Orteronel as Monotherapy in Patients With Metastatic Breast Cancer (MBC) That Expresses the Androgen Receptor (AR)
Verified June 2014 by SCRI Development Innovations, LLC
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
SCRI Development Innovations, LLC
First received: November 8, 2013
Last updated: June 12, 2014
Last verified: June 2014
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.
Metastatic Breast Cancer
||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
||A Phase II Study With Orteronel as Monotherapy in Patients With Metastatic Breast Cancer (MBC) That Expresses the Androgen Receptor (AR)
Primary Outcome Measures:
- Response rate (RR) [ Time Frame: 36 months ] [ Designated as safety issue: No ]
- RR following treatment with orteronel in patients with refractory metastatic triple-negative breast cancer expressing AR (ER-/PR-/HER2-/AR+); and
- RR following treatment with orteronel in patients with refractory ER+ and/or PR+/AR+ breast cancer.
- Disease Control Rate (DCR) [ Time Frame: 36 months ] [ Designated as safety issue: No ]
- DCR following treatment with orteronel in patients with refractory metastatic triple-negative breast cancer expressing AR (ER-/PR-/HER2-/AR+); and
- DCR following treatment with orteronel in patients with refractory ER+ and/or PR+/AR+ breast cancer.
Secondary Outcome Measures:
- Assessment of safety based on frequency of Adverse Events (AEs) [ Time Frame: 36 months ] [ Designated as safety issue: Yes ]
Assessment of safety will be based on frequency of AEs and on the number of laboratory events that fall outside of predetermined ranges as assessed by the investigator. The incidence of treatment-emergent AEs will be summarized by system organ class, severity (NCI CTCAE, Version 4.0), type of AE, and relationship to study drug.
- Progression-free survival (PFS) [ Time Frame: 36 months ] [ Designated as safety issue: No ]
- Overall survival (OS) [ Time Frame: 48 months ] [ Designated as safety issue: No ]
- Serum hormone levels [ Time Frame: 36 months ] [ Designated as safety issue: No ]
Measurement of serum estradiol levels, total and free testosterone levels, and sex hormone binding globulin (SHBG) during treatment with orteronel
- ACTH levels [ Time Frame: 36 months ] [ Designated as safety issue: No ]
Measurement of adrenocorticotropic hormone (ACTH)levels during treatment with orteronel
- DHEA-S levels [ Time Frame: 36 months ] [ Designated as safety issue: No ]
Measurement of dehydroepiandrosterone sulfate (DHEA-S) levels during treatment with orteronel
- Cortisol levels [ Time Frame: 36 months ] [ Designated as safety issue: No ]
Measurement of cortisol levels during treatment with orteronel
| Estimated Enrollment:
| Study Start Date:
| Estimated Study Completion Date:
| Estimated Primary Completion Date:
||January 2018 (Final data collection date for primary outcome measure)
The planned dose of orteronel is 300mg orally (PO) twice daily (BID), for a total daily dose of 600mg.
Other Name: Tak-700
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.
|Ages Eligible for Study:
||18 Years and older
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
- Voluntary written informed consent before performance of any study-related procedure not part of normal medical care
- 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.
- 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.
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.
- Female or male patients ≥18 years-of-age
- Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
- Patient has recovered (to Grade ≤1) from all clinically significant toxicities related to prior antineoplastic therapies (with the exception of alopecia)
Adequate hematological function, defined as:
- Absolute neutrophil count (ANC) ≥1.25 x 109/L
- Platelets ≥75 x 109/L
- Hemoglobin ≥9 g/dL
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)
Adequate renal function, defined as:
- Creatinine ≤1.5 x ULN or creatinine clearance ≥40 mL/min as calculated by the Cockcroft-Gault method
- Screening calculated LVEF of ≥50% by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan
- Ability to swallow and retain oral medication
- 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
- 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
- Life expectancy of ≥3 months
- Willingness and ability to understand the nature of this study and to comply with the study and follow-up procedures.
- Known hypersensitivity to orteronel or to orteronel excipients, which are listed by formulation in the Investigator Brochure
- 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.
- Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period.
- Prior anti-androgen therapy
- 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.
- 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.
- Patients with known adrenal insufficiency, or patients receiving treatment with ketoconazole, abiraterone, or aminoglutethimide.
- 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.
- Major surgical procedures ≤28 days of beginning study treatment or minor surgical procedures ≤7 days. No waiting is required following port-a-cath placement.
- 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).
- 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.
- New York Heart Association (NYHA) Class III or IV heart failure
- Electrocardiogram (ECG) abnormalities of Q-wave infarction, unless identified 6 or more months prior to screening or QTc Fridericia (F) interval >460 msec
- 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.
- 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
- 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.
- 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
- Inability or unwillingness (including psychological, familial, sociological, or geographical conditions) to comply with study and/or follow-up procedures as outlined in the protocol.
- Use of a prohibited concomitant medication that cannot be safely discontinued or substituted.
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, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01990209
|Florida Hospital Cancer Institute
|Orlando, Florida, United States, 32804 |
|Hope Cancer Center
|Terre Haute, Indiana, United States, 47802 |
|Baptist Hospital East
|Louisville, Kentucky, United States, 40207 |
|Center for Cancer and Blood Disorders
|Bethesda, Maryland, United States, 20817 |
|Tennessee Oncology PLLC
|Chattanooga, Tennessee, United States, 37404 |
|Tennessee Oncology PLLC
|Nashville, Tennessee, United States, 37203 |
SCRI Development Innovations, LLC
Millennium Pharmaceuticals, Inc.
||Howard A Burris, III, MD
||SCRI Development Innovations, LLC
No publications provided
||SCRI Development Innovations, LLC
History of Changes
|Other Study ID Numbers:
||SCRI BRE 203
|Study First Received:
||November 8, 2013
||June 12, 2014
||United States: Food and Drug Administration
Keywords provided by SCRI Development Innovations, LLC:
triple-negative breast cancer
metastatic breast cancer
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on July 24, 2014
Neoplasms by Site
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs