An study to investigate the combination therapy of MLN0128 plus Exemestane or Fulvestrant in post-menopausal women with advanced breast cancer or cancer that has spread and whose disease had worsened while on combination therapy with Everolimus plus Exemestane or Fulvestrant
- Conditions
- ER+/HER2- Advanced or Metastatic Breast CancerMedDRA version: 18.1Level: LLTClassification code 10072737Term: Advanced breast cancerSystem Organ Class: 100000004864MedDRA version: 18.1Level: LLTClassification code 10027475Term: Metastatic breast cancerSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2014-001921-34-FR
- Lead Sponsor
- Millennium Pharmaceuticals, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- Female
- Target Recruitment
- 118
1. Histological or cytological confirmation of ER+ (defined as > 1% positive tumor cells) advanced or metastatic breast cancer.
2. Histological or cytological confirmation of HER2-negative (HER2-) advanced or metastatic breast cancer by local laboratory testing using criteria in the American Society of Oncology (ASCO)/College of American Pathologists (CAP) Clinical Practice Guideline update.
3. Female patients 18 years of age or older who:
- Are postmenopausal for at least 1 year before the Screening visit, where menopause is defined by:
o Age = 55 years and 1 year or more of amenorrhea
o Age < 55 years and 1 year or more of amenorrhea, with an estradiol assay < 20 pg/mL
o Surgical menopause with bilateral oophorectomy
4. Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met:
- Brain metastases which have been treated
- No evidence of disease progression for ? 3 months or hemorrhage after treatment
- Off-treatment with dexamethasone for 4 weeks before administration of the first dose of MLN0128
- No ongoing requirement for dexamethasone or anti-epileptic drugs
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 as defined in the protocol
6. Clinical laboratory values as specified below within 4 weeks before the first dose of MLN0128:
- Bone marrow reserve consistent with absolute neutrophil count (ANC) = 1.5 x 109/L; platelet count = 100 x 109/L; hemoglobin = 9 g/dL
- Total bilirubin = 1.5 x the upper limit of the normal range (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2.5 x ULN (= 5 xULN if liver metastases are present)
- Creatinine clearance = 50 mL/min based either on Cockcroft-Gault estimate or based on a 12- or 24-hour urine collection
- Fasting serum glucose = 130 mg/dL and fasting triglycerides = 300 mg/dL
7. Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of institutional standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks before the first dose of MLN0128 (ie, if the institutional standard of normal is 50%, LVEF may be as low as 45% to be eligible for the study).
8. Able to provide paraffin blocks or a minimum of 10 unstained slides of available archival tumor tissues (paraffin blocks are preferred). If archival tumor tissue is not available, a tumor biopsy may be performed before the patient begins treatment with MLN0128. If fewer than 10 slides are available or the tumor content/area
requirements are not met, study eligibility will be determined upon discussion with the sponsor.
9. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and suitable venous access for the study-required blood sampling.
10. Voluntary written consent must be given before the performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
Phase 1b Only:
11. Patients may have SD or disease progression during their most recent treatment with exemestane or fulvestrant, or everolimus treatment in combination with either exemestane or fulvestrant. Exemestane or fulvestrant in combination with MLN0128 can also be initiated as a new line of therapy.
Phase 2 Only
12. Measureable disease defined as follows:
- At least 1 extra-osseous lesion that can be accurately measure
1. Prior anticancer therapy or other investigational therapy within 2 weeks before administration of the first dose of MLN0128 (except for exemestane or fulvestrant, which should be continued). Treatment with everolimus must be discontinued 2 weeks before administration of the first dose of MLN0128.
2. Chronic concomitant therapy with bisphosphonates or denosumab for the prevention of bone metastases. Concomitant treatment with bisphosphonates is permitted for treatment of osteoporosis or management of existing bone metastases if initiated at least 4 weeks before administration of the first dose of MLN0128.
3. Treatment with strong CYP3A4 and CYP2C19 inhibitors and/or inducers and moderate inhibitors of CYP2C9 must be discontinued at least 1 week before administration of the first dose of MLN0128.
4. Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids (either IV or oral steroids, excluding inhalers) within 1 week before administration of the first dose of MLN0128 (patients already receiving erythropoietin on a chronic basis for = 4 weeks are eligible).
5. Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, TORC1/2 inhibitors or TORC1 inhibitors, with the exception of everolimus.
6. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of MLN0128.
7. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) > 7%; patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/exclusion criteria are met.
8. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise participation of the patient in the study.
9. Known human immunodeficiency virus infection.
10. History of any of the following within the last 6 months before administration of the first dose of MLN0128:
- Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures
- Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures
- Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia)
- Placement of a pacemaker for control of rhythm
- New York Heart Association Class III or IV heart failure
- Pulmonary embolism
11. Significant active cardiovascular or pulmonary disease before administration of the first dose of MLN0128, including:
- Uncontrolled hypertension (ie, systolic blood pressure > 180 mm Hg; diastolic blood pressure > 95 mm Hg)
- Pulmonary hypertension
-Uncontrolled asthma or oxygen saturation < 90% by arterial blood gas analysis or pulse oximetry on room air
- Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention; or history of valve replacement
- Medically significant (symptomatic) bradycardia
- History of arrhythmia requiring an implantable cardiac defibrillator
- Baseline prolongation of the rate-corrected QT interval (QTc; eg, repeated demonstration of QTc interval > 480 ms, or history of congenital long QT syndrome, or torsades de pointes)
12. Diagnosed
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method