Orteronel as Monotherapy in Patients With Metastatic Breast Cancer (MBC) That Expresses the Androgen Receptor (AR)
Condition: Metastatic Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Orteronel
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 71.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: triple-negative breast cancer; orteronel; TAK-700; metastatic breast cancer

Summary:

      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.
    

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.