Clinical Trials /

Study of BYL719 (Alpelisib) in Combination With Androgen Receptor Inhibitor (Enzalutamide) in Patients With Androgen Receptor (AR)-Positive and PTEN Positive Metastatic Breast Cancer

NCT03207529

Description:

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. 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 cancer. 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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of BYL719 (Alpelisib) in Combination With Androgen Receptor Inhibitor (Enzalutamide) in Patients With Androgen Receptor (AR)-Positive and PTEN Positive Metastatic Breast Cancer
  • Official Title: Phase Ib Study of BYL719 (Alpelisib) in Combination With Androgen Receptor Inhibitor (Enzalutamide) in Patients With Androgen Receptor (AR)-Positive and PTEN Positive Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2016-0538
  • NCT ID: NCT03207529

Conditions

  • Malignant Neoplasm of Breast

Interventions

DrugSynonymsArms
AlpelisibBYL719Alpelisib + Enzalutamide
EnzalutamideMDV3100, XTANDIAlpelisib + Enzalutamide

Purpose

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.

Detailed Description

      Study Groups:

      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).

      Study Visits:

      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.

      End-of-Dosing Visit:

      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
      cancer.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Alpelisib + EnzalutamideExperimentalDose Escalation Phase: Participants take Alpelisib at starting dose of 250 mg by mouth daily. Enzalutamide taken at 160 mg fixed dose by mouth daily. Dose Expansion Phase: If any specific molecular subtype or other signals such as PIK3CA status among responder patients are observed, 10 additional patients enrolled with that specific characteristic (e.g., TNBC patients only, or patients with PIK3CA H1047R mutation only) as an expansion cohort at RP2D. Participants take the maximum tolerated dose (MTD) of Alpelisib that was tolerated during Dose Escalation Phase. All 10 patients enrolled in the dose-expansion cohort receive one-week single agent treatment with Alpelisib. Enzalutamide taken at 160 mg fixed dose daily. Study cycle is 28 days.
  • Alpelisib
  • Enzalutamide

Eligibility Criteria

        Inclusion Criteria:

          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.

        Exclusion Criteria:

          1. Patient has a known hypersensitivity to any of the excipients of BYL719 and/or
             enzalutamide.

          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
             study procedures.

         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
             screening ECG.

         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
             resection).

         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
             consent.

         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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose of Alpelisib with Enzalutamide in Patients With Androgen Receptor (AR)-Positive and PTEN Positive Metastatic Breast Cancer
Time Frame:28 days
Safety Issue:
Description:MTD defined as the highest dose level at which 6 patients have been treated with at most 1 instance of dose limiting toxicity (DLT).

Secondary Outcome Measures

Measure:Profession-Free Survival (PFS) of Alpelisib with Enzalutamide in Patients With Androgen Receptor (AR)-Positive and PTEN Positive Metastatic Breast Cancer
Time Frame:16 weeks
Safety Issue:
Description:Profession-free survival (PFS) determined per RECIST version 1.1.
Measure:Clinical Benefit Rate (CBR) of Alpelisib with Enzalutamide in Patients With Androgen Receptor (AR)-Positive and PTEN Positive Metastatic Breast Cancer
Time Frame:16 weeks
Safety Issue:
Description:Clinical benefit rate (CBR) determined per RECIST version 1.1.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Malignant neoplasm of breast
  • Metastatic breast cancer
  • Androgen receptor (AR)-positive and PTEN positive
  • Alpelisib
  • BY719
  • Enzalutamide
  • MDV3100
  • XTANDI

Last Updated

September 12, 2017