Phase Ib/III Study of Capivasertib + CDK4/6 Inhibitors + Fulvestrant as Treatment for Advanced/Metastatic HR+/HER2-Breast Cancer (CAPItello-292)

Recruitment & Eligibility

Status: Recruiting

Sex: All

Target Recruitment: 629

Inclusion Criteria

Key inclusion criteria for both phases: 1. Adult females (pre- and post-menopausal), and adult males. 2. Histologically confirmed HR+/ HER2- breast cancer determined from the most recent tumour sample (primary or metastatic) per the American Society of Clinical Oncology and College of American Pathologists guideline. To fulfil the requirement of HR+ disease, a breast cancer must express ER with or without co-expression of progesterone receptor. 3. Eligible for fulvestrant therapy and at least one of the following: palbociclib, ribociclib, or abemaciclib, as per local investigator assessment. Previous tolerance to specific CDK4/6 inhibitors and dose levels required. 4. Adequate organ and bone marrow functions. 5. Consent to provide a mandatory FFPE tumour sample., Inclusion criteria only for phase III: 1. Previous treatment with an (neo)adjuvant ET (tamoxifen, AI, or oral SERD) as a single agent or in combination, with radiological evidence of breast cancer recurrence or progression while on, or within 12 months of, completing a (neo)adjuvant ET regimen 2. Received up to a maximum of 1 lines of prior chemotherapy in the advanced setting.

Exclusion Criteria

Key exclusion criteria for both phases: 1. 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. 2. Radiotherapy within 2 weeks prior to study treatment initiation. 3. Major surgery within 4 weeks of the first dose of study treatment. 4. Persistent toxicities (CTCAE Grade >1) caused by previous anticancer therapy, excluding alopecia. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss or peripheral sensory neuropathy) after consultation with the AstraZeneca study physician. 5. Spinal cord compression, brain metastases or leptomeningeal metastases unless these lesions are definitively treated (eg. radiotherapy, surgery) and clinically stable off steroids for management of symptoms for at least 4 weeks prior to study treatment initiation. 6. Any of the following cardiac criteria at screening: (a). Mean resting corrected QT interval (QTcF): (i) Palbociclib arm: QTcF = 470 ms obtained from the average of 3 consecutive (triplicate) ECGs (ii) Phase Ib only: Ribociclib arm: QTcF = 450 ms obtained from the average of 3 consecutive (triplicate) ECGs (iii) Phase Ib only: Abemaciclib arm: QTcF = 470 ms obtained from the average of 3 consecutive (triplicate) ECGs (b). Any clinically important abnormalities in cardiac rhythm, conduction or morphology of resting ECG (c). Any factors that increase the risk of QTc prolongation or risk of arrhythmic events (d). Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, unstable angina pectoris, congestive heart failure New York Heart Association (NYHA) grade = 2 (e). Uncontrolled hypotension or uncontrolled hypertension (f). Cardiac ejection fraction outside institutional range of normal or < 50% (whichever is higher) (g). uncontrolled or high grade or symptomatic arrhythmia and atrial fibrillation 7. Any of these clinically significant abnormalities of glucose metabolism at screening: (a). diabetes mellitus type I or type II requiring insulin treatment (b). HbA1c = 8.0% (63.9 mmol/mol) 8. Previous allogeneic bone marrow transplant or solid organ transplant., Key exclusion criteria for the phase III only: 1. Any prior treatment with SERDs, AKT, PI3K or mTOR inhibitors. Any line of endocrine-based therapy for inoperable locally advanced or metastatic disease. 2. Prior treatment with CDK4/6 inhibitors in the metastatic setting (prior CDK4/6 inhibitors permitted in the adjuvant setting provided there was a CDK4/6i treatment free interval of at least 12 months). 3. More than 1 line of chemotherapy for metastatic disease

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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