Advanced or Metastatic Breast Cancer. MedDRA version: 19.0 Level: PT Classification code 10006187 Term: Breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: MLN0128
Product Code: TAK-228
Pharmaceutical Form: Capsule
INN or Proposed INN: TAC-228
CAS Number: 1224844-38-5
Current Sponsor code: MLN0128
Concentration unit: mg milligram(s)
Concent
Sponsors
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Female patients aged 18 years or older who are postmenopausal. Postmenopausal is defined as: - Aged > or = 55 years and 1 year or more of natural amenorrhea prior to the Screening visit, or - Aged 40 mIU/mL and an estradiol level of <20 pg/mL, or - Surgical menopause with bilateral oophorectomy. Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression. 2. Histologically proven diagnosis of breast cancer with evidence of metastatic disease or locoregional recurrence, not amenable to resection or radiation therapy with curative intent. 3. Histological confirmation and documentation of ER-positive status (?1% positive stained cells) by local laboratory testing utilizing an assay consistent with local standards. 4. Histological or cytological confirmation and documentation of HER2-negative status by local laboratory testing using criteria in the American Society of Oncology (ASCO)/College of American Pathologists (CAP) Clinical Practice Guideline update. 5. Measureable disease defined as: - At least 1 extra-osseous lesion that can be accurately measured in at least 1 dimension. The lesion must measure ?20 mm with conventional imaging techniques or ?10 mm with spiral CT or MRI, or - Bone lesions (lytic or mixed [lytic plus sclerotic]) in the absence of measurable disease as defined above. Note: Patients with sclerotic/osteoblastic bone lesions only, in the absence of measurable disease, are not eligible. 6. PD during prior AI therapy defined as: - Progression during or within 12 months after completion or discontinuation of adjuvant therapy or - Progression during or within 1 month after the end of therapy in the metastatic setting. Note: AI is not required to be the most recent therapy, but progression on AI and progression on most recent therapy are both required for eligibility. 7. Patients who have a history of brain metastasis are eligible for the study provided that all of the following criteria are met: - Brain metastases have been treated. - No evidence of PD for 3 months before the first dose of study drug. - No hemorrhage after treatment. - Off dexamethasone treatment for ?4 weeks before the first dose of study drug. - No ongoing requirement for dexamethasone or anti-epileptic drugs. 8. ECOG performance status of 0 or 1 (refer to Appendix D). 9. Clinical laboratory values as specified below within 4 weeks before the first dose of study drug: - Bone marrow reserve consistent with absolute neutrophil count (ANC) ?1.5x10^9/L; platelet count ?100x10^9/L; hemoglobin (Hgb) ?9 g/dL. - Total bilirubin ?1.5 x the upper limit of the normal range (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ?2.5xULN (?5xULN if liver metastases are present). - Creatinine clearance ?40 mL/min based on Cockcroft-Gault estimate (refer to Appendix E) or based on a 12- or 24-hour urine collection. - Fasting serum glucose ?130 mg/dL and fasting triglycerides ?300 mg/dL. 10. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and suitable venous access for the study-required blood sampling. 11. Voluntary written consent must be given by the patient (or the patient?s legally acceptable representative) before performance of any study-related procedure that is not p
Exclusion criteria
Exclusion criteria: 1. Prior therapy with mTOR, PI3K, or dual PI3K-mTOR inhibitors, AKT inhibitors, or fulvestrant. 2. Prior treatment with >1 line of chemotherapy for metastatic breast cancer or for locoregional recurrence that was not amenable to resection or radiation therapy with curative intent. 3. Experienced recurrent or PD on >2 endocrine therapies for metastatic breast cancer or for locoregional recurrence that was not amenable to resection or radiation therapy with curative intent. 4. Life-threatening metastatic visceral disease (defined as extensive hepatic involvement or symptomatic pulmonary lymphangitic spread). Patients with discrete pulmonary parenchymal metastases are eligible, provided their respiratory function is not compromised as a result of disease. 5. Other clinically significant comorbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the patient?s participation in the study. 6. History of any of the following within the last 6 months before the first dose of study drug: - 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 (see Appendix F). - Pulmonary embolism. 7. Significant active cardiovascular or pulmonary disease, including: - Uncontrolled hypertension (ie, either systolic blood pressure >180 mm Hg or diastolic blood pressure >95 mm Hg). - Pulmonary hypertension. - Uncontrolled asthma or oxygen saturation 480 ms, or history of congenital long QT syndrome, or torsades de pointes). 8. Diagnosed with or treated for another malignancy within 2 years before the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. 9. Prior anticancer therapy or other investigational therapy within 2 weeks before the first dose of study drug. 10. Chronic concomitant therapy with bone-targeting agents (eg, bisphos, denosumab) for the prevention of bone metastases. Concomitant treatment with bone-targeting agents is permitted for treatment of osteoporosis or management of existing bone metastases if initiated at least 4 weeks before the first dose of study drug. 11. Treatment with strong cytochrome P450 (CYP) 3A4, CYP2C9, and/or CYP2C19 inhibitors and/or inducers within 1 week before the first dose of study drug (see Appendix G). 12. Initiation of treatment with systemic corticosteroids (either IV or oral steroids) within 1 week before the first dose of study drug. However, inhale
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - To compare the PFS of patients treated with the combination of fulvestrant+daily MLN0128 versus patients treated with single-agent fulvestrant. - To compare the PFS of patients treated with the combination of fulvestrant+weekly MLN0128 versus patients treated with single-agent fulvestrant.;Secondary Objective: - To compare secondary efficacy endpoints in patients treated with the combination of fulvestrant+daily MLN0128 versus patients treated with single-agent fulvestrant. - To compare secondary efficacy endpoints in patients treated with the combination of fulvestrant+weekly MLN0128 versus patients treated with single-agent fulvestrant. - To assess the safety and tolerability of the combination of fulvestrant+MLN0128. - To collect plasma concentration-time data with sparse PK sampling (combination fulvestrant+MLN0128 treatment arms [Arm B and Arm C] only), to contribute to future population PK analysis.;Primary end point(s): The primary endpoint is: - PFS.;Timepoint(s) of evaluation of this end point: A final analysis of PFS will be performed after the required number of events has been observed which is expected approximately 20 months after the first patient is randomized. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Overall survival (OS). - Time to progression (TTP). - Objective response rate (ORR); defined as CR+PR per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [1]. - CBR; defined as CR+PR+SD with SD of any duration, and CBR with SD duration of at least 6 months. - The number and percentage of patients with treatment-emergent AEs.;Timepoint(s) of evaluation of this end point: ORR is defined as the proportion of patients who achieve a best response of complete response (CR) or partial response (PR) according to RECIST 1.1 criteria [1]. CBR is defined as the proportion of patients who achieve a best response of CR, PR, or SD. The CBR will also be presented for a best response of CR, PR, and SD of at least 6 months. TTP is defined as the time from the date of randomization to the date of first documentation of progression. For a patient whose disease has not progressed, TTP will be censored at the last response assessment that is SD or better. TTP will be analyzed using similar methods as the primary endpoint of PFS. AEs will be collected throughout the study. | — |
Countries
Spain, United States
Contacts
Public ContactClinical Operations
GEICAM (Grupo Español de Investigación en Cáncer de Mama)
Outcome results
None listed