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    Summary
    EudraCT Number:2015-002133-22
    Sponsor's Protocol Code Number:C31005
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-05-24
    Trial 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 ConcernedSpain - AEMPS
    A.2EudraCT number2015-002133-22
    A.3Full title of the trial
    A Phase 2, Open-label Study to Evaluate the Efficacy and Safety of Single-Agent MLN0128 and the Combination of MLN0128+MLN1117 Compared With Everolimus in the Treatment of Adult Patients With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma That Has Progressed on Vascular Endothelial Growth Factor-Targeted Therapy
    Estudio abierto en fase II para evaluar la eficacia y la seguridad de MLN0128 en monoterapia y la combinación de MLN0128 + MLN1117 en comparación con everolimus en el tratamiento de pacientes adultos con carcinoma renal de células claras avanzado o metastásico que ha progresado con tratamiento dirigido contra el factor de crecimiento endotelial vascular
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of the drug substances MLN0128 and MLN0128+MLN1117 Compared With
    Everolimus in the Treatment of Patients with metastatic clear cell renal carcinoma
    Estudio de los fármacos MLN0128 y MLN0128 + MLN1117 en comparación con Everolimus en el tratamiento de pacientes con carcinoma de células renales metastásico
    A.3.2Name or abbreviated title of the trial where available
    A Phase 2, Open-label Study of MLN0128 and MLN0128+MLN1117 Compared With Everolimus in the Treatment
    Estudio abierto en fase II de MLN0128 y MLN0128 + MLN1117 en comparación con everolimus en el tratam
    A.4.1Sponsor's protocol code numberC31005
    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 SponsorMillenium Pharmaceuticals, a wholly owned subsidiary of Takeda pharmaceutical Company Limited
    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 supportMillenium 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 number+3490099 1071
    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
    D.3.2Product code INK128; TAK-228
    D.3.4Pharmaceutical form Capsule, hard
    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 INNSAPANISERTIB
    D.3.9.1CAS number 1224844-38-5
    D.3.9.2Current sponsor codeMLN0128
    D.3.9.3Other descriptive nameINK128;TAK-228
    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
    D.3.2Product code INK128;TAK-228
    D.3.4Pharmaceutical form Capsule, hard
    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 INNSAPANISERTIB
    D.3.9.1CAS number 1224844-38-5
    D.3.9.2Current sponsor codeMLN0128
    D.3.9.3Other descriptive nameINK128;TAK-228
    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
    D.3.2Product code INK128;TAK-228
    D.3.4Pharmaceutical form Capsule, hard
    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 INNSAPANISERTIB
    D.3.9.1CAS number 1224844-38-5
    D.3.9.2Current sponsor codeMLN0128
    D.3.9.3Other descriptive nameINK128;TAK-228
    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 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 nameMLN1117
    D.3.2Product code INK1117;TAK-117
    D.3.4Pharmaceutical form Capsule, hard
    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 INNNot available
    D.3.9.2Current sponsor codeMLN1117
    D.3.9.3Other descriptive nameINK1117;TAK-117
    D.3.9.4EV Substance CodeSUB126088
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 Afinitor®
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm 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 nameEverolimus
    D.3.4Pharmaceutical form 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 INNNot available
    D.3.9.1CAS number 159351-69-6
    D.3.9.3Other descriptive nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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: 6
    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 Afinitor®
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm 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 nameEverolimus
    D.3.4Pharmaceutical form 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 INNNot available
    D.3.9.1CAS number 159351-69-6
    D.3.9.3Other descriptive nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    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: 7
    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 Afinitor®
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm 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 nameEverolimus
    D.3.4Pharmaceutical form 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 INNNot Available
    D.3.9.1CAS number 159351-69-6
    D.3.9.3Other descriptive nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    metastatic clear-cell renal cell carcinoma (mccRCC)
    carcinoma renal de células claras metastásico (CRCcm)
    E.1.1.1Medical condition in easily understood language
    renal cell carcinoma
    carcinoma renal
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10050018
    E.1.2Term Renal cancer metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10038407
    E.1.2Term Renal cell cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objectives of the study are:
    ? To compare the efficacy of single-agent MLN0128 versus single-agent everolimus in patients
    with mccRCC.
    ? To compare the efficacy of the combination of MLN0128+MLN1117 versus single-agent
    everolimus in patients with mccRCC.
    - Comparar la eficacia de MLN0128 en monoterapia frente a la de everolimus en monoterapia en pacientes con CCRccm.
    - Comparar la eficacia de la combinación de MLN0128 + MLN1117 frente a la del everolimus en monoterapia en pacientes con CCRccm.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are:
    ? To assess the safety and tolerability of MLN0128 and MLN0128+MLN1117.
    ? To compare the efficacy of the combination of MLN0128+MLN1117 versus single-agent
    MLN0128 in patients with mccRCC.
    ? To evaluate the efficacy (endpoints other than PFS; ie, overall survival [OS],
    time-to-progression [TTP], objective response rate [ORR], and clinical benefit rate [CBR])
    among the 3 treatment groups.
    ? To collect plasma concentration-time data with sparse PK sampling to contribute to future
    population PK analysis
    Los objetivos secundarios del estudio son:
    - Evaluar la seguridad y la tolerabilidad de MLN0128 y MLN0128 + MLN1117.
    - Comparar la eficacia de la combinación de MLN0128 + MLN1117 frente a la de MLN0128 en monoterapia en pacientes con CCRccm.
    - Evaluar la eficacia (criterios de valoración distintos a la SSP, como la supervivencia general [SG], el tiempo transcurrido hasta la progresión [TTP], la tasa de respuesta objetiva [TRO] y la tasa de beneficio clínico [TBC]) en los 3 grupos de tratamiento.
    - Recoger datos de concentración plasmática y tiempo con muestreo FC aislado que contribuya a futuros análisis FC poblacionales.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Each patient must meet all of the following inclusion criteria to be enrolled in the study.
    1. Male or female patients aged 18 years or older.
    2. Histologically confirmed renal cell carcinoma with a clear-cell component.
    3. Evidence that the renal cell carcinoma is advanced or metastatic.
    4. Radiologic evidence of progressive disease (according to RECIST Version 1.1) either during or within 6 months after stopping their most recent systemic therapy for RCC before enrollment into this study.
    5. At least 1 prior line of VEGF-targeted therapy, but not more than 4 total prior lines of systemic therapy. Exposure to more than 1 line of VEGF-targeted therapy is acceptable. Patients may also have received prior therapies with interferon, IL-2, anti-PD1 antibodies, cabozantinib, or other experimental agents, but not prior therapy with any agent that targets PI3K, AKT, or mTOR.
    6. Karnofsky Performance Status (KPS) ?70% (refer to Appendix D).
    7. Life expectancy of ?3 months.
    8. Female patients who:
    Are postmenopausal for at least 1 year before the Screening visit, OR
    ? Are surgically sterile, OR If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method (See Appendix E), at the same time, from the time of signing the informed consent through 90 days (or longer, as mandated by local labeling [eg, USPI, SmPC, etc;]) after the last dose of study drug, OR Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle
    of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
    Male patients, even if surgically sterilized (ie, status postvasectomy), who:
    Agree to practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug (or longer, as mandated by local labeling [eg, USPI, SmPC, etc]), OR
    Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
    Agree not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug.
    9. Suitable venous access for the study-required blood sampling.
    10. Screening clinical laboratory values as specified below:
    ? Absolute neutrophil count ?2000/?L and platelet count ?100,000/?L.
    ? Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ?2.5?the upper limit of normal (ULN).
    ? Total bilirubin ?1.5?ULN.
    ? Estimated creatinine clearance by Cockcroft-Gault ?40 mL/min/1.73m2 (see Appendix F).
    ? Glycosylated hemoglobin (HbA1c) <7.0%, fasting serum glucose ?130 mg/dL, and fasting triglycerides ?300 mg/dL.
    11. At least 14 days since the end of prior systemic VEGF-targeted treatment (ie, sunitinib,pazopanib, axitinib, or sorafenib), radiotherapy, or surgical procedure with resolution of all treatment-related toxicity (except alopecia and hypothyroidism) either to Grade 0 or 1 (NCI CTCAE Version 4.03) or to Baseline.
    12. At least 21 days since the last dose of bevacizumab, other antibody, or interferon.
    13. 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.
    Cada paciente debe cumplir todos los criterios de inclusión siguientes para ser inscrito en el estudio.
    1. Pacientes varones o mujeres de 18 años de edad o mayores.
    2. Carcinoma de células renales con componente de células claras avanzado o metastásico confirmado histológicamente.
    3. Evidencia de que el carcinoma de células renales es avanzado o metastásico.
    4. . Pruebas radiológicas de progresión de la enfermedad (según los RECIST, versión 1.1), ya sea durante el tratamiento o en los 6 meses posteriores a la interrupción del tratamiento dirigido contra el VEGF, que deberá ser el tratamiento más reciente antes de la inscripción en este estudio.
    5. Al menos 1 línea anterior de tratamiento sistémico. Se acepta la exposición a más de 1 línea de tratamiento dirigido contra el VEGF pero no más de 4. Se acepta que los pacientes también hayan recibido tratamientos anteriores con interferón, IL-2 u otro tipo de fármacos experimentales, pero no con agentes dirigidos a PI3K, AKT o mTOR.
    6. Estado general de Karnofsky (EGK) ?70 % (véase el apéndice D).
    7. Esperanza de vida ?3 meses.
    8. Mujeres que:
    - Sean posmenopáusicas al menos desde 1 año antes de la visita de selección o hayan sido esterilizadas quirúrgicamenteo si están en edad fértil, acepten el uso de 2 métodos anticonceptivos eficaces al mismo tiempo desde el momento de firmar el formulario de consentimiento informado y hasta 90 días después de la administración de la última dosis del fármaco del estudio o acepten la práctica de una abstinencia verdadera, si ello es compatible con el estilo de vida preferido y habitual del paciente. (La abstinencia periódica [por ejemplo, los métodos del calendario, de la ovulación, los sintotérmicos o los de postovulación] y la interrupción del coito no se consideran métodos anticonceptivos aceptables. Condones femeninos y masculinos no deben usarse en conjunto).
    Hombres, aunque hayan sido esterilizados quirúrgicamente (es decir, después de someterse a una vasectomía), que:
    - Acepten utilizar métodos anticonceptivos eficaces de barrera durante todo el periodo de tratamiento del estudio y durante los 120 días y durante los 120 días después de la última dosis del fármaco del estudio (o más, según lo dispuesto por el etiquetado locales [por ejemplo, USPI, RCP, etc.]) o acepten la práctica de una abstinencia verdadera, si ello es compatible con el estilo de vida preferido y habitual del paciente. (La abstinencia periódica [por ejemplo, los métodos del calendario, de la ovulación, los sintotérmicos o los de postovulación para la pareja de sexo femenino y la interrupción del coito no se consideran métodos anticonceptivos aceptables. Condones femeninos y masculinos no deben usarse en conjunto).
    -Acepten no donar esperma durante el transcurso de este estudio o 120 días después de recibir su última dosis del fármaco del estudio.
    9.Acceso venoso adecuado para la extracción de muestras de sangre necesarias para el estudio.
    10.Los valores analíticos en el momento de la selección deben cumplir los requisitos siguientes:
    ? Recuento absoluto de neutrófilos ?2000/?l y número de trombocitos ?100 000/?l.
    ? Aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) ?2,5? veces el límite superior de la normalidad (LSN).
    ? Bilirrubina total ?1,5?LSN.
    ? Aclaramiento de creatinina estimado según Cockcroft-Gault ?40 ml/min/1,73 m2 (véase el apéndice E).
    ? Glucohemoglobina (HbA1c) <7,0 %, glucosa sérica en ayunas ?130 mg/dl y triglicéridos en ayunas ?300 mg/dl.
    10. Fracción de eyección ventricular izquierda (FEVI) dentro del porcentaje de 5 puntos absolutos del valor considerado normal por la institución, cuando se determina mediante ecocardiografía (ECO) o exploración mediante ventriculografía isotópica (MUGA), en las 4 semanas anteriores a la primera administración del fármaco del estudio (p. ej., si el valor institucional normal es del 50 %, un paciente con una FEVI de incluso el 45 % seguiría siendo apto).
    11. Un mínimo de 14 días transcurridos desde la finalización del anterior tratamiento sistémico dirigido contra el VEGF (esto es, sunitinib, pazopanib, axitinib o sorafenib), radioterapia o intervención quirúrgica, con resolución de toda la toxicidad relacionada con el tratamiento (excepto la alopecia y el hipotiroidismo) ya sea a grado 0 o 1 (CTCAA del NCI, versión 4.03) o al valor inicial.
    12. Un mínimo de 21 días transcurridos desde la última dosis de bevacizumab, otros anticuerpos o interferón.
    13. El consentimiento voluntario por escrito debe otorgarse antes de realizar cualquier procedimiento relacionado con el estudio distinto de la atención médica estándar, siendo consciente de que el paciente puede retirar su consentimiento en cualquier momento sin perjuicio de su atención médica futura.
    E.4Principal exclusion criteria
    Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
    1. Central nervous system (CNS) metastasis.
    2. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active CNS disease, active infection, or any other condition that might compromise the patient?s participation in the study.
    3. Known human immunodeficiency virus infection.
    4. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
    5. Treatment with strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, CYP2C9, or CYP2C19 within 1 week preceding the first dose of study drug.
    Manifestations of malabsorption due to prior GI surgery, GI disease, or for an unknown reason that may alter the absorption of everolimus, MLN0128, or MLN1117. In addition, patients with enteric stomata are excluded.
    6. Manifestations of malabsorption due to prior GI surgery, GI disease, or for an unknown reasonthat may alter the absorption of everolimus, MLN0128, or MLN1117. In addition, patients with enteric stomata are excluded.
    7. Women who are either breast feeding or pregnant.
    8. History of any of the following within the last 6 months before administration of 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 G). Pulmonary embolism.
    9. Significant active cardiovascular or pulmonary disease including:
    ? Uncontrolled hypertension (ie, either systolic blood pressure >160 mm Hg or diastolic blood pressure >95 mm Hg). Use of anti-hypertensive agents to control hypertension before Cycle 1 Day 1 is allowed.
    ? 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).
    10. Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer, superficial bladder cancer, very low risk prostate on observation, or carcinoma in situ of any type are not excluded if they have
    undergone complete resection.
    11. Prior therapy with agents that target PI3K, AKT, or mTOR. Patients with known hypersensitivity to everolimus or rapamycin derivatives are also excluded.
    12. Any serious medical or psychiatric illness that could, in the investigator?s opinion, potentially interfere with the completion of treatment according to this protocol.
    13. Patients requiring daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within 7 days before receiving the first dose of study drug.
    No deben inscribirse en el estudio los pacientes que cumplan cualquiera de los siguientes criterios de exclusión.
    1. Metástasis del sistema nervioso central (SNC).
    2. Otras comorbilidades clínicamente significativas, como neumopatías no controladas, enfermedad del SNC activa, infección activa u otras enfermedades que pudieran comprometer la participación del paciente en el estudio.
    3. Infección conocida por el virus de la inmunodeficiencia humana.
    4. Resultado positivo conocido del antígeno de superficie del virus de la hepatitis B o infección conocida o sospechada de hepatitis C activa.
    5. Tratamiento con inhibidores o inductores potentes del citocromo P450 (CYP) 3A4, CYP2C9 o CYP2C19 en la semana anterior a la primera dosis del fármaco del estudio.
    6. Manifestaciones de malabsorción como consecuencia de intervenciones quirúrgicas gastrointestinales (GI) anteriores, enfermedades GI o por motivos desconocidos que puedan alterar la absorción de everolimus, MLN0128 o MLN1117. También se excluyen los pacientes con estomas intestinales.
    7. Mujeres que están en periodo de lactancia o embarazadas.
    8. Antecedentes de cualquiera de las siguientes circunstancias en los 6 meses anteriores a la administración de la primera dosis del fármaco del estudio:
    - Acontecimiento miocárdico isquémico, incluidos angina que requiera tratamiento y procedimientos de revascularización arterial.
    - Acontecimiento cerebrovascular isquémico, incluidos accidente isquémico transitorio y procedimientos de revascularización arterial.
    - Necesidad de apoyo inotrópico (excluida la digoxina) o arritmia cardíaca (no controlada) grave (incluyendo fibrilación o aleteo auricular, fibrilación ventricular o taquicardia ventricular).
    -Colocación de un marcapasos para el control del ritmo cardíaco.
    - Insuficiencia cardíaca de clase III o IV según la Asociación Cardiológica de Nueva York (New York Heart Association) (véase el apéndice G).
    - Embolia pulmonar.
    9. Enfermedad cardiovascular o neumopatía activa significativa, lo que incluye:
    - Hipertensión no controlada (tensión arterial sistólica >160 mm Hg; tensión arterial diastólica >95 mm Hg). Se permite el uso de antihipertensores para controlar la hipertensión antes del día 1 del - - - Hipertensión pulmonar.
    - Asma no controlada o saturación de oxígeno <90 % según gasometría arterial o pulsioximetría en aire ambiente.
    - Valvulopatía significativa, regurgitación o estenosis importante según diagnóstico por la imagen independiente del control de los síntomas con intervención médica o antecedentes de valvuloplastia.
    - Bradicardia (sintomática) médicamente significativa.
    - Antecedentes de arritmia que requiso la colocación de un desfibrilador cardíaco implantable.
    - Prolongación al inicio del intervalo QT corregido según la frecuencia (QTc; p. ej., demostración repetida de un intervalo QTc >480 ms, antecedentes de síndrome de QT largo congénito o torsades de pointes).
    10. Diagnóstico o tratamiento para otra neoplasia maligna en los 2 años anteriores a la administración de la primera dosis del fármaco del estudio o diagnóstico previo de otra neoplasia maligna con algún indicio de enfermedad residual. Los pacientes con cáncer de piel distinto del melanoma, carcinoma de vejiga superficial, de próstata de riesgo bajo en observación o carcinoma in situ de cualquier tipo no están excluidos si se han sometido a una resección completa.
    11. Tratamiento anterior con fármacos dirigidos a PI3K, AKT o mTOR. También se excluyen los pacientes con hipersensibilidad conocida a los derivados de rapamicina o everolimus.
    12. Cualquier enfermedad clínica o psiquiátrica grave que pudiese, en opinión del investigador, interferir en la finalización del tratamiento conforme a este protocolo.
    13. Pacientes que requieran el uso diario o crónico de inhibidores de la bomba de protones (IBP) o que hayan tomado IBP en los 7 días anteriores a la administración de la primera dosis del fármaco del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is PFS (progression-free survival)
    El criterio de valoración principal es la SLP (supervivencia libre de progresión)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time from date of randomization to disease progression or death, whichever occurs first, assessed until post treatment follow up of last patient. (For a patient whose disease has not progressed and is last known to be alive, PFS will be censored at the last response assessment that is SD or better).
    The final analysis for the pair-wise comparisons of PFS between single-agent MLN0128
    and everolimus and between the combination of MLN0128+MLN1117 and everolimus will occur
    approximately 6 months after the last patient is randomized.
    La SG se define como el tiempo desde la fecha de la aleatorización hasta la fecha de la muerte. Los pacientes cuya muerte no se haya documentado en el momento del análisis serán censurados en la última fecha en la que se haya sabido por última vez que estaban vivos.
    El análisis final de las comparaciones por pares de la SLP entre MLN0128 y everolimus y entre la combinación de MLN0128 + MLN1117 y everolimus se producirá aproximadamente 6 meses después de que el último paciente sea aleatorizado.
    E.5.2Secondary end point(s)
    The secondary endpoints are:
    ?1) The number and percentage of patients with treatment-emergent adverse events.
    ?2) Overall survival (OS).
    ? 3)Time-to-progression (TTP).
    ? 4) Objective response rate (ORR; defined as complete response [CR]+partial response [PR] per
    Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1).
    ? 5)Clinical benefit rate (CBR; defined as CR+PR+stable disease) with SD of any duration, and
    CBR with SD duration of at least 4 months.
    Los objetivos secundarios son:
    1) El número y el porcentaje de pacientes con eventos adversos emergentes del tratamiento.
    2) supervivencia general [SG]
    3) el tiempo transcurrido hasta la progresión [TTP]
    4) la tasa de respuesta objetiva [(TRO)definida como respuesta completa (RC)+ respuesta parcial (RP)] por
    Criterios de evaluación de respuesta en tumores sólidos [RECIST] Versión 1.1
    5) la tasa de beneficio clínico [(TBC) definida como RC+RP+ enfermedad estable]
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Serious adverse events will be reported from signing of the informed consent form through 30 days after the last dose of study drug
    2) OS is defined as the time from the date of randomization to the date of death, assessed until post treatment follow up.
    3) TTP is defined as the time from the date of randomization to the date of first documentation of progression. For apatient whose disease has not progressed, TTP will be censored at the last response assessment that is SD or better. TPP will be assessed at day 28 of Cycle 2, Day 28 cycle 4, day 28 of cycle 5 and beyond up to 24 months
    5) CR,PR and SD will be assessed at day 28 of Cycle 2, Day 28 cycle 4, day 28 of cycle 5 and beyond up to 24 months
    1) Los eventos adversos graves se registrarán a la firma del formulario de consentimiento informado dentro de los 30 días posteriores a la última dosis del fármaco del estudio.
    2)La supervivencia general se define como el tiempo transcurrido desde la fecha de la aleatorización hasta la fecha de la muerte.
    3)La tasa de respuesta global se define como la proporción de pacientes que alcanzan una RC o RP como mejor respuesta. La TBC se define como la proporción de pacientes que logran una RC, RP o EE como mejor respuesta.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    tratamiento cruzado potencial para los pacientes inicialmente asignados al azar al brazo del everoli
    potential crossover treatment for patients initially randomized to the single-agent everolimus arm A
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    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
    France
    Italy
    Spain
    United Kingdom
    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
    LVLS
    Última Visita del Último Paciente (UVUP)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months48
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months48
    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: 95
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 94
    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 state49
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 189
    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
    Ninguno
    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 Decision2016-05-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-02
    P. End of Trial
    P.End of Trial StatusCompleted
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