Overview

Patients who have histologically confirmed metastatic or unresectable (not amenable to curative therapy) breast cancer may be screened for eligibility. All patients must have HER2 negative breast cancer with the identified PIK3CA mutation and received at least one line of endocrine therapy. The study will consist of a screening phase, a treatment phase, and a post-treatment phase which includes safety, efficacy, and follow-up. The treatment phase will include taking alpelisib daily in combination with continued use of either Fulvestrant or Aromatase Inhibitor per standard of care until disease progression or unacceptable toxicity.

Eligibility

Eligibility Criteria Individuals from populations who are underrepresented in clinical

        research (e.g., racial and ethnic minorities, women, individuals from rural/frontier
        communities, older individuals) will be enrolled with a goal of ensuring that all eligible
        patients are given the opportunity to participate in novel clinical trials and that
        research findings can be generalizable to the entire population.
        Inclusion Criteria
          -  Written informed consent and HIPAA authorization for release of personal health
             information. NOTE: HIPAA authorization may be included in the informed consent or
             obtained separately.
          -  Age ≥ 18 years at the time of consent.
          -  ECOG Performance Status of 0-2 within 28 days prior to registration.
          -  Men and postmenopausal female patients. Premenopausal patients (age 18 or older) who
             have been rendered postmenopausal will also be included. Postmenopausal is defined as:
               -  Age >= 55 years and one year or more of amenorrhea.
               -  Age < 55 years and one year or more of amenorrhea, with estradiol < 20 pg/ml
               -  Age < 55 years with prior hysterectomy but intact ovaries, with estradiol < 20
                  pg/ml
               -  Prior bilateral oophorectomy
        NOTE: Women who do not fit the criteria for being postmenopausal as above are deemed
        premenopausal. Premenopausal patients (age 18 or older) who can be rendered postmenopausal
        will also be eligible. Methods eligible for rending premenopausal patients postmenopausal
        include:
          -  Ongoing treatment with luteinizing hormone-releasing hormone (LHRH) agonist, with
             treatment starting at least 4 weeks prior to randomization and with estradiol < 20
             pg/ml. LHRH agonist must be administered within 7 days of scheduled administration
             date during the length of the clinical trial.
          -  Histologically confirmed metastatic or unresectable (not amenable to curative therapy)
             breast cancer.
          -  Has confirmed hormone receptor positivity with ER >=1% and/or PR >=1%. Preferred
             receptor testing is obtained from a metastatic site, but can be from the primary
             breast or axilla biopsy as long as this is most recent biopsy.
          -  Has confirmed HER2 negative breast cancer. HER2 negative or non-amplified is
             determined by the current ASCO-CAP criteria which are as follows: HER2 testing by IHC
             as 0 or 1+. Or negative by in situ hybridization (FISH/CISH/SISH) defined as
             Her2/CEP17 ratio <2 and for single probe assessment a HER2 copy number <6). Preferred
             receptor testing is obtained from a metastatic site, but can be from the primary
             breast or axilla biopsy as long as this is most recent biopsy.
          -  PIK3CA mutation identified via local testing from tumor tissue or blood.
          -  Has either measurable disease, i.e. at least one measurable lesion as per RECIST 1.1
             criteria OR if no measurable disease is present, then at least one predominantly lytic
             bone lesion must be present, within 28 days prior to registration. 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.
          -  Has received at least one line of therapy with an endocrine therapy or endocrine
             therapy combination with other agents in the metastatic setting.
          -  Must have received endocrine therapy (aromatase inhibitor or fulvestrant as single
             agent or in combination with other agents) as last line of therapy with progressive
             disease, as determined by treating physician.
          -  No more than two prior lines of endocrine therapy or endocrine therapy combinations in
             the metastatic setting. Transition from one nonsteroidal aromatase inhibitor to a
             second nonsteroidal aromatase inhibitor due to tolerance will only count as one line
             of endocrine therapy. Combination therapy will be considered one line even if one of
             the agents is discontinued and the other continued.
          -  Patient must have received treatment with a CDK4/6 inhibitor for breast cancer in the
             metastatic setting. CDK4/6 inhibitor discontinuation due to intolerance or reasons
             other than progression is allowed.
          -  Demonstrate adequate organ function as defined in the protocol; all screening labs to
             be obtained within 28 days prior to registration.
          -  Men who are not surgically or medically sterile must agree to use an acceptable method
             of contraception. Acceptable forms of contraception include castration, vasectomy, and
             condom/occlusive cap with spermicidal foam/gel/film/cream/suppository. Male patients
             with female sexual partners who are pregnant, possibly pregnant, or who could become
             pregnant during the study must agree to use condoms at least one month after the last
             dose of study drug. Total abstinence for the same study period is an acceptable
             alternative.
          -  Premenopausal females must agree to use an acceptable method of contraception or to
             abstain from sexual intercourse for the duration of their participation in the study
             and for 3 months after discontinuation of therapy. Adequate forms of contraception
             include: total abstinence, surgery intended to prevent pregnancy (defined as
             hysterectomy, bilateral oophorectomy or bilateral tubal ligation), non-hormonal IUD,
             or condom/occlusive cap with spermicidal foam/gel/film/cream/suppository).
          -  As determined by the enrolling physician or protocol designee, ability of the subject
             to understand and comply with study procedures for the entire length of the study
          -  HIV-infected patients on effective anti-retroviral therapy with undetectable viral
             load within 6 months of registration are eligible for this trial.
        Exclusion Criteria
          -  Patients with prior chemotherapy for metastatic or advanced disease.
          -  Active infection requiring systemic therapy.
          -  Patients with a prior or concurrent malignancy whose natural history or treatment has
             the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are not eligible for this trial.
          -  Uncontrolled, active CNS metastases causing clinical symptoms or metastases that
             require therapeutic intervention, including leptomeningeal disease.
        NOTE: Subjects who are symptomatic and have not undergone prior brain imaging must undergo
        a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) within 28
        days prior to registration to exclude brain metastases.
          -  Treatment with any investigational drug within 14 days prior to registration.
          -  Radiotherapy to index lesion <= 4 weeks or limited field radiation to index lesion for
             palliation <= 2 weeks prior to randomization.
          -  Established diagnosis of diabetes mellitus type I or persistent poorly controlled
             diabetes mellitus, with an uninterrupted hemoglobin A1c > 8.0% for 1 year or greater
             despite standard care. For patients with newly diagnosed diabetes mellitus without 1
             year of hemoglobin A1c values, available hemoglobin A1c values cannot all be > 8.0%.
          -  Symptomatic visceral disease or any disease burden that makes the patient ineligible
             for endocrine therapy per the investigator's best judgment.
          -  As determined by the enrolling physician or protocol designee, impairment of
             gastrointestinal function or disease that may significantly alter the absorption of
             the study drugs.
          -  Currently documented clinically active pneumonitis. Patients could have received prior
             treatment for pneumonitis but pneumonitis must have clinically resolved and treatments
             for pneumonitis (e.g. steroids) must be completed prior to randomization.
          -  Active cardiac disease, defined as any of the following within 6 months prior to the
             start of study treatment:
               -  History of angina pectoris, coronary artery bypass graft, symptomatic
                  pericarditis, or myocardial infarction.
               -  History of documented congestive heart failure (New York Heart Association
                  functional classification III-IV).
               -  History of any 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), supraventricular, nodal arrhythmias, or
                  conduction abnormality.
               -  Systolic blood pressure (SBP) >180 mmHg and/or Diastolic Blood Pressure (DBP) ≥
                  100 mm Hg at screening. Initiation or adjustment of antihypertensive
                  medication(s) is allowed prior to screening.
          -  History of acute pancreatitis within 1 year of screening or a past medical history of
             chronic pancreatitis.
          -  Prior treatment with PI3K, mTOR or AKT inhibitor in the metastatic setting.
          -  History of chronic steroid use (defined as daily steroid use > 14 days) and
             requirement for continued chronic steroid use.