Clinical Trials /

Orteronel as Monotherapy in Patients With Metastatic Breast Cancer (MBC) That Expresses the Androgen Receptor (AR)

NCT01990209

Description:

The androgen receptor (AR) is expressed in 70-90 percent of primary breast tumors and in 75 percent of breast metastases. There is evidence to suggest that Androgen Receptor (AR) may be a target in patients with advanced breast cancer. Breast cancer patients whose tumors do not express the ER, PR or HER2 (triple negative) have very few options for treatment. Orteronel is being developed as an endocrine therapy for relevant hormone-sensitive cancers such as prostrate cancer and breast cancer. Triple-negative metastatic breast cancer patients with AR expression could potentially benefit from anti-androgen therapy like orteronel.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Orteronel</span> as Monotherapy in Patients With Metastatic <span class="go-doc-concept go-doc-disease">Breast Cancer</span> (MBC) That Expresses the Androgen Receptor (<span class="go-doc-concept go-doc-biomarker">AR</span>)

Title

  • Brief Title: Orteronel as Monotherapy in Patients With Metastatic Breast Cancer (MBC) That Expresses the Androgen Receptor (AR)
  • Official Title: A Phase II Study With Orteronel as Monotherapy in Patients With Metastatic Breast Cancer (MBC) That Expresses the Androgen Receptor (AR)
  • Clinical Trial IDs

    NCT ID: NCT01990209

    ORG ID: SCRI BRE 203

    Trial Conditions

    Metastatic Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Orteronel Tak-700 Orteronel

    Trial Purpose

    The androgen receptor (AR) is expressed in 70-90 percent of primary breast tumors and in 75
    percent of breast metastases. There is evidence to suggest that Androgen Receptor (AR) may
    be a target in patients with advanced breast cancer. Breast cancer patients whose tumors do
    not express the ER, PR or HER2 (triple negative) have very few options for treatment.
    Orteronel is being developed as an endocrine therapy for relevant hormone-sensitive cancers
    such as prostrate cancer and breast cancer. Triple-negative metastatic breast cancer
    patients with AR expression could potentially benefit from anti-androgen therapy like
    orteronel.

    Detailed Description

    This open-label multicenter study will be conducted in 2 stages.

    - Lead-in Phase: The first 6 patients treated will be evaluated to confirm the safety and
    feasibility of this regimen. After all 6 patients complete at least 4 weeks of
    treatment, and if no prohibitive toxicities are identified, continuous study treatment
    will begin.

    - Continuous Study Treatment: Patients will continue to be enrolled into both cohorts
    based on their tumor specificities with a total of 31 patients in Cohort 1
    (ER-/PR-/HER2-/AR+) and 55 patients in Cohort 2 (ER+ and/or PR+/AR+).

    Patients will be evaluated every eight weeks for response to treatment. All patients who
    respond to treatment (complete response [CR] or partial response [PR]) or have stable
    disease (SD) will continue to receive orteronel until they develop progressive disease (PD)
    or unacceptable toxicity.

    Trial Arms

    Name Type Description Interventions
    Orteronel Experimental The planned dose of orteronel is 300mg orally (PO) twice daily (BID), for a total daily dose of 600mg. Orteronel

    Eligibility Criteria

    Inclusion Criteria:

    1. Voluntary written informed consent before performance of any study-related procedure
    not part of normal medical care

    2. Patients must have MBC that is measurable or evaluable as defined by Response
    Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Patients with metastases
    limited to the bones are eligible.

    3. Patients with breast tumors that are AR+ (10% staining by immunohisto-chemistry).
    Archived tumor tissue from a primary biopsy or metastatic lesion for centralized
    determination of AR expression is mandatory. If tissue is limited, the additional
    correlative testing is optional. If tissue is not available, a patient will not be
    eligible for enrollment into the study. Patients may enroll based on local laboratory
    AR assessment, but will need to submit tissue for confirmation at the central
    laboratory.

    4. In addition to having AR+ tumors, patients must fit into 1 of the 2 following
    categories:

    - Triple negative (ER-/PR-/HER2-) (Note: This group of patients must have received
    at least 1 and up to 3 prior chemotherapy regimens in the advanced setting.)

    - ER+ and/or PR+ (Note: This group of patients must have received at least 1 and
    up to 3 prior hormonal therapies and at least one prior chemotherapy treatment
    in the advanced setting. HER2+ patients in this group must have received a
    minimum of 2 lines of HER2-directed therapy in the advanced setting.) This group
    of patients may be pre-menopausal with ovarian suppression or post-menopausal.
    LHRH agonists maybe used to render ovarian suppression with post-menopausal
    ranges of estradiol or FSH per institutional guidelines.

    5. Female or male patients 18 years-of-age

    6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2

    7. Patient has recovered (to Grade 1) from all clinically significant toxicities
    related to prior antineoplastic therapies (with the exception of alopecia)

    8. Adequate hematological function, defined as:

    - Absolute neutrophil count (ANC) 1.25 x 109/L

    - Platelets 75 x 109/L

    - Hemoglobin 9 g/dL

    9. Adequate liver function, defined as:

    - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5 x the
    upper limit of normal (ULN), if no liver involvement or 5 x ULN with liver
    involvement

    - Total bilirubin 1.5 times the upper limit of normal (ULN) (in patients with
    known Gilbert Syndrome, a total bilirubin 3.0 x ULN, with direct bilirubin 1.5
    x ULN)

    10. Adequate renal function, defined as:

    - Creatinine 1.5 x ULN or creatinine clearance 40 mL/min as calculated by the
    Cockcroft-Gault method

    11. Screening calculated LVEF of 50% by echocardiogram (ECHO) or multiple-gated
    acquisition (MUGA) scan

    12. Ability to swallow and retain oral medication

    13. Male patients (even those post vasectomy) who are willing to use adequate
    contraceptive measures or abstain from heterosexual intercourse during the entire
    study treatment period and for 4 months after the last dose of study drug

    14. Female patients who are not of child-bearing potential and female patients of
    child-bearing potential who agree to use adequate contraceptive measures or abstain
    from heterosexual intercourse during the entire study treatment period and for 4
    months after the last dose of study drug, who are not breastfeeding, and who have had
    a negative serum/urine pregnancy test 7 days prior to dosing

    15. Life expectancy of 3 months

    16. Willingness and ability to understand the nature of this study and to comply with the
    study and follow-up procedures.

    Exclusion Criteria:

    1. Known hypersensitivity to orteronel or to orteronel excipients, which are listed by
    formulation in the Investigator Brochure

    2. Patients receiving other treatment for breast cancer (includes standard hormonal
    therapy, chemotherapy, biologic therapy, immunotherapy, or radiation therapy).
    Patients receiving chronic bisphosphonate or denosumab therapy are eligible.

    3. Female patients who are both lactating and breastfeeding or have a positive serum
    pregnancy test during the screening period.

    4. Prior anti-androgen therapy

    5. Use of an investigational drug 21 days or 5 half-lives (whichever is shorter) prior
    to the first dose of orteronel, or concurrent treatment. For investigational drugs
    for which 5 half-lives is less than 21 days, a minimum of 10 days between termination
    of the investigational drug and administration of orteronel is required.

    6. Active brain metastases or leptomeningeal disease. Previously treated brain
    metastases are allowed provided lesions are stable for at least 3 months as
    documented by head CT scan or magnetic resonance imaging (MRI) of the brain. Patients
    must be off steroids, but anti-convulsants are allowed.

    7. Patients with known adrenal insufficiency, or patients receiving treatment with
    ketoconazole, abiraterone, or aminoglutethimide.

    8. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89)
    administered 28 days or limited field radiation for palliation 7 days prior to
    starting study drug or has not recovered from side effects of such therapy.

    9. Major surgical procedures 28 days of beginning study treatment or minor surgical
    procedures 7 days. No waiting is required following port-a-cath placement.

    10. Presence of active gastrointestinal (GI) disease or other condition that will
    interfere significantly with the absorption, distribution, metabolism, or excretion
    of oral therapy (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhea
    Grade 2, and malabsorption syndrome).

    11. History of myocardial infarction, unstable symptomatic ischemic heart disease,
    ongoing arrhythmias > Grade 2 (National Cancer Institute [NCI] Common Terminology
    Criteria for Adverse Events [CTCAE], Version 4.0), thromboembolic events (eg, deep
    vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any
    other cardiac condition (eg, pericardial effusion restrictive cardiomyopathy) within
    6 months prior to first dose of study drug. Chronic stable atrial fibrillation on
    stable anticoagulant therapy is allowed.

    12. New York Heart Association (NYHA) Class III or IV heart failure

    13. Electrocardiogram (ECG) abnormalities of Q-wave infarction, unless identified 6 or
    more months prior to screening or QTc Fridericia (F) interval >460 msec

    14. Inadequately controlled hypertension (ie, systolic blood pressure [SBP] >160 mmHg or
    diastolic BP [DBP] >90 mmHg) at 2 separate measurements no more than 60 minutes apart
    during the Screening visit. Note: patients may be rescreened after adjustment of
    antihypertensive medications.

    15. Known diagnosis of human immunodeficiency virus, active chronic hepatitis B, or C,
    life-threatening illness unrelated to cancer, or any serious medical or psychiatric
    illness that could, in the investigator's opinion, potentially interfere with
    participation in this study

    16. Uncontrolled diabetes mellitus. Patients with Type II diabetes are eligible if they
    require only oral hypoglycemic agents and fasting blood glucose level is 120.
    Patients with Type I diabetes are eligible if their glycosylated hemoglobin (HbAlc)
    is 7.

    17. Diagnosis or treatment for another malignancy within 2 years of enrollment, with the
    exception of adequately treated in-situ carcinoma of the cervix, uteri, basal or
    squamous cell carcinoma or non-melanomatous skin cancer

    18. Inability or unwillingness (including psychological, familial, sociological, or
    geographical conditions) to comply with study and/or follow-up procedures as outlined
    in the protocol.

    19. Use of a prohibited concomitant medication that cannot be safely discontinued or
    substituted.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Response rate (RR)

    Disease Control Rate (DCR)

    Secondary Outcome Measures

    Assessment of safety based on frequency of Adverse Events (AEs)

    Progression-free survival (PFS)

    Overall survival (OS)

    Measurement of changes in serum hormone levels

    Trial Keywords

    triple-negative breast cancer

    orteronel

    TAK-700

    metastatic breast cancer