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    Summary
    EudraCT Number:2010-023772-71
    Sponsor's Protocol Code Number:C16006
    National Competent Authority:Czech Republic - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-03-03
    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 ConcernedCzech Republic - SUKL
    A.2EudraCT number2010-023772-71
    A.3Full title of the trial
    An Open-Label, Dose-Escalation, Phase 1/2 Study of the Oral Form of MLN9708, a Next-Generation Proteasome Inhibitor, Administered in Combination with a Standard Care Regimen of Melphalan and Prednisone in Patients With Newly-Diagnosed Multiple Myeloma Requiring Systemic Treatment.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/ 2 Study of the Oral Form of MLN9708 with Melphalan and Prednisone for Patients with Newly Diagnosed Multiple Myeloma
    A.4.1Sponsor's protocol code numberC16006
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01335685
    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 number001800 881-6092
    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 nameMLN9708 Capsules 0.2mg
    D.3.2Product code MLN9708
    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 INNixazomib
    D.3.9.1CAS number 1239908-20-3
    D.3.9.2Current sponsor codeMLN9708
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.2
    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 nameMLN9708 Capsules 0.5mg
    D.3.2Product code MLN9708
    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 INNixazomib
    D.3.9.1CAS number 1239908-20-3
    D.3.9.2Current sponsor codeMLN9708
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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 nameMLN9708 Capsules 2.0mg
    D.3.2Product code MLN9708
    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 INNixazomib
    D.3.9.1CAS number 1239908-20-3
    D.3.9.2Current sponsor codeMLN9708
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.0
    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 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 nameMLN9708 Capsules 2.3mg
    D.3.2Product code MLN9708
    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 INNixazomib
    D.3.9.1CAS number 1239908-20-3
    D.3.9.2Current sponsor codeMLN9708
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.3
    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 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 nameMLN9708 Capsules 3.0mg
    D.3.2Product code MLN9708
    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 INNixazomib
    D.3.9.1CAS number 1239908-20-3
    D.3.9.2Current sponsor codeMLN9708
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.0
    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: 6
    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 nameMLN9708 Capsules 4.0mg
    D.3.2Product code MLN9708
    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 INNixazomib
    D.3.9.1CAS number 1239908-20-3
    D.3.9.2Current sponsor codeMLN9708
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4.0
    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
    Newly diagnosed multiple myeloma
    E.1.1.1Medical condition in easily understood language
    Type of cancer of the white blood cells
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    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 1:
    -To determine the safety, MTD, and RP2D of once weekly MLN9708 on Days 1, 8, and 15 of a 28-day cycle when added to SOC MP on Days 1 through 4 of each cycle

    -To determine the safety, MTD, and RP2D once weekly MLN9708 on Days 1, 8, 15, 22, and 29 of a 42-day cycle when added to SOC MP on Days 1 through 4 of each cycle

    -To determine the safety, MTD, and RP2D once weekly MLN9708 on Days 1, 8, 22, and 29 of a 42-day cycle when added to SOC MP on Days 1 through 4 of each cycle

    Phase 2:
    To determine CR + VGPR during the induction therapy period following MLN9708 administration once weekly on Days 1, 8, and 15 of a 28-day cycle when added to SOC MP on Days 1 through 4 of every cycle

    To determine CR + VGPR during the induction therapy period following MLN9708 administration once weekly on either Days 1, 8, 15, 22, and 29 or Days 1, 8, 22, and 29 of a 42-day cycle when added to SOC of MP on
    Days 1 through 4 of every cycle
    E.2.2Secondary objectives of the trial
    Phase 1
    To characterize the PK in plasma of oral MLN9708 when added to standard care MP
    To evaluate the ORR, including CR; including stringent complete response [sCR]), very good partial response (VGPR) and partial
    response (PR), during the entire during the induction therapy period and throughout the entire treatment period

    Phase 2
    To determine the time to response during the induction therapy period
    To evaluate the DOR for patients who responded during the induction therapy period
    To determine ORR during the induction therapy period and through the entire treatment period
    To assess the time to progression (TTP)
    To evaluate time to next therapy and treatment-free interval
    To evaluate the progression-free survival (PFS)
    To evaluate the overall survival (including 1-year survival rate)
    To determine the safety profile of MLN9708
    To evaluate changes in QOL
    To assess pain response rate, as assessed by the BPI-SF and analgesic use
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patient for whom standard MP treatment is indicated and who is not a candidate for HDT-SCT for 1 of the following reasons:
    The patient is 65 years of age or older.
    The patient is less than 65 years of age but has significant comorbid condition(s) that are likely to have a negative impact on tolerability of HDT-SCT.

    2. Symptomatic MM or asymptomatic myeloma with myeloma-related organ damage diagnosed according to standard criteria

    3. Patients must have measurable disease defined by at least 1 of the following 3 measurements:
    Serum M-protein ≥ 1 g/dL (≥ 10 g/L)
    Urine M-protein ≥ 200 mg/24 hours
    Serum free light chain assay: involved free light chain level ≥ 10 mg/dL (≥ 100 mg/L), provided that the serum free light chain ratio is abnormal

    4. Patients must meet the following clinical laboratory criteria within 3 days before the first dose of study treatment to be enrolled in the study:
    Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3.
    platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days prior to study drug dosing.
    Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN).
    Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN.
    Calculated creatinine clearance ≥ 30 mL/min

    5. ECOG performance status of 0 to 2

    6. Female patients who:
    If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, AND
    Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
    Agree to practice true abstinence when this is line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are
    not acceptable methods of contraception.)

    7. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
    Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
    Must also adhere to the guidelines of any treatment-specific pregnancyprevention program, if applicable, OR
    Agree to practice true abstinence when this is line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are
    not acceptable methods of contraception.)

    8. Voluntary written consent must be given before 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.
    E.4Principal exclusion criteria
    1. Peripheral neuropathy ≥ Grade 2 on clinical examination during the screening period.

    2. Female patients who are lactating or pregnant.

    3. Major surgery within 14 days before the first dose of study drug. (Note: kyphoplasty or vertebroplasty is not considered major surgery.)

    4. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before the first dose of study drug.

    5. Diarrhea >Grade 1, based on the NCI CTCAE grading, in the absence of antidiarrheals.

    6. Prior systemic therapy for MM, including investigational drugs. Prior treatment with corticosteroids or localized radiation therapy does not disqualify the patient (the maximum dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone, a total of which can be given in a 2-week period.
    7. Radiotherapy within 14 days before the first dose of study treatment.

    8. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort within 14 days before the first dose of study treatment.

    9. Central nervous system involvement.

    10. Diagnosis of smoldering MM, Waldenstrom’s macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.

    11. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.

    12. QTc > 470 msec on a 12-lead ECG obtained during the Screening period. If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG.

    13. Known or suspected human immunodeficiency virus (HIV) positive.

    14. Known or suspected hepatitis B surface antigen-positive status or known or suspected active hepatitis C infection.

    15. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.

    16. Known allergy to any of the study medications, their analogues, or excipients in the various formulations.

    17. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing.

    18. Diagnosed or treated for another malignancy within 2 years before the first dose 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.
    E.5 End points
    E.5.1Primary end point(s)
    Phase I:
    DLT, MTD, and RP2D of oral MLN9708 when added to a standard care regimen of MP

    Phase 2:
    Combined response rate of CR + VGPR in patients treated with MLN9708 when
    added to a standard care regimen of MP during the induction period
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1
    Only DLTs occurring in Cycle 1 in phase 1 will necessarily influence decisions regarding dose escalation, expansion of a dose level, or
    evaluation of intermediate dose levels.

    However, DLTs occurring in later cycles may be taken into consideration for dose-escalation decisions, at the discretion of the investigators/sponsor. The MTD or RP2D estimation will be made following evaluation of the available data from Phase 1. The
    RP2D will require first-cycle DLTs in not more than 1 in 6 DLT-evaluable patients enrolled in a single cohort.

    Phase 2
    Arm B Induction Period: End of each 28 day cycle.
    Arm C&D Induction Period: End of each 42 day cycle
    E.5.2Secondary end point(s)
    Phase 1 Secondary Endpoint:
    Single and multiple-dose plasma PK
    Whole blood 20S proteasome inhibition parameters
    ORR during the entire study

    Phase 2 Secondary Endpoint
    Time to response, defined as the time interval from the date of enrollment to the date of first documented response during the induction period
    DOR, defined for responders as the time interval from the date of first response to
    the date of disease progression
    ORR during the induction period and throughout the entire study
    TTP, defined as the time interval from the date of enrollment to the date of first documented disease progression
    Time to next therapy, defined as the time interval from the date of enrollment to the
    date of subsequent antineoplastic therapy; treatment-free interval, defined as the time
    interval from the date of last dose of any study drug to the date of subsequent
    antineoplastic therapy
    PFS, defined as the time interval from the date of enrollment to the date of first
    documented disease progression or death
    OS, defined as the time from the date of enrollment to the date of death
    All AEs; Grade 3 or higher AEs; SAEs; AEs resulting in treatment discontinuation;
    and AEs resulting in dose reduction
    Comparison of change in global health status between baseline and each postbaseline
    assessment, as measured by the global health scale, functioning, and symptoms of
    the EORTC QLQ-C30 and MY-20
    Pain response rate, measured by the proportion of pain responders, as determined by the BPI-SF and analgesic use
    Development of new or worsening of existing selected skeletal-related events,
    defined as new fractures (excluding vertebral compression or rib fractures),
    irradiation of or surgery on bone, or spinal cord compression
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase 1
    PK and whole blood 20S proteasome Activity
    Arm A Cycle 1 (Day 1,2,4,8,11,12,15,16,17) Cycle 2 (Day 1), Cycle 3 (Day 1)

    Arm B Cycle 1 (Day 1,2,3,4,8,15,16,17,18,22) Cycle 2 (Day 1), Cycle 3 (Day 1)

    PK only Arms C&D Cycle 1 (Day 1,2,3,5,8,29,30,31,33,36), Cycle 2 (Day 1)

    Phase 2
    PK
    Arm B: Cycle 1&2 (Day 1,8,15,22-28)
    Arm C&D: Cycle 1 to 32 (Day 1,8,15,22, 29, 35

    Response:
    Arm B Induction Period: End of each 28 day cycle.
    Arm C & D Induction Period: End of each 42 day cycle
    Response will be assessed every 2 cycles for all patients during maintenance therapy.

    QoL and Pain Response:
    Screening, Day 1 each cycle, EoT and PFS follow-up

    Skeletal Assessment: Once annually or at investigator discretion

    Safety evaluations - ongoing
    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 Yes
    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 No
    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.8.2.4Number of treatment arms in the trial4
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    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
    Canada
    European Union
    Russian Federation
    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
    Last patient, last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months92
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months92
    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.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 48
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 110
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 94
    F.4.2.2In the whole clinical trial 158
    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)
    Not applicable.
    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 Decision2011-05-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-03-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-12-30
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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