Capivasertib+Fulvestrant asTreatment for Locally Advanced(Inoperable) or Metastatic HR+/HER2- Breast Cancer in Chinese Patients

This is a multi-center, two-cohorts, phase IIIb study of Capivasertib+Fulvestrant in HR+/HER2-ABC who had disease recurrence/progression following 1-2L endocrine therapy.

The Primary objective is to assess the efficacy of capi+ful by assessment of TFST (Time to first subsequent treatment) in cohort1.

This study will enroll 560 patients in 2 cohorts . Cohort1 will include patients without prior fulvestrant treated and Cohort2 will include patients who received fulvestrant as the first-line treatment and progression ≥6 months after the first dosing of fulvestrant. Approximately 400 patients will be enrolled in Cohort1 and 160 patients will be enrolled in Cohort2.

All patients will receive weekly capivasertib (400 mg, oral, twice daily; 4 days on and 3 days off) and fulvestrant (at the approved dose regimen \[500 mg intramuscular injections on Day 1 of Weeks 1 and 3 of Cycle 1, and then on Day 1, Week 1 of each cycle thereafter\]). All patients will attend a screening visit a maximum of 28 days prior to the start of study treatment.

Eligibility Criteria:
Inclusion Criteria:

1. Adult females, pre- and/or post-menopausal, and adult males - Pre-menopausal (and peri-menopausal i.e., those that do not meet the criteria for post-menopausal defined below) women can be enrolled if amenable to treatment with an LHRH agonist.
2. Histologically confirmed HR+/HER2- breast cancer determined from the most recent tumour sample (primary or metastatic), as per the American Society of Clinical Oncology and College of American Pathologists guideline recommendations. To fulfil the requirement of HR+ disease, a breast cancer must express ER with or without co-expression of progesterone receptor.
3. Metastatic or locally advanced disease with radiological or objective evidence of progression;locally advanced disease must not be amenable to resection with curative intent (patients who are considered suitable for surgical or ablative techniques following potential down-staging with study treatment are not eligible)
4. Patients are to have received treatment with an endocrine therapy containing regimen (single agent or in combination) and have: (a) Radiological evidence of breast cancer progression during previous hormone-therapy in the context of locally advanced or metastatic disease or (b) as progression during or within 12 months after the end of treatment with a neoadjuvant or adjuvant endocrine therapy.

3. Patients must have at least 1 measurable lesion. 4.Patients must be eligible for fulvestrant therapy as per local investigator assessment.

5. Consent to submit and provide a mandatory FFPE tumour sample for central testing.

6.Patients must be able to swallow and retain oral medication. 7.Eastern Cooperative Oncology Group (ECOG)/ World Health Organisation (WHO) performance status 0 or 1 and life expectancy of ≥12 weeks.

Exclusion Criteria

1. A disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgement.
2. 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. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease. Radiotherapy within 2 weeks prior to the first dose of study intervention. Major surgery (excluding placement of vascular access) within 4 weeks prior to study treatment initiation.
3. With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment
4. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids within 4 weeks prior to study treatment initiation
5. Leptomeningeal metastases
6. Active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
7. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
8. Any of the following cardiac criteria:

   * Mean resting QT interval corrected by Fridericia's formula (QTcF) \>470 msec obtained from 3 consecutive ECGs
   * History of QT prolongation associated with other medications that required discontinuation of that medication. - Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block)
   * Medical history significant for arrhythmia (e.g., multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted to enter the study based on the Investigator judgement with cardiologist consultation recommended.
   * Any factors that increase the risk of corrected QT interval (QTc) prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, potential for Torsades de pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
   * Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, myocardial infarction, unstable angina pectoris,
   * Congestive heart failure New York Heart Association (NYHA) grade ≥2
9. Clinically significant abnormalities of glucose metabolism defined as HbA1c ≥8.0% (63.9 mmol/mol) at screening
10. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

    1. Absolute neutrophil count \<1.5 × 109/L
    2. Platelet count \<100 × 109/L
    3. Haemoglobin \<9 g/dL (\<5.59 mmol/L). \[NOTE: any blood transfusion must be \>14 days prior to the determination of a haemoglobin ≥9 g/dL (≥5.59 mmol/L)\]
    4. Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) \>2.5 times upper limit of normal (ULN) if no demonstrable liver metastases or \>5 × ULN in the presence of liver metastases
    5. Total bilirubin \>1.5 × ULN (Patients with confirmed Gilbert's syndrome may be included in the study)
    6. Creatinine \>1.5 × ULN concurrent with creatinine clearance \<50 mL/min (measured or calculated by Cockcroft and Gault formula (using actual body weight) without the need for chronic dialysis therapy.
11. As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, or active infection.
12. Known HIV infection that is not well controlled.
13. Known active hepatitis B or C infection, positive hepatitis C antibody, positive hepatitis B virus surface antigen. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients receiving antiretroviral therapies which are strong inhibitors or inducers of CYP3A4 will be excluded due to the potential for drug-drug interaction with capivasertib as per Table 19 Drug Interactions that affect Capivasertib.
14. Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant or LHRH agonist (if applicable)
15. Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection, or other condition that would preclude adequate absorption of capivasertib
16. Previous allogenic bone marrow or solid organ transplant
17. Known immunodeficiency syndrome
18. History of hypersensitivity to active or inactive excipients of capivasertib, fulvestrant and LHRH agonists .
19. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
20. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
21. More than 2 lines of endocrine therapy for inoperable locally advanced or metastatic disease in Cohort 1; More than 1 lines endocrine therapy for inoperable locally advanced or metastatic disease in Cohort2.

    For Cohort 2, Patients must receive fulvestrant as the first-line treatment and progression \<6 months after the first dosing of fulvestrant.
22. 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.
23. Prior treatment with any of the following:

    * AKT, PI3K and mTOR inhibitors
    * Fulvestrant, and other SERDs in Cohort1
    * Nitrosourea or mitomycin C within 6 weeks prior to study treatment initiation
    * Any other chemotherapy, immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents within 3 weeks prior to study treatment initiation. A longer washout period may be required for drugs with a long half-life (e.g., biologics) as agreed by the sponsor
    * Systemic therapy: Prior exposure to any chemotherapy or anti-cancer agents other than those specified in the protocol without appropriate washout period before randomization/enrolment, for example, randomisation within 3 half-lives of a small molecule anti-cancer agent, or within 4 weeks for any antibody-based anticancer agents.
    * Potent inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose of study treatment (3 weeks for St John's wort) or drugs that are sensitive to CYP3A4 inhibition within 1 week prior to study treatment initiation.
    * Any concomitant medication that may interfere with fulvestrant safety and efficacy based on the prescribing information of fulvestrant and local clinical guidelines.
24. Participation in another clinical study with a non-marketed investigational medicinal product (IMP) administered in the last 30 days or 5 half-lives, whichever is longer.
25. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
26. Pregnant women (confirmed with positive pregnancy test) or breast-feeding women or woman who are planning to become pregnant.