I. To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of
the combination of alpelisib (BYL719) and enzalutamide in patients with androgen receptor
(AR)-positive and PTEN-positive metastatic breast cancer.
I. To determine the dose-limiting toxicity (DLT) of the combination of BYL179 and
II. To determine the safety profile of BYL179 and enzalutamide used in combination.
III. Progression-free survival (PFS) and clinical benefit rate (CBR) (complete response or
partial response + prolonged stable disease) after a 16-week treatment of BYL719 and
enzalutamide per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
I. To determine the association between aberrant circulating tumor cells (CTCs), circulating
tumor deoxyribonucleic acid (ctDNA), and CBR at 16 weeks.
II. To determine the association between PIK3CA and PTEN mutations and treatment response to
the combination of BYL179 and enzalutamide.
III. To determine the association between PIK3CA mutation status change in ctDNA and
IV. To determine the molecular (CTC, ctDNA) profile of tumors that become resistant to
treatment in comparison with those prior to treatment.
V. To determine the association between the AR expression level measured by
immunohistochemistry (IHC) staining of tumor and CBR at 16 weeks.
OUTLINE: This is a dose-escalation study of alpelisib.
Patients receive alpelisib orally (PO) and enzalutamide PO on days 1-28. Cycles repeat every
28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days.
- Patient is >/= 18 years old.
- Patient has signed the informed consent form prior to the performance of any screening
procedures and is able to comply with protocol requirements.
- Patients with central nervous system (CNS) involvement unless they meet ALL of the
- At least 4 weeks from prior therapy completion (including radiation and/or
surgery to starting the study treatment) * Clinically and radiographically stable
CNS tumor at the time of screening and not receive steroids and/or an enzyme
inducing anti-epileptic mediations for brain metastasis
- Absence of leptomeningeal disease
- Patient has metastatic breast cancer that is not suitable for surgery or radiation
therapy for local disease control at the time of screening.
- Patient has disease that is hormone-receptor positive (estrogen receptor [ER] and/or
progesterone receptor [PR] positive [+], HER-2/neu negative [-]) or triple-negative
- Patient has an AR-positive and PTEN-positive tumor as determined by using Clinical
Laboratory Improvement Amendments (CLIA) compliant assays to identify AR-positive and
PTEN-positive disease (AR positivity is defined as >= 1% of nuclear staining, PTEN
positivity is defined as > 0% of nuclear staining).
- Patient has an Eastern Cooperative Oncology Group performance status (ECOG PS) =< 1
that the investigator believes is stable at the time of screening.
- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
- Platelets >= 100 x 10^9/L
- Hemoglobin >= 9.0 g/dL
- Serum creatinine =< 1.5 x upper limit of normal (ULN)
- Total serum bilirubin =< 1.5 x ULN
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN; in
the event of liver metastasis, AST/ALT =< 5 ULN
- Fasting plasma glucose (FPG) =< 140 mg/dL or =< 7.8 mmol/L
- Patient is able to swallow and retain oral medication and does not have any clinically
significant gastrointestinal abnormalities that may alter drug absorption, such as
malabsorption syndrome or major resection of the stomach or bowels.
- For dose-escalation cohort, patient has at least 1 measurable disease as defined by
RECIST criteria (Version 1.1). For dose-expansion cohort, patient has at least 1
measurable disease as defined by RECIST criteria (version 1.1) with a lesion larger
than 1.5 cm that can be biopsied by core needle biopsy.
- For dose-escalation portion of study, patients must be refractory to or intolerant of
existing therapies known to provide clinical benefit for their condition.
- Patient has a life expectancy of at least 3 months in the opinion of the investigator.
- Patient has a known hypersensitivity to any of the excipients of BYL719 and/or
- Patient has a known or suspected primary central nervous system (CNS) tumor or CNS
tumor involvement or active leptomeningeal disease.
- Patient has a history of seizures or any condition that may predispose to seizures
(e.g., prior cortical stroke, significant brain trauma) at any time in the past and/or
a history of loss of consciousness or transient ischemic attack within 12 months of
the cycle 1, day 1 visit.
- Patient has uncontrolled diabetes.
- Patient has a history of another malignancy within 2 years prior to starting study
treatment, except for cured basal cell carcinoma of the skin or excised carcinoma in
situ of the cervix.
- Patient has not recovered to Common Terminology Criteria for Adverse Events (CTCAE)
(version 4.03) grade 1 or better (except alopecia) from related side effects of any
prior antineoplastic therapy.
- Patient has had any systemic therapy within 2 weeks prior to initiating study drug.
- Patient has participated in a prior investigational study within 3 weeks prior to
initiating study drug.
- Patient has completed radiotherapy within 2 weeks prior to treatment initiation.
- Patient has any serious and/or unstable pre-existing medical disorder (aside from
malignancy exception above), psychiatric disorder, or other conditions that could
interfere with patient's safety, provision of informed consent, or compliance with the
- Patient has known clinically significant cardiac disease or impaired cardiac function,
- Congestive heart failure requiring treatment (New York Heart Association grade >=
2), left ventricular ejection fraction (LVEF) < 50% as determined by multigated
acquisition (MUGA) scan or ECHO.
- History or current evidence of clinically significant cardiac arrhythmias, atrial
fibrillation, and/or conduction abnormality, e.g., congenital long QT syndrome,
high-grade/complete arteriovenous blockage.
- Acute coronary syndromes (including myocardial infarction, unstable angina,
coronary artery bypass graft, coronary angioplasty, or stenting) < 3 months prior
- Patient has a QT interval adjusted by the Fridericia formula (QTcF) > 480 msec on
screening electrocardiogram (ECG).
- Patient is currently receiving medication with a known risk of prolonging the QT
interval or inducing torsades de pointes (TdP) and whose treatment cannot be either
discontinued or switched to a different medication prior to starting treatment with
the study drug.
- Patient has any prior use of PI3K inhibitors.
- Patient has any prior use of anti-androgen therapies.
- Patient is currently receiving warfarin or other Coumarin-derived anticoagulant for
treatment, prophylaxis, or other reasons. Therapy with heparin, low molecular weight
heparin, or fondaparinux is allowed.
- Patient is currently receiving treatment with drugs known to be strong inhibitors or
inducers of isoenzymes CYP3A or CYP2C8. The patient must have discontinued strong
inducers for at least 1 week and must have discontinued strong inhibitors before the
start of the study treatment. Switching to a different medication prior to initiation
of the trial treatment is allowed.
- Patient has impaired gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral BYL719 (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
- Patient has known positive serology for human immunodeficiency virus (HIV).
- Patient has any other condition that would, in the investigators' judgment, preclude
the patient's participation in the clinical study due to concerns about safety or
compliance with clinical study procedures; e.g., infection/inflammation, intestinal
obstruction, inability to swallow oral medication, social/psychological complications.
- Patient has a history of noncompliance to medical regimens or is unable to grant
- Female patients of childbearing potential have positive urine or serum pregnancy test
no more than 7 days prior to starting study drug.
- Female patients of childbearing potential are not willing to use highly effective
contraception to prevent pregnancy or agree to abstain from heterosexual activity
throughout the study. Highly effective contraception is defined as:
- Surgical birth control/sterilization (such as male vasectomy or female
- Birth control pills, injections, implants, or patches.
- Intrauterine devices (IUDs).
- Two barrier methods (male condom and female diaphragm, cervical cap, or sponge)
in combination with a spermicide.
- Highly effective contraception must be used by both sexes during the study and
must be continued for 6 months after the last dose of study treatment. (Women of
not childbearing potential: post-menopausal [age > 55 years with cessation of
menses > 12 months or < 55 years but not spontaneous menses for at least 2 years
or < 55 years and spontaneous menses within the past 1 year, but currently
amenorrheic (e.g., spontaneous or secondary to hysterectomy), and with
postmenopausal gonadotropin levels (luteinizing hormone and follicle-stimulating
hormone levels > 40 IU/L) or postmenopausal estradiol levels (< 5 ng/dL) or
according to the definition of "postmenopausal range" for the laboratory
involved] or who have had a hysterectomy, bilateral salpingectomy, or bilateral
- Female patients who are breast-feeding.