Health Condition 1: null- The study will include approximately 560 men and postmenopausal women with HR postive, HER2-negative advanced breast cancer which progressed on or after AI treatment.
Conditions
Interventions
Intervention1: Alpelisib 300 mg p.o. Plus fulvestrant 500 mg i.m. administered orally once daily. A complete cycle of treatment is defined as 28 days (± 3 days) of once daily continuous
treatment of a
Sponsors
Novartis Healthcare Private Limited
Eligibility
Inclusion criteria
Inclusion criteria: 1. Patient is an adult = 18 years old at the time of informed consent and has signed informed consent before any trial related activities and according to local guidelines. 2. Patient has adequate tumor tissue for the analysis of PIK3CA mutational status by a Novartis designated laboratory. One new or recent biopsy(collected at screening if feasible) or archival tumor block or slides(15 slides minimum from a surgical specimen, 20 slides minimum from a biopsy) must be provided. it is recommended to provide a tumor sample collected after the most recent progression or recurrence. 3. Patient has identified PIK3CA status (mutant or non-mutant; determined by a Novartis designated laboratory). 4. If female, then the patient is postmenopausal. Postmenopausal status is defined either by: a. Prior bilateral oophorectomy b. Age less than or equal to 60 c. Age greater than 60 and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and Follicle-stimulating Hormone (FSH) and estradiol in the postmenopausal range per local normal range. 5. Patient has radiological or objective evidence of recurrence or progression. 6. Patient has a histologically and/or cytologically confirmed diagnosis of ER positive and/or PgR positive breast cancer by local laboratory. 7. Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1 positive or 2 positive.If IHC is 2 positive,a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing. 8. Patient has either: a. Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1 criteria (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation ) OR b. If no measurable disease is present, then at last one predominantly lytic bone lesion must be present (patients with no measurable disease and only one predominantly lytic bone lesion that has been previously irradiated are eligible if there is documented evidence of disease progression of the bone lesion after irradiation). 9. Patient has advanced (loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer. Patients may be: a.relapsed with documented evidence of progression while on or after completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease b.relapsed with documented evidence of progression more than 12 months from completion of adjuvant endocrine therapy and then subsequently progressed with documented evidence of progression after one line of endocrine therapy for metastatic disease c.newly diagnosed advanced breast cancer, then relapsed with documented evidence of progression while on or after one line of endocrine therapy. 10. Patient has recurrence or progression of disease during or after AI therapy (i.e. letrozole, anastrozole, exemestane). AI therapy does not need to be the latest treatment regimen. 11. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 12. Patient has adequate bone marrow and organ function as defined by the following <br/
Exclusion criteria
Exclusion criteria: 1. Patient with symptomatic visceral disease or any disease burden that makes the patientineligible for endocrine therapy per the investigator’s best judgment. 2. Patient has received prior treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant, any PI3K, mTOR or AKT inhibitor 3. Patient has a known hypersensitivity to alpelisib or fulvestrant, or to any of the excipients of alpelisib or fulvestrant. 4. Patient with inflammatory breast cancer at screening. 5. Patient is concurrently using other anti-cancer therapy. 6. Patient has had surgery within 14 days prior to starting study drug or has not recovered from major side effects. 7. Patient has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade less than or equal to 1. Exception to this criterion: patients with any grade of alopecia are allowed to enter the study. 8. Patients with Child pugh score B or C. 9. Patient has received radiotherapy less than or equal to 4 weeks or limited field radiation for palliation less than or equal to 2 weeks prior to randomization, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia) and/or from whom greater than or equal to 25percentage of the bone marrow was irradiated. 10. Patient has a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer. 11. Patients with an established diagnosis of diabetes mellitus type I or not controlled type II (based on FPG and HbA1c, see inclusion criterion 12) 12. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) 13. Patient has a known history of Human Immunodeficiency Virus (HIV) infection (testing not mandatory) 14. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, contraindicate patient participation in the clinical study (e.g chronic active hepatitis, severe hepatic impairment, etc.) 15. Patient has currently documented pneumonitis (the chest CT scan performed at baseline for the purpose of tumor assessment should be reviewed to confirm that there are no relevant pulmonary complications present). 16. Patient has 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 12 months prior to study entry b. History of documented congestive heart failure (New York Heart Association functional classification III-IV) c. Documented cardiomyopathy d.Patient has a Left Ventricular Ejection Fraction (LVEF) less than 50percentage as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) d.History of any cardiac arrhythmias, (e.g., ventricular tachycardia),complete left bundle block, high
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To determine whether treatment with alpelisib in combination with fulvestrant prolongs PFS compared to treatment with placebo in combination with fulvestrant for patients with PIK3CA mutant statusTimepoint: Time at which progression free survival is achieved. | — |
Secondary
| Measure | Time frame |
|---|---|
| To assess additional molecular alterations associated with response or resistance to treatmentTimepoint: Molecular analysis of tumor tissue and blood ctDNA such as but not limited to NGS, NanoString, IHC (tissue only) and association with clinical parameters such as OS, ORR, CBR;To characterize the pharmacokinetics (PK) of fulvestrant and alpelisib when given in combination with fulvestrantTimepoint: Summary statistics for PK: plasma concentration-time profiles of alpelisib given in combination with fulvestrant and appropriate individual PK parameters based on population PK model Summary statistics of fulvestrant trough plasma concentrations in each treatment arm (alpelisib/placebo);To describe time to response and duration of response in the two treatment arms and cohorts of interest.Timepoint: Time to response and duration of response in each of the PIK3CA mutant and non-mutant cohorts;To determine whether treatment with alpelisib in combination with fulvestrant prolongs overall survival (OS) compared to treatment with placebo in combination with fulvestrant for patients with PIK3CA mutant statusTimepoint: OS in the PIK3CA mutant cohorts. Time-point is overall survival of patient.;to establish proof of concept of treatment benefit with alpelisib in combination with fulvestrant with respect to PFS for patients with PIK3CA non-mutant statusTimepoint: PFS based on local radiology assessments and using RECIST 1.1 criteria in the PIK3CA non mutant cohort;To evaluate change in global health status/QOL in the two treatment arms and cohorts of interestTimepoint: - Time to 10% deterioration in the global health status/QOL scale score of the EORTC QLQ-C30 - Change from baseline in the global health status/QOL scale score of the EORTC QLQ-C30 in each of the PIK3CA mutant and non-mutant cohorts;To evaluate the association between PIK3CA mutation status as measured in ctDNA at baseline with PFS upon treatment with alpelisib.Timepoint: PFS based on local radio | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czech Republic, Denmark, France, Germany, Greece, Hong Kong, India, Israel, Italy, Japan, Lebanon, Mexico, Netherlands, Peru, Portugal, Republic of Korea, Romania, Russian Federation, Singapore, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey, United Arab Emirates, United Kingdom, United States of America
Contacts
Public ContactMurugananthan K
Novartis Healthcare Private Limited
Outcome results
None listed