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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02971761
Recruitment Status : Active, not recruiting
First Posted : November 23, 2016
Last Update Posted : August 16, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Brief Summary:
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. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and 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 than pembrolizumab alone in treating patients with androgen receptor positive triple negative breast cancer.

Condition or disease Intervention/treatment Phase
Androgen Receptor Positive Estrogen Receptor Negative HER2/Neu Negative Progesterone Receptor Negative Stage IV Breast Cancer AJCC V6 and V7 Metastatic Triple-Negative Breast Carcinoma Drug: Enobosarm Other: Laboratory Biomarker Analysis Biological: Pembrolizumab Phase 2

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) positive (+) 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.

EXPLORATORY OBJECTIVES:

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

II. To evaluate genomic and phenotypic status of breast tumor.

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

IV. To evaluate the effect of combination therapy on tumor-derived exosomes (TEX) and TEX associated immune biomarkers.

V. Immune correlatives:

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

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

Vc. To evaluate change in TILs as a result of the combination therapy. Vd. 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 cycles 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Clinical Trial of the Combination of Pembrolizumab and Selective Androgen Receptor Modulator (SARM) GTX-024 in Patients With Metastatic Androgen Receptor (AR) Positive Triple Negative Breast Cancer (TNBC)
Actual Study Start Date : June 1, 2017
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : October 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Treatment (pembrolizumab, enobosarm)
Patients receive pembrolizumab IV over 30 minutes on day 1 and enobosarm PO QD on days 1-21. Courses repeat every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
Drug: Enobosarm
Given PO
Other Names:
  • Gtx-024
  • Ostarine

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Dose limiting toxicities [ Time Frame: Up to 21 days ]
    Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

  2. Incidence of adverse events (AEs) [ Time Frame: Up to 36 months ]
    Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Adverse events will be analyzed including but not limited to all adverse events, serious adverse events, fatal adverse events and laboratory changes. Immune-related adverse events will also be collected.

  3. Response rate (CR or PR) [ Time Frame: Up to 36 months ]
    Assessed using Response Evaluation Criteria in Solid Tumors version 1.1.


Secondary Outcome Measures :
  1. Clinical benefit rate (CBR) [ Time Frame: At 24 weeks ]
    Assessed by immune-related Response Evaluation Criteria in Solid Tumors version 1.1.

  2. Duration of response in complete response or partial response patients [ Time Frame: From documentation of tumor response to disease progression or death, assessed up to 36 months ]
    Assessed by immune-related Response Evaluation Criteria in Solid Tumors.

  3. Event free survival [ Time Frame: Up to 1 year ]
    Defined as failure of treatment or death as a result of any cause assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Kaplan-Meier estimates will be generated

  4. Overall Survival [ Time Frame: Time to death as a result of any cause, assessed up to 36 months ]
    Assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Kaplan-Meier estimates will be generated.

  5. Progression-free survival (PFS) [ Time Frame: Time to disease progression/relapse or death as a result of any cause, assessed up to 36 months ]
    Assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Kaplan-Meier estimates will be generated.

  6. Time-to-treatment failure [ Time Frame: Up to 36 months ]
    Defined as time to treatment termination for any reason. Assessed by Response Evaluation Criteria in Solid Tumors version 1.1.


Other Outcome Measures:
  1. Androgen receptor expression profile [ Time Frame: Up to 36 months ]
    Assessed in tumor by immunohistochemistry.

  2. Micro ribonucleic acid (miRNA)/messenger ribonucleic acid (mRNA) profiling [ Time Frame: Up to 36 months ]
    Assessed in tumor and blood.

  3. Number of circulating tumor cells and quantitation of circulating tumor deoxyribonucleic acid (ctDNA) [ Time Frame: Up to 36 months ]
    Assessed in blood.

  4. PD-L1 and tumor infiltrating lymphocyte profile, immune signatures, and genomic analysis [ Time Frame: Up to 36 months ]
    Assessed in tumor.

  5. Temporal profile of tumor-derived exosomes [ Time Frame: Up to 36 months ]
    assessed in peripheral blood

  6. Temporal profile of tumor infiltrating lymphocyte subsets and other immunological correlatives [ Time Frame: Up to 36 months ]
    Assessed in tumor and blood.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 =< 10% positive tumor nuclei), progesterone receptor (PR) negative (PR expression =< 10% positive tumor nuclei) and HER2 negative breast cancer by IHC and /or fluorescence in situ hybridization (FISH)
  • Androgen receptor positive (AR+)

    • Defined as >= 50% nuclear AR staining by immunohistochemistry (IHC) in either the primary or metastatic lesion
    • NOTE: Research testing of AR status is available at City of Hope Pathology
  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02971761


Locations
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United States, California
City of Hope Corona
Corona, California, United States, 92879
City of Hope Medical Center
Duarte, California, United States, 91010
City of Hope Antelope Valley
Lancaster, California, United States, 93534
City of Hope Mission Hills
Mission Hills, California, United States, 91345
City of Hope Rancho Cucamonga
Rancho Cucamonga, California, United States, 91730
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States, 95817
City of Hope South Pasadena
South Pasadena, California, United States, 91030
City of Hope West Covina
West Covina, California, United States, 91790
United States, Kansas
University of Kansas Cancer Center
Kansas City, Kansas, United States, 66160
United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
United States, Utah
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, United States, 84112
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Yuan Yuan, MD, PhD City of Hope Medical Center

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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02971761     History of Changes
Other Study ID Numbers: 16131
NCI-2016-01759 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
16131 ( Other Identifier: City of Hope Medical Center )
First Posted: November 23, 2016    Key Record Dates
Last Update Posted: August 16, 2019
Last Verified: November 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Pembrolizumab
Androgens
Antineoplastic Agents, Immunological
Antineoplastic Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs