Fulvestrant and Ipatasertib for Advanced HER-2 Negative and Estrogen Receptor Positive (ER+) Breast Cancer Following Progression on First Line CDK 4/6 Inhibitor and Aromatase Inhibitor

Inclusion Criteria: * Histologically and/or cytologically confirmed ER positive, HER-2 negative breast cancer * Female patients must be post-menopausal; female patients who are pre-menopausal must have ovarian suppression using LHRH agonist while on study * Clinical and/or radiographic progression during treatment with or within 28 days after discontinuation of first line of treatment with a CDK 4/6 inhibitor and an aromatase inhibitor (AI) for advanced/metastatic disease * Evidence of clinically and/or radiologically documented disease * ≥ 18 years of age * ECOG performance status of 0 or 1 * No concurrent anti-cancer therapy and must satisfy the following criteria for previous therapy * Must not have received more than one prior line of treatment with a CDK 4/6 inhibitor and an AI in the advanced disease setting. * Treatment with CDK 4/6 inhibitor and AI must have been the most recent treatment prior to registration for this study * Adequate hematology and organ function, in the absence of growth factors * Absolute neutrophils \> 1.5 x 10\^9/L * Platelets ≥ 100 x 10\^9/L * Hemoglobin \> 90 g/L * Total Bilirubin ≤ 1.5 x ULN (upper limit of normal) or ≤ 3 x ULN if confirmed Gilbert's Syndrome * ALT and AST ≤ 2.5 x ULN (or ≤ 5.0 x ULN if liver or bone metastasis) * Alkaline phosphatase ≤ 2.0 x ULN (or ≤ 5.0 x ULN if liver metastases, ≤ 7.0 x ULN if bone metastasis) * Fasting glucose ≤ 8.3 mmol/L * HbA1c ≤ 7.5% * Serum albumin ≥ 30 g/L * INR ≤ 1.2 * Serum Creatinine or Creatinine clearance ≤ 1.5 x ULN or ≥ 50 mL/min; measured directly by 24-hour urine sampling or as calculated by Crockcroft and Gault equation Exclusion Criteria: * Untreated or symptomatic CNS metastases, radiation treatment for CNS metastases within 28 days * Active inflammatory bowel disease, bowel inflammation, inability to swallow oral medication or GI condition that alters oral absorption * Prior treatment with fulvestrant, selective estrogen receptor degraders (SERDs) or known inhibitors of the PI3K pathway including PI3K inhibitors, AKT inhibitors, or mTOR inhibitors * Mean QT interval corrected for heart rate (QTc) ≥ 480 msec by ECG or history of familial long QT syndrome * Active or uncontrolled infections or serious illnesses or medical conditions * Clinically significant liver diseases * History of lung disease or history of opportunistic infections * Type 1 or Type 2 diabetes mellitus requiring insulin * Grade ≥ 2 uncontrolled hypercholesterolemia or hypertriglyceridemia * Known abnormalities in coagulation * History of hypersensitivity to the study drugs or components * Pregnant or lactating women