Safety and Efficacy Study of MLN0128 in Combination With Exemestane or Fulvestrant in Postmenopausal Women With ER/PR+ Metastatic Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2016 by Millennium Pharmaceuticals, Inc.
Sponsor:
Information provided by (Responsible Party):
Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT02049957
First received: December 12, 2013
Last updated: February 22, 2016
Last verified: February 2016
  Purpose
This is a phase 1b/2 study of the safety and efficacy of MLN0128 in combination with exemestane or fulvestrant therapy in women with estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) advanced or metastatic breast cancer that has progressed on treatment with everolimus in combination with exemestane or fulvestrant.

Condition Intervention Phase
Breast Cancer
Drug: MLN0128
Drug: Fulvestrant
Drug: Exemestane
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Study of Safety and Efficacy of MLN0128 (Dual TORC1/2 Inhibitor) in Combination With Exemestane or Fulvestrant Therapy in Postmenopausal Women With ER+/HER2- Advanced or Metastatic Breast Cancer That Has Progressed on Treatment With Everolimus in Combination With Exemestane or Fulvestrant

Resource links provided by NLM:


Further study details as provided by Millennium Pharmaceuticals, Inc.:

Primary Outcome Measures:
  • Phase 1B: Percentage of Number of participants experiencing adverse events [ Time Frame: From frist dose through 30 days after the last dose of study drug ] [ Designated as safety issue: Yes ]
    Adverse events, SAEs, assessments of clinical laboratory values, vital sign measurements, physical examination findings, and electrocardiograms (ECGs)

  • Phase 2: Clinical benefit rate at 16 weeks [ Time Frame: At screening and at 16 weeks ] [ Designated as safety issue: No ]
    Proportion of patients who achieve complete response (CR) or partial response (PR) of any duration or have stable disease (SD) at 16 weeks


Secondary Outcome Measures:
  • Clinical benefit rate at 24 weeks [ Time Frame: At screening and at 24 weeks ] [ Designated as safety issue: No ]
  • Overall response rate (ORR, best response of complete or partial response) [ Time Frame: Time from the start of treatment to the occurrence of disease progression, unacceptable toxicities, discontinuation of study due to any other reasons, or end of study (EOS) up to 24 months ] [ Designated as safety issue: No ]
  • Change in tumor size from baseline [ Time Frame: At screening, every 2 cycles from cycles 2 through 6, and every 3 cycles thereafter in a 28-day cycle up to 24 months ] [ Designated as safety issue: No ]
  • Steady-state PK parameters [ Time Frame: Day 15 of cycles 1 and 2, cycle 2 day 1, cycle 3 day 8 in a 28-day cycle ] [ Designated as safety issue: No ]
    Includes single-dose maximum (peak) concentration (Cmax), Tmax, area under the plasma concentration versus time curve from zero to 24 hours (AUC24h), area under the plasma concentration versus time curve from zero to the last measurable concentration (AUCt), and t1/2

  • Pharmacodynamic activity of MLN0128 with respect to TORC1 and TORC2 markers in the presence of exemestane in patients in the PK/Tumor-PD Cohort [ Time Frame: At screening, once in cycle 1 in a 28-day cycle, and at the end of treatment to occur within 24 months ] [ Designated as safety issue: No ]
  • Progression-free survival (PFS) [ Time Frame: Time from the start of treatment to the occurrence of disease progression or initiation of a new anticancer therapy, whichever occurs first, within a 24 month period. ] [ Designated as safety issue: No ]
  • Overall survival (OS) [ Time Frame: Time from the start of treatment to the occurrence of death or 24 months, whichever occurs first. ] [ Designated as safety issue: No ]

Estimated Enrollment: 126
Study Start Date: February 2014
Estimated Study Completion Date: November 2017
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: MLN0128 + Exemestane Drug: MLN0128
Phase 1B: 2, 3, 4, or 5 mg once daily; Phase 2: dose determined after Phase 1B
Drug: Exemestane
25 mg once daily
Experimental: MLN0128 + Fulvestrant Drug: MLN0128
Phase 1B: 2, 3, 4, or 5 mg once daily; Phase 2: dose determined after Phase 1B
Drug: Fulvestrant
Phase 1B: 500 mg monthly; Phase 2: 250 or 500 mg monthly

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Each patient must meet all of the following inclusion criteria to be enrolled in the study:

Phase 1b and Phase 2

  1. Advanced or metastatic breast cancer.
  2. Histological or cytological confirmation of ER+ status (defined as > 1% positive tumor cells), and histological or cytological confirmation of HER2-negative (HER2-) status by local laboratory testing using criteria in the American Society of Oncology (ASCO)/College of American Pathologists (CAP) Clinical Practice Guideline update.[44]
  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: Age ≥ 55 years and 1 year or more of amenorrhea

    Age < 55 years and 1 year or more of amenorrhea, with an estradiol assay < 20 pg/mL oSurgical 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.

  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 to 2.
  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 10^9/L; platelet count ≥ 100 x 10^9/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 x ULN 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: In addition to the previously mentioned inclusion criteria, each patient must meet the following inclusion criterion to be enrolled in the phase 1b portion of the study:

  11. Patients may have SD or disease progression during their most recent treatment with exemestane or fulvestrant, or everolimus in combination with either exemestane (any country) or fulvestrant (US only). Exemestane or fulvestrant in combination with MLN0128 can also be initiated as a new line of therapy.

    Phase 2 Only: In addition to the previously mentioned inclusion criteria, each patient must meet all of the following inclusion criteria to be enrolled in the phase 2 portion of the study:

  12. Measureable disease defined as follows:

    • 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
  13. Patients must have had disease progression during treatment with everolimus in combination with either exemestane (any country) or fulvestrant (US only) (duration of treatment ≥ 4 weeks) and must have tolerated everolimus treatment in combination with exemestane (any country) or fulvestrant (US only) adequately according to the treating physician's judgment. Everolimus in combination with exemestane or fulvestrant is not required to be the most recent treatment before enrollment, but progression on the most recent anticancer therapy is required for enrollment.
  14. Patients enrolling in the PK/Tumor-PD Cohort must have extra-osseous disease that is assessable for serial tumor biopsy

Exclusion Criteria

Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

Phase 1b and Phase 2

  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 or denosumab 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 inhibitors and/or inducers of CYP3A4, CYP2C19, and 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 dual PI3K/mTOR inhibitors or TORC1/2 inhibitors.
  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 or treated for another malignancy within 2 years before administration of the first dose of MLN0128 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.

    Phase 1b Only: In addition to the previously mentioned exclusion criteria, patients meeting the following exclusion criterion are not to be enrolled in the phase 1b portion of the study:

  13. More than 3 prior chemotherapy regimens for locally advanced or metastatic disease.

    Phase 2 Only: In addition to the previously mentioned exclusion criteria, patients meeting the following exclusion criterion are not to be enrolled in the phase 2 portion of the study:

  14. More than 1 prior chemotherapy regimen for locally advanced or metastatic disease.
  Contacts and Locations
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: NCT02049957

Contacts
Contact: For an updated listing of recruitment sites contact: Millennium Medical and Drug Information Center 1-877-674-3784 medical@mlnm.com

  Show 36 Study Locations
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
Study Director: Medical Monitor Millennium Pharmaceuticals, Inc.
  More Information

Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02049957     History of Changes
Other Study ID Numbers: C31001 
Study First Received: December 12, 2013
Last Updated: February 22, 2016
Health Authority: United States: Food and Drug Administration
Belgium: Federal Agency for Medicinal Products and Health Products
France: Agence Nationale de Sécurité du Médicament et des produits de santé

Keywords provided by Millennium Pharmaceuticals, Inc.:
MLN0128

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Fulvestrant
Exemestane
Estradiol
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Estrogens
Hormones
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 25, 2016