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