HER2- Breast Cancer

Eligibility Criteria

• 1. Female or male patients must be ≥ 18 years of age on the day of signing the informed consent and be able to provide written informed consent for the study.
• 2. Patients with histologically or cytologically confirmed HR+/HER2- BC characterized by the absence of HER2 expression and the presence of ER and/or PR expression.
• 3. HR+/HER2- BC patients must meet all the following criteria to join this study:
• 1. Relapsed locally advanced (LABC) or metastatic (mBC) disease; AND
• 2. Have received 1 to 2 prior lines of systemic treatments for LABC or mBC(at least one line was ET).
• 4. For phase Ib part, patients must have at least one lesion that meets the definition of measurable disease by RECIST 1.1 criteria; for phase III, have measurable disease and/or at least 1 lytic or mixed (lytic + sclerotic) bone lesion that can be assessed by CT or MRI; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible.
• 5. In the Phase Ib part, Patients must provide informed consent for the procedures and the tests for PIK3CA/AKT/PTEN alterations and ESR1 mutations. The biomarkers will be tested retrospectively by gene sequencing tests using archival tumor sample (preferably within 18 months/78 weeks) or from peripheral blood or from a tumor biopsy sample. Formalin-fixed, paraffin embedded (FFPE) tissue blocksare preferred. In phase III, blood sample is mandatory for this test.
• 6. In Phase III, subjects need to provide blood sample during the screening period for PIK3CA/AKT1/PTEN test, which will be conducted in the central laboratory. Only patients with PIK3CA/AKT1/PTEN alterations could include.
• 7. Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1.
• 8. Patients who have adequate organ function
• 9. Female patients of childbearing potential must have a negative pretreatment serum pregnancy test.
• 10. Female patients of childbearing potential must agree to use effective contraception from enrollment to 1 year after discontinuation from the last dose of this study treatment,
• 11. Patients who are able to swallow and retain oral medication and without gastrointestinal diseases to interfere with drug absorption.
• 12. Patients must have no contraindications to fulvestrant.
• 1. Patients who had a recent major surgery that required hospitalization for longer than 48 hours (\< 8 weeks from scheduled treatment starting date) or have used IV antibiotics for the treatment of systemic infection (\< 2 weeks from scheduled treatment starting date).
• 2. Patients who have additional known malignancies that are progressing or have required active treatments within 3 years of scheduled treatment starting date. (Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, that have undergone potentially curative therapy are not excluded).
• 3. Patients who have a history of seizure or conditions that may predispose them to seizure and require anti-epileptic medications, or patients who have brain arteriovenous malformation, or intracranial masses that are causing edema or clinical symptoms.
• 4. Patients who have known active CNS metastases and/or carcinomatous meningitis.
• 5. Patients who had prior treatment with fulvestrant or other selective estrogen receptor degraders (SERDs), or any PI3K/AKT/mTOR inhibitors, or any CDK4/6 inhibitors in phase I, II study.
• 6. Patients with QT interval corrected by the Frederica's correction formula (QTcF) \> 470 msec
• 7. Patients who have uncontrolled hypertension (systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg under anti-hypertensive treatment).
• 8. Patients with active Hepatitis B infection \[defined as HBsAg (+) and HBV-DNA ≥ 200 IU/ml (1000 copy/ml)\] or active Hepatitis C virus \[defined as HCV antibody positive and HCV RNA (qualitative) test positive\].
• 9. Patients with known HIV seropositivity
• 10. Patients who are receiving medications that are sensitive substrates of CYP3A4, OATP1B1, or BCRP with low therapeutic index.
• 11. Patients who are ineligible for endocrine therapy (e.g., visceral crisis, inflammatory breast cancer).