A Phase IIIB Study to Evaluate the Use of Capivasertib in Combination With Fulvestrant in Patients With Advanced Breast Cancer Who Have Relapsed/Progressed on ET and CDK4/6 Inhibitor Reflecting Real World Clinical Practice in Spain

Prior treatment

• History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥2 years before the first dose of study intervention and of low potential risk for recurrence.
• Unresolved toxicities from prior therapy greater than CTCAE grade 1.
• Leptomeningeal metastases or symptomatic, unstable, or steroid-dependent brain metastases.
• Previous allogenic bone marrow or solid organ transplant.
• Prior/concomitant therapy:
• More than 1 line of chemotherapy for inoperable locally advanced or metastatic disease. Adjuvant and neoadjuvant chemotherapy are not classed as lines of chemotherapy for ABC.
  • AKT1, PIK3CA and mTOR inhibitors not allowed.
  • Adequate washout or dose reduction may be required for some CYP3A.
  • Participation in another clinical study with a study intervention.

Other illness

• Disease burden making the patient ineligible for endocrine therapy per the investigator judgement.
• Severe or uncontrolled systemic diseases, uncontrolled hypertension, active infections including hepatitis B, hepatitis C, HIV, and confirmed COVID-19.
• Refractory nausea, vomiting, malabsorption syndrome, chronic gastrointestinal diseases, inability to swallow formulated product, or significant bowel resection.
• Known immunodeficiency syndrome.
• Evidence of dementia altered mental status or any psychiatric condition.
• More than 2 lines of endocrine therapy or in combination with CDK4/6i for inoperable locally advanced or metastatic disease.

Lab values

• HbA1c ≥8.0% (63.9 mmol/mol).
• Participants with significant QT interval prolongation or a history of related cardiac conditions, including arrhythmias or recent cardiac procedures.

Other

• Inadequate bone marrow reserve or organ function.
• Known abnormalities in coagulation.
• Unknown or non-altered PIK3CA/AKT1/PTEN-status.
• Pregnant women.

• Histologically confirmed HR+/HER2- breast cancer (primary or metastatic):
• HR+ defined as ER+ with or without PRg+
• HER2- defined as IHC 0 or 1+, or IHC 2+/ISH-
  • Patient with tumours harbouring at least one PIK3CA/AKT1/PTEN qualifying alteration detected by a validated test (including NGS on tissue, cell block, or if tissue/cell block is not available, on ctDNA, as per protocol requirements. If alteration is initially detected by a method other than NGS, NGS on tissue/cell block must be performed within 45 days unless not available, which must be documented.)
  • Metastatic or locally advanced disease with radiological or objective evidence of recurrence or progression.
  • Patients must have received treatment with an ET in combination with CDK4/6i and have:
• Radiological evidence of breast cancer recurrence or progression while on, or within 12 months of the end of (neo)adjuvant treatment with an ET with CDK4/6i, OR
• Radiological evidence of progression while on prior ET with CDK4/6i administered as a treatment line for locally advanced or metastatic breast cancer.
  • Informed consent
  • Eastern Cooperative Oncology Group (ECOG)/ World Health Organisation (WHO) performance status ≤ 2 at enrollment (not more than 20% of patients with ECOG PS2 will be allowed).
  • Reproduction:
• Women of childbearing potential (WOCBP) patients with ovarian suppression induced by LHRH agonist should agree to use 2 forms of highly effective methods of accepted contraception to prevent pregnancy.
• Male patients should use barrier contraception.