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.
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)
