Clinical Trials

Inclusion Criteria:

• Written informed consent must be obtained prior to any screening procedures.
• Patient is an adult male or female ≥ 18 years old at the time of consent and has signed informed consent (ICF) before any trial related activities and according to local guidelines.
• Males or females with advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy.
• Patient has a histologically and/or cytologically confirmed diagnosis of ER+ and/or PgR+ breast cancer by local laboratory.
• Patient has a confirmed, HER2-negative aBC. HER2-negative defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing.
• Patient has PIK3CA mutation confirmed by a Novartis designated laboratory, in which adequate formalin-fixed paraffin-embedded tissue sections with > 10% tumor tissue must be provided. It is recommended to provide a tumor sample collected after the most recent progression or recurrence OR
• Patient has a pathology report confirming PIK3CA mutant status by a certified laboratory using a validated PIK3CA mutation assay (either from tissue or blood). It is also mandatory to provide a tumor sample (either archival or newly obtained) for PIK3CA mutation confirmation by a Novartis designated laboratory. It is recommended the tumor sample is collected after the most recent progression or recurrence.
• In case of women, both premenopausal and postmenopausal patients are allowed to be included in this study; menopausal status is relevant for the requirement of goserelin or leuprolide to be used concomitantly with alpelisib in combination with fulvestrant or letrozole.
  • Patient is postmenopausal woman defined as either:
    • Prior bilateral oophorectomy; or
    • Age ≥ 60; or
    • Age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and/or estradiol in the postmenopausal range per local normal range.
    • If patient is taking tamoxifen or toremifene and age < 60, then FSH and plasma estradiol levels should be in post-menopausal range per local normal range.
      • Note: For women using therapy-induced amenorrhea other than ovarian radiation, goserelin or leuprolide, serial measurements (per local guidelines) of FSH and/or estradiol are needed to ensure menopausal status.
  • Patient is premenopausal defined as either:
    • Patient had last menstrual period within the last 12 months; OR
    • If on tamoxifen or toremifene with in the past 14 days, plasma estradiol and FSH must be in the premenopausal range per local normal range; OR 
    • In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the premenopausal range per local normal range.
      • Note: Throughout this document, peri-menopausal and pre-menopausal status is grouped together and referred as “Premenopausal.”
• Patients must have documented evidence of tumor progression on or after: 
  • CDK 4/6 inhibitor treatment as last treatment regimen in cohorts A and B;
  • AI treatment (either in adjuvant or metastatic setting) and received systemic chemotherapy or ET (monotherapy or combination except CDK 4/6i + AI) as last treatment regimen in cohort C:
    • Note, upon completion of enrollment of Cohort B, patients whose receive CDK4/6i+  Fulvestrant as immediate prior therapy are eligible for Cohort C.
  • No more than two (2) prior anti-cancer therapies for aBC. Each unique regimen or ‘line’ is defined as a single or combination of medications given for a new relapse/recurrence. Maintenance therapies, where applicable, must be regarded as part of the main treatment.
  • Received no more than one prior regimen of chemotherapy for the treatment of advanced/metastatic disease is permitted.
    • Note: Patients who received chemotherapy in (neo) adjuvant therapy for breast cancer are eligible.
  • Recovered to grade 1 or better from any adverse events (except alopecia or other toxicities not considered a safety risk for the patient at investigator’s discretion) related to previous anti-cancer therapy prior to study entry.
• Patients must have either:
  • Measurable disease; i.e., at least one measurable lesion as per RECIST v1.1 criteria.  (Tumor lesions previously irradiated or subjected to other locoregional therapy will only be considered measurable if disease progression at the treated site after completion of therapy is clearly documented); or
• If no measurable disease is present, then at least 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).
• Patient has adequate bone marrow and coagulation function as shown by the following laboratory values:
  • Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/L;
  • Platelets ≥ 100 x 10^9/L (For patients with lesions involving the bone marrow, platelet count  ≥ 75 x 10^9/L may be acceptable);
  • Hemoglobin ≥ 9.0 g/dL;
  • INR ≤ 1.5 (INR ≤ 2.0 will be allowed for those patients treated with vitamin K antagonist).
• Patient has adequate liver function as shown by:
  • In absence of liver metastases, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN or ≤ 5 x upper limit of normal (ULN) if hepatic metastases are present;
  • Total serum bilirubin < 2 x ULN (any elevated bilirubin should be asymptomatic at enrollment) except for patients with Gilbert’s syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN.
• Patient has adequate renal function:
  • Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 35 ml/min using Cockcroft-Fault formula.
• Patient has fasting plasma glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L) and glycosylated hemoglobin (HbA1c) ≤ 6.4% (both criteria have to be met).  *For patients with FPG ≥ 100 mg/dL and/or HbA1c ≥ 5.7% (i.e., threshold for pre-diabetes) at screening, recommend lifestyle changes according to ADA guidelines; i.e. dietary advice (e.g., small frequent meals, low carbohydrate content, high fiber, balancing carbohydrate intake over the course of the day, three small meals and 2 small snacks rather than one large meal) and exercise. A consultation with a diabetologist is highly
• recommended.
• Patient has potassium, magnesium and calcium (corrected for albumin), within normal limits (either by central or local lab), or ≤ Grade 1 severity according to NCI-CTCAE v4.03 if judged clinically not significant by the investigator, or correctable with supplements before entry of study; re-screen is allowed.
• Fasting serum amylase ≤ 2 × ULN.
• Fasting serum lipase ≤ ULN.
• Patient has ECOG (Eastern Cooperative Oncology Group) Performance Status ≤ 2.

Exclusion Criteria:

• Patient has a known hypersensitivity to alpelisib, fulvestrant, letrozole, goserelin or leuprolide or to any of the excipients of alpelisib, fulvestrant, letrozole, goserelin or leuprolide.
• Patient has received prior treatment with any PI3K inhibitors.
• Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
  • At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment;
  • Clinically stable CNS tumor at the time of screening untreated or without evidence of progressions for at least 4 weeks after treatment as determined by clinical examination and brain imaging (MRI or CT) during screening period and stable low dose of steroids for 2 weeks prior to initiating study treatment.
• Patients with an established diagnosis of diabetes mellitus type I or uncontrolled type II (based on FPG and HbA1c).
• Patient has a concurrent malignancy or malignancy within 3 years of study screening period, with the exception of adequately treated, basal or squamous cell carcinoma, nonmelanoma skin cancer or curatively resected cervical cancer.
• Patient has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to enrollment, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia).
• Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting treatment with alpelisib, or 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 diseases), eye drops or local injections (e.g., intra-articular), stable CNS tumor on consistent low dose of steroids.
• Patients with a known history of HIV seropositivity. Screening for HIV infection at baseline is not mandatory (unless required by local HA regulations).
• Any concurrent severe and/ or uncontrolled medical conditions that would, in the investigator’s judgment, contraindicate patient participation in the clinical study (e.g., chronic active hepatitis [testing not mandatory unless required by local regulations or requirements], severe hepatic impairment, etc.).
• Patients being concurrently treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A4 or inhibitors of BCRP; switching to different medications prior to entry of treatment phase is allowed within the last 5 days prior to study treatment.
• Patient has a history of noncompliance to medical regimens.
• Patient with severe liver impairment (Child Pugh score B/C).
• 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) based on investigator discretion.
• Patient has documented pneumonitis / interstitial lung disease which is active and requiring treatment (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).
• Patient is concurrently using other anti-cancer therapy. All anti-cancer therapy must be discontinued prior to day one of study treatment. Drugs with overlapping toxicities must be discontinued within 7 days and AE resolved to NCI CTCAE v4.03 Grade ≤ 1 prior to study treatment. Exception to this criterion: patients with any grade of alopecia are allowed to enter the study.  Patient has had major surgery within 14 days prior to starting treatment with alpelisib or has not recovered from major side effects.
• Patient has any of the following cardiac abnormalities:
  • Symptomatic congestive heart failure:
    • History of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy;
    • Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO).
  • Myocardial infarction ≤ 6 months prior to enrollment;
  • Unstable angina pectoris;
  • Serious uncontrolled cardiac arrhythmia;
  • Symptomatic pericarditis;
  • Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening.
• History of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis.
• Patient has a history of severe cutaneous reactions like Stevens-Johnson-Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN) or Drug Reaction with Eosinphilia and Systemic Symptoms (DRESS).
• Patient who does not apply highly effective contraception during the treatment with alpelisib and through the duration as defined below after the final dose of alpelisib:
  • 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 8 months after stopping alpelisib plus fulvestrant, letrozole, goserelin or leuprolide 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;
  • 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 8 months after stopping the study medication.  Highly effective contraception methods include:
    • Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception;
    • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.