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    Summary
    EudraCT Number:2014-001921-34
    Sponsor's Protocol Code Number:C31001
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-06-19
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2014-001921-34
    A.3Full title of the trial
    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
    Étude de phase 1b/2 évaluant la sécurité d’emploi et l’efficacité du MLN0128 (inhibiteur double TORC1/2) associé à un traitement par exémestane ou fulvestrant chez les femmes ménopausées atteintes de cancer du sein ER+/HER2- avancé ou métastatique qui a progressé sous évérolimus associé à exémestane ou fulvestrant
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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
    A.4.1Sponsor's protocol code numberC31001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02049957
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMillennium Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMillennium Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMillennium Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointDrug Information Call Center
    B.5.3 Address:
    B.5.3.1Street Address40 Landsdowne St
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post code02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number001510740-2412
    B.5.5Fax number001800881-6092
    B.5.6E-mailmedical@mlnm.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMLN0128 1mg
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMLN0128
    D.3.9.1CAS number 1224844-38-5
    D.3.9.3Other descriptive nameINK128
    D.3.9.4EV Substance CodeSUB79236
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMLN0128 3mg
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMLN0128
    D.3.9.1CAS number 1224844-38-5
    D.3.9.3Other descriptive nameINK128
    D.3.9.4EV Substance CodeSUB79236
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMLN0128 5mg
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMLN0128
    D.3.9.1CAS number 1224844-38-5
    D.3.9.3Other descriptive nameINK128
    D.3.9.4EV Substance CodeSUB79236
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameExemestane
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNExemestane
    D.3.9.1CAS number 107868-30-4
    D.3.9.3Other descriptive nameEXEMESTANE
    D.3.9.4EV Substance CodeSUB07492MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Faslodex
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca UK Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameFulvestrant
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFULVESTRANT
    D.3.9.1CAS number 129453-61-8
    D.3.9.3Other descriptive nameFULVESTRANT
    D.3.9.4EV Substance CodeSUB13933MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    ER+/HER2- Advanced or Metastatic Breast Cancer
    E.1.1.1Medical condition in easily understood language
    Advanced Breast cancer or cancer that has spread
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10072737
    E.1.2Term Advanced breast cancer
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 1b
    - To evaluate the safety and tolerability of MLN0128 in combination with either exemestane or fulvestrant

    Phase 2
    - To evaluate the antitumor activity by clinical benefit rate (CBR) at 16 weeks (CBR-16 is defined as the proportion of patients who achieve complete response [CR] or partial response of any duration, or have stable disease [SD] at 16 weeks) of treatment with MLN0128 in combination with either exemestane or fulvestrant
    E.2.2Secondary objectives of the trial
    - To further evaluate the antitumor activity of MLN0128 in combination with either exemestane or fulvestrant

    - To evaluate the pharmacokinetics of MLN0128 and exemestane when administered in combination and to evaluate the pharmacokinetics of MLN0128 when administered in combination with fulvestrant

    - To evaluate the pharmacodynamic activity of MLN0128 in combination with exemestane in tumor tissue obtained from serial biopsies from patients in the Pharmacokinetic/Tumor-Pharmacodynamic (PK/Tumor-PD) Cohort

    - To assess the safety and tolerability of MLN0128 in combination with either exemestane or fulvestrant
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    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 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 or fulvestrant (duration of treatment ≥ 4 weeks) as the most recent anticancer therapy and must have tolerated everolimus treatment in combination with exemestane or fulvestrant adequately according to the treating
    physician’s judgment.

    14. Patients enrolling in the PK/Tumor-PD Cohort must have extra-osseous disease that is assessable for serial tumor biopsy
    E.4Principal exclusion criteria
    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 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.

    13. More than 3 prior chemotherapy regimens for locally advanced or metastatic disease. (Phase 1b Only)

    14. More than 1 prior chemotherapy regimen for locally advanced or metastatic disease. (Phase 2 Only)
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1b
    - Adverse events, SAEs, assessments of clinical laboratory values, vital sign measurements, physical examination findings, and electrocardiograms (ECGs)

    Phase 2
    - CBR-16
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1b
    AEs:
    From first dose to 30 days post last dose

    SAEs:
    From ICF signature to 30 days post last dose

    Lab values:
    Screening; Cycle 1 & 2 D1, D15; Cycle 3 & above D1 plus EOT

    Vital signs & Physical Exam:
    Screening; Cycle 1 & 2 D1, D15; Cycle 3 & above D1 plus EOT

    ECGs:
    Screening; Cycle 1 D1 (0.5 pre dose, 2 & 4 hrs post dose) & D15 (0.5 pre dose & 2 hrs post dose); Cycle 2 D1 (0.5 pre dose & 2 hrs post dose; EOT

    Phase 2
    CBR-16:
    Week 16 of treatment
    E.5.2Secondary end point(s)
    - Clinical benefit rate at 24 weeks (CBR-24 is defined as the proportion of patients who achieve CR or partial response of any duration or have SD at 24 weeks)

    - Overall response rate (ORR; defined as best response of CR or partial response)

    - Progression-free survival

    - Overall survival (OS)

    - Change in tumor size from baseline

    - Steady-state PK parameters of MLN0128 and exemestane including, but not limited to, 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

    - Adverse events, SAEs, assessments of clinical laboratory values, vital sign measurements, physical examination findings, and ECGs
    E.5.2.1Timepoint(s) of evaluation of this end point
    CBR-24: Week 24 of treatment

    ORR; PFS; OS & Change in tumor size from baseline: D28 Cycle 1 then D28 every 2 cycles from C2 through C6 and then D28 every 3 cycles; PFS&OS Q3mo after EOT

    PK: Cycle 1 D15 (0.5 pre dose, 0.5, 1, 2 4 & 8 hrs post dose); Cycle 2 D1 (0.5, 1, 2 & 4 hrs post dose)

    PD activity: screening, Cycle 1 D15; EOT (for responders who relapse)

    AEs: From first dose to 30 days post last dose

    SAEs: From ICF to 30 days post last dose

    Lab values, Vital signs & Physical Exam: Screening; Cycle 1 & 2 D1, D15; Cycle 3+ D1 plus EOT

    ECGs:
    Screening; Cycle 1 D1 (0.5 pre dose, 2 & 4 hrs post dose) & D15 (0.5 pre dose & 2 hrs post dose); Cycle 2 D1 (0.5 pre dose & 2 hrs post dose; EOT
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    France
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The study will be terminated 6 months after the last patient completes an EOT study visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 86
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 50
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state9
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 138
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None (patient will return to normal standard of care)
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-12-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-06-02
    P. End of Trial
    P.End of Trial StatusOngoing
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