Clinical Trials /

Alpelisib and Enzalutamide in Treating Patients With Androgen Receptor and PTEN Positive Metastatic Breast Cancer

NCT03207529

Description:

This phase I trial studies the side effects and best dose of alpelisib when given together with enzalutamide in treating patients with androgen receptor and PTEN positive breast cancer that has spread to other places in the body. Alpelisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Androgen receptor can cause the growth of breast cancer cells. Hormone therapy using enzalutamide may fight breast cancer by lowering the amount of androgen the body makes. Giving alpelisib and enzalutamide may work better in treating patients with breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Alpelisib and Enzalutamide in Treating Patients With Androgen Receptor 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
  • SECONDARY ID: NCI-2018-01127
  • SECONDARY ID: 2016-0538
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03207529

Conditions

  • Advanced Breast Carcinoma
  • Anatomic Stage III Breast Cancer AJCC v8
  • Anatomic Stage IIIA Breast Cancer AJCC v8
  • Anatomic Stage IIIB Breast Cancer AJCC v8
  • Anatomic Stage IIIC Breast Cancer AJCC v8
  • Anatomic Stage IV Breast Cancer AJCC v8
  • Androgen Receptor Positive
  • HER2/Neu Negative
  • Metastatic Breast Carcinoma
  • Prognostic Stage III Breast Cancer AJCC v8
  • Prognostic Stage IIIA Breast Cancer AJCC v8
  • Prognostic Stage IIIB Breast Cancer AJCC v8
  • Prognostic Stage IIIC Breast Cancer AJCC v8
  • Prognostic Stage IV Breast Cancer AJCC v8
  • PTEN Positive
  • Recurrent Breast Carcinoma
  • Refractory Breast Carcinoma
  • Triple-Negative Breast Carcinoma

Interventions

DrugSynonymsArms
AlpelisibBYL719, Phosphoinositide 3-kinase Inhibitor BYL719, PiqrayTreatment (alpelisib, enzalutamide)
EnzalutamideASP9785, MDV3100, XtandiTreatment (alpelisib, enzalutamide)

Purpose

This phase I trial studies the side effects and best dose of alpelisib when given together with enzalutamide in treating patients with androgen receptor and PTEN positive breast cancer that has spread to other places in the body. Alpelisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Androgen receptor can cause the growth of breast cancer cells. Hormone therapy using enzalutamide may fight breast cancer by lowering the amount of androgen the body makes. Giving alpelisib and enzalutamide may work better in treating patients with breast cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      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.

      SECONDARY OBJECTIVES:

      I. To determine the dose-limiting toxicity (DLT) of the combination of BYL179 and
      enzalutamide.

      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.

      EXPLORATORY OBJECTIVES:

      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
      treatment response.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (alpelisib, enzalutamide)ExperimentalPatients receive alpelisib PO and enzalutamide PO on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Alpelisib
  • Enzalutamide

Eligibility Criteria

        Inclusion Criteria:

          -  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
             following criteria:

               -  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
             (ER/PR/HER-2/neu -).

          -  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.

        Exclusion Criteria:

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

          -  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
             study procedures.

          -  Patient has known clinically significant cardiac disease or impaired cardiac function,
             such as:

               -  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
                  to screening.

          -  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
             resection).

          -  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
             consent.

          -  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
                  sterilization).

               -  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
                  oophorectomy).

          -  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 (MTD) of alpelisib in combination with enzalutamide
Time Frame:Up to 28 days
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 16 weeks
Safety Issue:
Description:Standard descriptive analysis will be used to summarize the data.
Measure:Profession-free survival (PFS)
Time Frame:Up to 16 weeks
Safety Issue:
Description:Will be estimated using Kaplan-Meier survival curves. From cycle 1 day 1 (cycle 1 is 28 days) to that of disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or death, whichever comes earlier, assessed up to 16 weeks]
Measure:Clinical benefit rate (CBR) (complete response or partial response + prolonged stable disease)
Time Frame:Up to 16 weeks
Safety Issue:
Description:Will be evaluated according to RECIST version 1.1. Standard descriptive analysis will be used to summarize the data.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

December 10, 2020