Clinical Trials /

Pembrolizumab and Enobosarm in Treating Patients With Androgen Receptor Positive Metastatic Triple Negative Breast Cancer

NCT02971761

Description:

This phase II trial studies the side effects and how well pembrolizumab and enobosarm work in treating patients with androgen receptor positive triple negative breast cancer that has spread to other places in the body. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Androgen can cause the growth of breast cancer cells. Hormone therapy using enobosarm may fight breast cancer by blocking the use of androgen by the tumor cells. Giving pembrolizumab and enobosarm may work better in treating patients with androgen receptor positive triple negative breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Enobosarm in Treating Patients With Androgen Receptor Positive Metastatic Triple Negative Breast Cancer
  • Official Title: A Phase 2 Clinical Trial of the Combination of Pembrolizumab and Selective Androgen Receptor Modulator (SARM) GTX-024 in Patients With Advanced Androgen Receptor (AR) Positive Triple Negative Breast Cancer (TNBC)

Clinical Trial IDs

  • ORG STUDY ID: 16131
  • SECONDARY ID: NCI-2016-01759
  • SECONDARY ID: 16131
  • NCT ID: NCT02971761

Conditions

  • Androgen Receptor Positive
  • Estrogen Receptor Negative
  • HER2/Neu Negative
  • Progesterone Receptor Negative
  • Recurrent Breast Carcinoma
  • Stage III Breast Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Breast Cancer
  • Triple-Negative Breast Carcinoma

Interventions

DrugSynonymsArms
EnobosarmGtx-024, OstarineTreatment (pembrolizumab, enobosarm)

Purpose

This phase II trial studies the side effects and how well pembrolizumab and enobosarm work in treating patients with androgen receptor positive triple negative breast cancer that has spread to other places in the body. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Androgen can cause the growth of breast cancer cells. Hormone therapy using enobosarm may fight breast cancer by blocking the use of androgen by the tumor cells. Giving pembrolizumab and enobosarm may work better in treating patients with androgen receptor positive triple negative breast cancer.

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the safety/tolerability of the combination regimen. II. To determine the response rate (complete response [CR] or partial response [PR] via Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) of the combination of pembrolizumab with enobosarm (GTx-024) in patients with advanced androgen receptor (AR) and triple negative breast cancer (TNBC).

SECONDARY OBJECTIVES:

I. To evaluate clinical outcomes by RECIST 1.1 including clinical benefit rate (CBR) at 24 weeks, progression free-survival (PFS), duration of response (DOR), event free survival (EFS), time-to-treatment failure (TTF); and overall survival (OS).

II. To evaluate the role of immune-related response criteria (irRECIST). III. To evaluate the association of AR by immunohistochemistry (IHC) and clinical response.

TERTIARY OBJECTIVES:

I. To evaluate the association of an AR gene expression signature and clinical response.

II. To evaluate the effect of the combination therapy on peripheral blood circulating tumor cells (CTCs) and circulating tumor deoxyribonucleic acid (DNA) (ctDNA).

III. To evaluate pre-treatment programmed death ligand 1 (PD-L1) and tumor infiltrating lymphocytes (TILs) as a predictor of response to combination therapy.

IV. To evaluate specific TIL subsets (e.g. CD4, CD8, regulatory T cell [Treg] distribution) and other immunological correlative (e.g. T cell receptor [TCR] repertoire analysis) as possible predictors of response.

V. To evaluate change in TILs as a result of the combination therapy. VI. To evaluate peripheral blood, immune biomarkers.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and enobosarm orally (PO) once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 90 days, every 3 months, and bi-annually.

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, enobosarm)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1 and enobosarm PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Enobosarm

    Eligibility Criteria

    Inclusion Criteria:

    - Documented informed consent

    - Willing to provide a sample from a recently obtained (within 42 days prior to initiation of day 1) biopsy of a tumor lesion;

    - If recently-obtained samples are unavailable an archived metastatic specimen not previously irradiated may be submitted upon agreement from the study principal investigator (PI)

    - Eastern Cooperative Oncology Group (ECOG) performance status of =< 1

    - Life expectancy of > 3 months

    - Metastatic triple negative breast cancer (TNBC)

    - Measurable disease per RECIST version (v)1.1 criteria: at least 1 lesion of > 10 mm in long axis diameter for non-lymph nodes or > 15 mm in short axis diameter for lymph nodes that is serially measurable according to RECIST 1.1 using computerized tomography, magnetic resonance imaging, or panoramic and close-up color photography

    - Histologically proven diagnosis of TNBC per current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline;

    - Estrogen receptor (ER) negative (ER expression =< 1% positive tumor nuclei), progesterone receptor (PR) (PR expression =< 1% positive tumor nuclei) and HER2 negative breast cancer by IHC and /or fluorescence in situ hybridization (FISH)

    - Androgen receptor positive (AR+)

    - Defined as >= 10% nuclear AR staining by immunohistochemistry (IHC) in either the primary or metastatic lesion

    - Received up to 2 lines of chemotherapy in the advanced or metastatic setting

    - Resolution of grade 2 and above toxicities of most recent therapy except for stable sensory neuropathy (=< grade 2) and alopecia

    - Female (childbearing potential): use an adequate method of birth control (except hormonal contraception) or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication

    - Childbearing potential defined as not being surgically sterilized or have not been free from menses for > 1 year

    - Male: use and adequate method of contraception with the first dose of study therapy through 120 days after the last dose of study therapy

    - Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

    - Absolute neutrophil count (ANC) >= 1500/mm^3

    - Platelets >= 100,000/mm^3

    - Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)

    - Serum total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN if total bilirubin levels > 1.5 x ULN

    - Albumin >= 2.5 mg/dL

    - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN OR =< 5.0 x ULN if liver metastases present

    - Serum creatinine =< 1.5 x ULN OR creatinine clearance (if measured or calculated per institutional standard; glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min if creatinine levels > 1.5 x ULN

    - Female of childbearing potential only: negative urine or serum pregnancy test; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

    Exclusion Criteria:

    - Anti-programmed cell death protein-1 (anti-PD-1), PD ligand-1 (PD-L1), PD ligand-2 (PD-L2) agent, an antibody targeting other immuno-regulatory receptors or mechanisms.

    - Radiotherapy within 14 days prior to day 1 of protocol therapy

    - AR targeted agents (including GTx-024, enzalutamide or other AR targeted therapies)

    - Investigational agent within 21 days prior to day 1 of protocol therapy

    - Hormone replacement therapies (estrogens, megestrol acetate) within 14 days prior to day 1 of protocol therapy

    - Live-virus vaccination within 30 days prior to day 1 of protocol therapy

    - Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery within 21 days of the first dose of trial medication

    - Testosterone or testosterone-like agents (methyltestosterone, oxandrolone, oxymetholone, danazol, fluoxymesterone, dehydroepiandrosterone, androstenedione) other androgenic compounds or anti-androgens within 30 days prior to day 1 of protocol therapy

    - Chronic systemic steroid therapy or on any other for, of immunosuppressive medication

    - Unstable or untreated brain/leptomeningeal metastasis

    - Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation)

    - Active central nervous system metastases and/or carcinomatous meningitis

    - Severe hypersensitivity reaction to treatment with another monoclonal antibody

    - Active autoimmune disease that has required systemic treatment in the past 2 years (replacement therapies for hormone deficiencies are allowed)

    - Known history of human immunodeficiency virus (HIV), hepatitis B or hepatitis C

    - History of pneumonitis (non-infectious) that required steroids or current pneumonitis

    - Diagnosed with or treated for cancer within the previous two years, other than breast cancer or non-melanoma carcinoma of the skin

    - Unable to swallow capsules

    - Currently on bisphosphonate or denosumab with elevated serum calcium levels corrected for albumin/ionized calcium levels outside of institutional normal limits

    - Female: pregnant or lactating

    - Concomitant medical condition that precludes adequate study treatment compliance or assessment, or increases subject risk, in the opinion of the investigator, such as but not limited to:

    - Myocardial infarction or arterial thromboembolic events within 6 months prior to baseline or severe or unstable angina, New York Heart Association (NYHA) class III or IV disease, or a QTCB (corrected according to Bazett's formula) interval > 470 msec; serious uncontrolled cardiac arrhythmia grade II or higher according to NYHA; uncontrolled hypertension (systolic > 150 and/or diastolic > 100 mm Hg)

    - Acute and chronic active infectious disorders and non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy

    - Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)

    - Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

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

    Primary Outcome Measures

    Measure:Dose limiting toxicities assessed by NCI CTCAE v4.0
    Time Frame:Up to 21 days
    Safety Issue:
    Description:AEs will be analyzed including but not limited to all AEs, serious adverse events, fatal AEs and laboratory changes. Immune-related adverse events will also be collected.

    Secondary Outcome Measures

    Measure:CBR assessed by irRECIST
    Time Frame:24 weeks
    Safety Issue:
    Description:
    Measure:DOR defined as time from documentation of tumor response to disease progression or death in CR or PR patients assessed by irRECIST
    Time Frame:Up to 36 months
    Safety Issue:
    Description:
    Measure:EFS defined as failure of treatment or death as a result of any cause assessed by RECIST v1.1
    Time Frame:Up to 1 year
    Safety Issue:
    Description:Kaplan-Meier estimates will be generated.
    Measure:OS assessed by RECIST v1.1
    Time Frame:Time to death as a result of any cause, assessed up to 36 months
    Safety Issue:
    Description:Kaplan-Meier estimates will be generated.
    Measure:PFS assessed using RECIST v1.1
    Time Frame:Time to disease progression/relapse or death as a result of any cause, assessed up to 36 months
    Safety Issue:
    Description:Kaplan-Meier estimates will be generated.
    Measure:TTF defined as time to treatment termination for any reason assessed by RECIST v1.1
    Time Frame:Up to 36 months
    Safety Issue:
    Description:

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:City of Hope Medical Center

    Trial Keywords

      Last Updated

      November 21, 2016