CAPTURE / BCT 1901

PRE-SCREENING: For inclusion in the pre-screening, participants must fulfil all the following criteria:

1) Female or Male, >= 18 years.

2) Advanced (locoregionally recurrent not amenable to curative therapy, or metastatic) ER-positive, HER2-negative breast cancer, histologically defined as:
|— a) ER positive: Locally assessed oestrogen receptor status based on assessment of primary or metastatic disease. ER-positive is defined as >=10% (any PR expression) by immunohistochemistry irrespective of staining intensity.
|— b) HER2 negative:
|— — ~) IHC 1+, as defined by incomplete membrane staining that is faint/barely perceptible and within > 10% of invasive tumour cells; OR
|— — ~) IHC 0, as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within <= 10% of the invasive tumour cells; OR
|— — ~) ISH (FISH or SISH) negative based on:
|— — — ~) Single-probe average HER2 copy number < 4.0 signals/cell, OR
|— — — ~) Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell.

3) ECOG performance status of 0–1.

4) No more than two prior lines of endocrine therapy for treatment of advanced disease setting (no prior fulvestrant).

5) No more than one line of chemotherapy for treatment of advanced breast cancer (no prior capecitabine).

RANDOMISATION: In addition to the above listed pre-screening inclusion criteria, participants must fulfil all of the following criteria prior to randomisation:

1) PIK3CA mutation (PIK3CA E542K, E545K, H1047L or H1047R mutation) identified through ctDNA testing.

2) Progression of disease during or after CDK4/6 inhibitor (i.e. ribociclib, palbociclib, abemaciclib) AND AI therapy (i.e. letrozole, anastrozole, exemestane) in the (neo) adjuvant OR advanced disease setting.

3) Evaluable disease (i.e. at least one measurable or non-measurable lesion as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

4) Adequate organ function:
|— a) Haematology: Absolute neutrophil count >= 1.5 × 10^9/L, Platelets >= 90 × 10^9/L, Haemoglobin >= 9.0 g/dL
|— b) Hepatic Function:
|— — ~) In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2.5 × ULN. If the participant has liver metastases, ALT and AST <= 5 × ULN. In addition, the elevated ALT or AST values must be stable for 2 weeks without evidence of biliary obstruction by imaging;
|— — ~) Total bilirubin < 2 x ULN (any elevated bilirubin should be asymptomatic at screening)except for participants with Gilbert’s syndrome who may only be included if the total bilirubin is <= 3.0 × ULN or direct bilirubin <= 1.5 × ULN.
|— — ~) Renal Function; Creatinine Clearance >= 35 mL/min using Cockcroft-Gault formula;
|— — ~) Calcium (corrected for serum albumin) and magnesium with normal limits or <= Grade 1 according to NCI-CTCAE V5.0 if judged clinically not significant by the investigator;
|— — ~) Potassium within normal limits, or corrected with supplements;
|— — ~) Blood Chemistry;
|— — — ~) Fasting plasma glucose (FPG) <= 6.0 mmol/L and Glycosylated Haemoglobin (HbA1c) <= 6.5% (both criteria have to be met);
|— — — ~) Fasting Serum amylase <= 2 × ULN;
|— — — ~) Fasting Serum lipase <= ULN.

5) Participants with metastatic CNS tumours may participate in this study if they are:
|— a) Four weeks from completion of prior therapy for CNS disease (including radiation and surgery) to starting study treatment;
|— b) Clinically stable with respect to the CNS tumour at the time of screening as determined by clinical examination and brain imaging (MRI or CT);
|— c) Not receiving steroid therapy at commencement of study treatment.

6) Female participants must have confirmation of menopausal status.
|— a) Participants assigned fulvestrant should be functionally postmenopausal. Pre- or peri-menopausal women can be enrolled if amenable to be treated with goserelin.
|— b) Female participants will be clinically defined as pre- or peri-menopausal unless one of the following criteria is met for the definition of postmenopausal:
|— — ~) Prior surgical bilateral oophorectomy;
|— — ~) Age >= 60 years;
|— — ~) Age 50 to 59 years with oestradiol, FSH and LH levels within the laboratory’s reference range for postmenopausal females (in the absence of ovarian suppression).
N.B. Female participants < 50 years will be considered pre- or peri-menopausal regardless of oestradiol, FSH and LH levels. This is because of the difficulties in ascertaining if menopause is permanent in women, particularly in those < 50 years, who have received prior chemotherapy and/or GnRH agonists and/or oral endocrine therapy.

13) Signed informed consent and is willing and able to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations;
|— a) Must also consent for donation of archival diagnostic tumour specimens, if available, for further correlative science research as specified in the protocol and Participant Information Sheet and Consent Form.

1) Any disease burden that makes participants ineligible for endocrine therapy as per the investigator’s best judgement.

2) Prior treatment with capecitabine, fulvestrant, any PI3K, mTOR or AKT inhibitor.

3) Known hypersensitivity or contra-indication to alpelisib, fulvestrant or capecitabine.

4) Concurrently using other anti-cancer therapy. Exception: goserelin.

5) Previous or concomitant invasive malignancy. The exceptions are:
|— a) participants with non-breast malignancy >= 3 years ago, treated with curative intent and without evidence of recurrence;
|— b) basal or squamous cell carcinoma of the skin or non-melanomatous skin cancer;
|— c) in situ carcinoma without invasion (includes in situ breast carcinoma);
|— d) curatively resected cervical cancer.

6) Radiotherapy <= 2 weeks prior to randomisation, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia).

7) Prior endocrine therapy <= 2 weeks prior to randomisation. Exception: goserelin.

8) Prior chemotherapy <= 2 weeks prior to randomisation.

9) Surgery <= 2 weeks prior to randomisation or has not recovered from major side effects.

10) Not recovered from all toxicities related to prior anticancer therapy to NCI-CTCAE V5.0 Grade <= 1. Exception: patients with any grade of alopecia or menopausal symptoms.

11) Participation in a prior investigational study within 30 days prior to the start of study treatment or within 5 half-lives of the investigational product, whichever is longer.

12) Established diagnosis of type I diabetes mellitus, type II diabetes mellitus requiring anti-hyperglycaemic medication or any participant with HbA1c > 6.5%.

13) Currently documented pneumonitis/interstitial lung disease.

14) Child Pugh score B or C.

15) Clinically significant, uncontrolled heart disease and/or recent cardiac events including any of the following:
|— a) History of angina pectoris, coronary artery bypass graft (CABG), symptomatic pericarditis, or myocardial infarction within 6 months prior to the start of study treatment;
|— b) History of documented congestive heart failure (New York Heart Association functional classification III-IV);
|— c) Left Ventricular Ejection Fraction (LVEF) < 50% as determined by echocardiogram (ECHO); |—
|— d) Clinically significant cardiac arrhythmias, (e.g. ventricular tachycardia), complete left bundle branch block, high grade AV block (e.g. bifascicular block, Mobitz type II and third degree AV block without pacemaker in place);
|— e) Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) >= 160 mmHg and/or Diastolic Blood Pressure (DBP) >= 100 mm Hg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening;
|— f) Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or corrected QT interval > 470msec at screening (using Fridericia correction);
|— g) Bradycardia (heart rate < 50 at rest), by ECG or pulse.

16) History of acute pancreatitis within 1 year of screening or a past medical history of chronic pancreatitis.

17) Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs based on investigator discretion.

18) Known history of Human Immunodeficiency Virus (HIV) infection (testing not mandatory).

19) Other non-malignant systemic diseases (cardiovascular, renal, hepatic, lung, etc.) that would prevent prolonged follow-up.

20) Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, lung disease, liver disease, serious chronic gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent.

21) Currently receiving any of the following medications and cannot be discontinued 7 days prior to randomisation:
|— a) Strong inducers of CYP3A4;
|— b) Inhibitors of Breast Cancer Resistance Protein (BCRP).

22) Unresolved osteonecrosis of the jaw.

23) History of Stevens-Johnson-Syndrome (SJS), Erythema Multiforme (EM), or Toxic Epidermal Necrolysis (TEN).

24) Currently receiving or has received systemic corticosteroids <= 2 weeks prior to randomisation, or who has not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airways disease), eye drops or local injections (e.g. intra-articular).

25) Pregnant or lactating at the time of randomisation. A pregnancy test is recommended for women of child-bearing potential who are sexually active and not using reliable contraceptive methods.

26) Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 6 months after stopping the study treatment. Highly effective contraception methods include:
|— a) Total abstinence;
|— b) Female sterilisation (bilateral oophorectomy, total hysterectomy or tubal ligation at least 6 weeks prior to screening);
|— c) Male partner sterilisation (at least 6 months prior to screening) if the sole partner of a female participant on the study.
|— d) Copper (non-hormonal) intra-uterine device (IUD).

27) Sexually active males unless they are sterilized (at least 6 months prior to screening) or use a condom during intercourse while taking drug and for at least 6 months after stopping alpelisib and/or Fulvestrant medication and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. In addition, male participants must not donate sperm during study and up to the time period specified above.

28) Not able to understand and to comply with study instructions and requirements.

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