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

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)

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 (metastatic). 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.

Study Overview

• Status: Completed
• Conditions: Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Metastatic Triple-Negative Breast Carcinoma; Stage IV Breast Cancer AJCC v6 and v7; Androgen Receptor Positive
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab; Drug: Enobosarm

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Corona, California, United States, 92879
      • City of Hope Corona
    • Duarte, California, United States, 91010
      • City of Hope Medical Center
    • Lancaster, California, United States, 93534
      • City of Hope Antelope Valley
    • Mission Hills, California, United States, 91345
      • City of Hope Mission Hills
    • Rancho Cucamonga, California, United States, 91730
      • City of Hope Rancho Cucamonga
    • South Pasadena, California, United States, 91030
      • City of Hope South Pasadena
    • West Covina, California, United States, 91790
      • City of Hope West Covina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 (COH) 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 (within 14 days prior to day 1 of protocol therapy)
• Platelets >= 100,000/mm^3 (within 14 days prior to day 1 of protocol therapy)
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (within 14 days prior to day 1 of protocol therapy)
• Serum total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN if total bilirubin levels > 1.5 x ULN (within 14 days prior to day 1 of protocol therapy)
• Albumin >= 2.5 mg/dL (within 14 days prior to day 1 of protocol therapy)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN OR =< 5.0 x ULN if liver metastases present (within 14 days prior to day 1 of protocol therapy)
• 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 (within 14 days prior to day 1 of protocol therapy)
• 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 (within 14 days prior to day 1 of protocol therapy)

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 form 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 cycles in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Pembrolizumab; Given IV; Other Names: Keytruda; MK-3475; Lambrolizumab; SCH 900475; Drug: Enobosarm; Given PO; Other Names: Ostarine; Gtx-024

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate (Complete Response or Partial Response)	Response rate (complete response or partial response) assessed using Response Evaluation Criteria in Solid Tumors version 1.1.	Up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Progression-free survival assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Kaplan-Meier estimates will be generated.	Time to disease progression/relapse or death as a result of any cause, assessed up to 36 months
Clinical Benefit Rate	Clinical benefit rate assessed by immune-related Response Evaluation Criteria in Solid Tumors version 1.1.	At 16 weeks
Overall Survival	Overall survival assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Kaplan-Meier estimates will be generated.	Time to death as a result of any cause, assessed up to 36 months
Progression-free Survival	Progression-free survival 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.	Up to 1 year

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Yuan Yuan, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2017
• Primary Completion (Actual): October 28, 2020
• Study Completion (Actual): August 16, 2022

Study Registration Dates

• First Submitted: November 21, 2016
• First Submitted That Met QC Criteria: November 21, 2016
• First Posted (Estimated): November 23, 2016

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: 16131 (Other Identifier: City of Hope Medical Center); NCI-2016-01759 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No