There are 2 parts to this study: Part 1 (dose escalation) and Part 2 (dose expansion).
The goal of Part 1 of this clinical research study is to find the highest tolerable dose of
alpelisib (also called BYL719) and enzalutamide that can be given to patients with breast
cancer that is metastatic (has spread) and has come back after standard treatment or is
intolerant to standard treatment.
The goal of Part 2 of this study is to learn if the dose of alpelisib and enzalutamide found
in Part 1 can help to control the disease.
The safety of alpelisib when combined with enzalutamide will also be studied.
If participant is found to be eligible to take part in this study, participant will be
assigned to a study group based on when participant joins this study. Up to 18 participants
will be enrolled in Part 1 of the study and up to 10 participants will be enrolled in Part 2.
If participant is enrolled in Part 1, the dose of alpelisib participant receives will depend
on when participant joins this study. The first group of participants will receive the lowest
dose level of alpelisib and enzalutamide. Each new group will receive a higher dose of
alpelisib and enzalutamide than the group before it, if no intolerable side effects were
seen. Up to 5 doses of alpelisib will be tested. This will continue until the highest
tolerable dose of alpelisib and enzalutamide is found.
If participant is enrolled in Part 2, participant will receive alpelisib and enzalutamide at
the highest dose that was tolerated in Part 1. If participant is taking part in Part 1 and is
receiving a dose lower than what will be given to Part 2 participants, participant's dose may
be changed to receive the highest tolerable dose.
Study Drug Administration:
Each study cycle is 28 days.
Participant will take alpelisib and enzalutamide by mouth each day with a cup (about 8
ounces) of water. Participant should not chew the tablets.
If participant is in Part 2 of the study, participant will take alpelisib alone for the first
week of the study. After that, participant will take both study drugs.
If participant vomits after taking a dose, participant should tell the study doctor or nurse
that participant vomited, but participant should not take an extra "make-up" dose.
Participant should also bring any study pill bottles with participant to each study visit.
Length of Study Participation:
Participant may continue taking the study drugs for as long as the doctor thinks it is in
participant's best interest. Participant will no longer be able to take the study drugs if
the disease gets worse, if intolerable side effects occur, or if participant is unable to
follow study directions.
Participation in this study will be over after the end-of-dosing visit (described below).
If participant is in Part 2 of the study, about 1 week before Cycles 1 and 2, participant
will have a tumor biopsy for biomarker testing.
On Day 1 of each cycle, participant will have a physical exam.
During Week 1 of Cycle 1 and Weeks 1 and 4 of Cycle 2 and then every 2 cycles after that
(Cycles 4, 6, 8, and so on):
- Blood (about 3 tablespoons) will be drawn for routine tests, biomarker testing that
includes genetic biomarkers, and immune system testing.
- Beginning at Cycle 2, participant will have an MRI, CT, or PET/CT scan.
On Day 1 of Cycles 2 and beyond, participant will have an EKG.
Within 30 days after participant's last dose of study drugs:
- Participant will have a physical exam.
- Participant will have an EKG.
- Blood (about 4 tablespoons) will be drawn for routine tests, biomarker testing including
genetic biomarkers, and immune system testing.
If participant has any side effects at this visit, the study staff will follow up with
participant until the side effect goes away or becomes stable. This may be a phone call or
this information may be collected from participant's medical record. If called, this call may
last about 5-10 minutes.
This is an investigational study. Alpelisib is not FDA approved or commercially available. It
is currently being used for research purposes only. Enzalutamide is FDA approved and
commercially available for the treatment of metastatic, castrate-resistant prostate cancer.
It is considered investigational to use alpelisib and enzalutamide to treat metastatic breast
It is considered investigational to give alpelisib and enzalutamide together for breast
cancer. The study doctor can explain how the study drugs are designed to work.
Up to 28 participants will be enrolled in this study. All will take part at MD Anderson.
1. Patient is >/= 18 years old.
2. Patient has signed the informed consent form prior to the performance of any screening
procedures and is able to comply with protocol requirements.
3. Patient has advanced or metastatic breast cancer that is refractory to at least one
standard therapy or that has relapsed after standard therapy or that has no standard
systemic therapy that increases survival by at least 3 months.
4. Patient has metastatic breast cancer that is not suitable for surgery or radiation
therapy for local disease control at the time of screening.
5. Patient has disease that is hormone-receptor positive (ER and/or PR+, HER-2/neu -) or
triple-negative (ER/PR/HER-2/neu -).
6. 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).
7. Patient has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) </= 1
that the investigator believes is stable at the time of screening.
8. Patient has adequate bone marrow and organ function as defined by the following
laboratory values: o 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 o Alanine aminotransferase (AST)
and aspartate aminotransferase (ALT) </= 2.5 x ULN ; Fasting plasma glucose (FPG) </=
140 mg/dL or </= 7.8 mmol/L
9. 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.
10. 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.
11. For dose-escalation portion of study, patients must be refractory to or intolerant of
existing therapies known to provide clinical benefit for their condition.
12. Patient has a life expectancy of at least 3 months in the opinion of the investigator.
1. Patient has a known hypersensitivity to any of the excipients of BYL719 and/or
2. Patient has a known or suspected primary central nervous system (CNS) tumor or CNS
tumor involvement or active leptomeningeal disease.
3. 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.
4. Patient has clinically manifest diabetes mellitus for the last 3 months or documented
steroid-induced diabetes mellitus.
5. 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.
6. Patient has not recovered to CTCAE (Version 4.03) grade 1 or better (except alopecia)
from related side effects of any prior antineoplastic therapy.
7. Patient has had any systemic therapy within 2 weeks prior to initiating study drug.
8. Patient has participated in a prior investigational study within 3 weeks prior to
initiating study drug.
9. Patient has completed radiotherapy within 2 weeks prior to treatment initiation.
10. 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
11. Patient has known clinically significant cardiac disease or impaired cardiac function,
such as: oCongestive heart failure requiring treatment (New York Heart Association
grade >/= 2), LVEF < 50% as determined by MUGA scan or ECHO oHistory 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 oAcute coronary syndromes (including myocardial infarction,
unstable angina, coronary artery bypass graft, coronary angioplasty, or stenting) < 3
months prior to screening
12. Patient has a QT interval adjusted by the Fredericia formula (QTcF) > 480 msec on
13. 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.
14. Patient has any prior use of PI3K inhibitors.
15. Patient has any prior use of anti-androgen therapies.
16. 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.
17. 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.
18. 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
19. Patient has known positive serology for HIV.
20. 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.
21. Patient has a history of noncompliance to medical regimens or is unable to grant
22. Female patients of childbearing potential have positive urine or serum pregnancy test
no more than 7 days prior to starting study drug.
23. 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 1) Surgical birth
control/sterilization (such as male vasectomy or female sterilization; 2) Birth
control pills, injections, implants, or patches; 3) Intrauterine devices (IUDs); 4)
Two barrier methods (male condom and female diaphragm, cervical cap, or sponge) in
combination with a spermicide.
24. Cont'd # 23 Highly effective contraception must be used by both sexes during the study
and must be continued for 3 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 (eg,
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 oophorectomy).
25. Female patients who are breast-feeding.