None listed
Conditions
Brief summary
This study aims to find out whether treatment with alpelisib plus fulvestrant increases progression-free survival compared to capecitabine in women and men with eostrogen receptor positive (ER+), HER2-negative advanced breast cancer who have a PIKC3A mutation identified in circulating tumour DNA (ctDNA). Who is it for? This study may be suitable for you if you are 18 years or older, have advanced ER+, HER2-negative breast cancer, and have already had treatment with a CDK4/6 inhibitor and an aromatase inhibitor. Potential participants will consent to a blood test to find out if the cancer has a PIK3CA mutation. This mutation occur in 35-40% of ER+ breast cancers and may make tumours more sensitive to treatments, such as alpelisib, that target the PI3K pathway (which is important for cell growth and survival). The PIKC3A gene mutation can be detected through a blood test for circulating tumour DNA. As a cancer grows, cancer cells die and are replaced by new ones. The dead cells get broken down and their contents, including DNA, go into the bloodstream. These very small pieces of DNA are called circulating tumour DNA (ctDNA). Trial Details If a PIK3CA mutation is identified, before being randomised, participants will have their health checked, medical history recorded, standard blood tests, and provide a tumour biopsy (either a new biopsy or provide material collected earlier). Participants will be randomised 1:1 to either: Arm A: alpelisib plus fulvestrant (clinic visits every 28 days) Arm B: capecitabine (clinic visits every 21 days) Participants on Arm A will take 1 alpelisib tablet per day with fulvestrant injected intramuscularly once every 28 days. Women who are pre- or perimenopausal will also have a goserelin implant inserted under their skin to stop their ovaries producing oestrogen. Participants on Arm B will take 1 capecitabine tablet twice per day on Days 1 to 14 of a 21 day cycle. All participants will be regularly monitored throughout treatment to evaluate their health. Tumours will be assessed by imaging (CT scan, Bone Scan, MRI or PET scan if clinically indicated) and as per RECIST 1.1 every 8 weeks during treatment. Treatment will continue until documented disease progression . The following biological samples will be collected: * Tumour samples of archived tissue or a new biopsy at screening (before first dose of study treatment); * Blood samples for ctDNA testing at pre-screening (to confirm eligibility), Cycle 1 Day 1, Cycle 1 Day 15 (Arm A only), at every cycle during treatment and the End of Treatment Visit. In the event of DNA extraction failure, a replacement blood sample may be requested from the participant. * Tissue collection at disease progression is suggested (optional). Participants will have their final visit 28 days after their last dose of study treatment. It is hoped this research will provide a new treatment option for people with incurable breast cancer.
Interventions
Alpelisib at a dose of 300 mg will be administered by oral tablet once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in combination with fulvestrant 500 mg intramuscular every 28 days.
Pre- or peri-menopausal women will also receive a 3.6 mg goserelin implant under the skin every 28 days.
Participants will be given a patient diary to monitor their alpelisib administration; the diary will be checked at each treatment visit.
Treatment will continue until one of the following c
Alpelisib at a dose of 300 mg will be administered by oral tablet once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in combination with fulvestrant 500 mg intramuscular every 28 days. Pre- or peri-menopausal women will also receive a 3.6 mg goserelin implant under the skin every 28 days. Participants will be given a patient diary to monitor their alpelisib administration; the diary will be checked at each treatment visit. Treatment will continue until one of the following criteria applies: * Documented disease progression#; * Intercurrent illness that prevents further administration of treatment; * Unacceptable adverse event(s) or toxicity; * Withdrawal of consent; * Investigator decision; * Protocol non-compliance. # Study treatment may continue after a restaging scan showing RECIST 1.1 progressive disease, if the investigator considers the participant to be experiencing ongoing clinical benefit, for up to 8 weeks or until confirmation of progressive disease on a subsequent staging scan (whichever comes first), after discussion with BCT and the Study Chairs. All participants who discontinue treatment for reasons other than disease progression will continue to be followed for documentation of progression by RECIST 1.1 until disease progression, death, withdrawal of consent, or loss to follow-up. If a participant starts a new antineoplastic treatment without withdrawing consent, the participant will continue to be followed until disease progression, death, withdrawal of consent or loss to follow-up.
Sponsors
Breast Cancer Trials
Study design
Allocation
Randomised controlled trial
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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: i. IHC 1+, as defined by incomplete membrane staining that is faint/barely perceptible and within > 10% of invasive tumour cells; OR ii. 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 iii. 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: i. 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; ii. 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. c. Renal Function; Creatinine Clearance >= 35 mL/min using Cockcroft-Gault formula; d. 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; e. Potassium within normal limits, or corrected with supplements; f. Blood Chemistry; i. Fasting plasma glucose (FPG) <= 6.0 mmol/L and Glycosylated Haemoglobin (HbA1c) <= 6.5% (both criteria have to be met); ii. Fasting Serum amylase <= 2 × ULN; iii. 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: i. Prior surgical bilateral oophorectomy; ii. Age >= 60 years; iii. 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.
Exclusion criteria
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.
Outcome results
None listed