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    Summary
    EudraCT Number:2015-005019-34
    Sponsor's Protocol Code Number:CTMT212X2106
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-09-25
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2015-005019-34
    A.3Full title of the trial
    A phase I/II study of safety and efficacy of ribociclib (LEE011) in combination with trametinib (TMT212) in patients with metastatic or advanced solid tumors
    Estudio fase I/II de seguridad y eficacia de ribociclib (LEE011) en combinación con trametinib (TMT212), en pacientes con tumores sólidos avanzados o metastásicos
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical research study to find out if the combination of two study drugs called ribociclib and trametinib is safe and has beneficial effects in people who have solid tumors
    Estudio de seguridad y de eficacia de ribociclib y trametinib en pacientes con tumores sólidos avanzados o metastásicos
    A.4.1Sponsor's protocol code numberCTMT212X2106
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02703571
    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 SponsorNovartis Farmacéutica, S.A.
    B.1.3.4CountrySpain
    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 supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farmacéutica, S.A.
    B.5.2Functional name of contact pointDepartamento Médico Oncología (GMO)
    B.5.3 Address:
    B.5.3.1Street AddressGran Vía de les Corts Catalanes, 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number3490 0353036
    B.5.5Fax number3493 2479903
    B.5.6E-maileecc.novartis@novartis.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 Yes
    D.2.1.1.1Trade name Trametinib (TMT212)
    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.3.4Pharmaceutical 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 INNTrametinib
    D.3.9.1CAS number 1187431-43-1
    D.3.9.2Current sponsor codeTMT212
    D.3.9.3Other descriptive nameTRAMETINIB DIMETHYL SULFOXIDE
    D.3.9.4EV Substance CodeSUB167251
    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: 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.3.2Product code LEE011
    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 INNRibociclib
    D.3.9.2Current sponsor codeLEE011
    D.3.9.4EV Substance CodeSUB31644
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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.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.3.2Product code LEE011
    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 INNRibociclib
    D.3.9.2Current sponsor codeLEE011
    D.3.9.4EV Substance CodeSUB31644
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 Yes
    D.2.1.1.1Trade name Trametinib (TMT212)
    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.3.4Pharmaceutical 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 INNTrametinib
    D.3.9.1CAS number 1187431-43-1
    D.3.9.3Other descriptive nameTRAMETINIB DIMETHYL SULFOXIDE
    D.3.9.4EV Substance CodeSUB167251
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 Yes
    D.2.1.1.1Trade name Mekinist
    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.3.4Pharmaceutical 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 INNTrametinib
    D.3.9.1CAS number 1187431-43-1
    D.3.9.2Current sponsor codeTMT212
    D.3.9.3Other descriptive nameTRAMETINIB DIMETHYL SULFOXIDE
    D.3.9.4EV Substance CodeSUB167251
    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: 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 Yes
    D.2.1.1.1Trade name Mekinist
    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.3.4Pharmaceutical 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 INNTrametinib
    D.3.9.1CAS number 1187431-43-1
    D.3.9.3Other descriptive nameTRAMETINIB DIMETHYL SULFOXIDE
    D.3.9.4EV Substance CodeSUB167251
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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
    Solid tumors, Pancreatic Cancer, Colorectal Cancer
    Tumores sólidos, Cáncer de pancreas, Cáncer colorrectal
    E.1.1.1Medical condition in easily understood language
    Solid tumors, Pancreatic Cancer, Colorectal Cancer
    Tumores sólidos, Cáncer de pancreas, Cáncer colorrectal
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10049280
    E.1.2Term Solid tumour
    E.1.2System Organ Class 100000020962
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10061451
    E.1.2Term Colorectal cancer
    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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10033604
    E.1.2Term Pancreatic cancer
    E.1.2System Organ Class 100000016908
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase Ib:
    To define the maximum tolerated dose (MTD) and/or the RP2R of ribociclib and trametinib in patients with solid tumors

    Phase II:
    To assess overall response rate (ORR) with the combination of ribociclib and trametinib in patients with:
    ● Advanced or metastatic pancreatic adenocarcinoma who have failed at least one prior systemic treatment (Arm 1)
    ● Advanced or metastatic KRAS-mutant CRC who have failed at least two prior lines of treatment (Arm 2)
    Fase Ib:
    - Definir la dosis máxima tolerada (MTD) y/o el RP2R de ribociclib y trametinib en pacientes con tumores sólidos.
    Fase II:
    -Evaluar la tasa de respuesta global (TRG) con la combinación de ribociclib y trametinib en pacientes con:
     .Adenocarcinoma pancreático avanzado o metastásico que ha fracasado al menos a un tratamiento sistémico previo (brazo 1)
     .CCR avanzado o metastásico con mutación KRAS que ha fracasado al menos a dos líneas previas de tratamiento (brazo 2)
    E.2.2Secondary objectives of the trial
    Phase Ib and II:
    ● To evaluate the safety and tolerability of ribociclib in combination with trametinib
    ● To characterize the pharmacokinetics (PK) of ribociclib (and metabolite LEQ803) and trametinib when administered in combination

    Phase Ib:
    ● To assess the preliminary anti-tumor activity of ribociclib in combination with trametinib

    Phase II:
    ● To evaluate duration of response (DOR), disease control rate (DCR), time to response (TTR), overall survival (OS) and progression-free survival (PFS) of ribociclib in combination with trametinib
    Fase Ib y II:
    - Evaluar la seguridad y la tolerabilidad de ribociclib en combinación con trametinib
    - Caracterizar la farmacocinética (PK) de ribociclib (y del metabolito LEQ803) y de trametinib cuando se administran en combinación
    Fase Ib:
    - Evaluar la actividad antitumoral preliminar de ribociclib en combinación con trametinib.
    Fase II:
    - Evaluar la duración de la respuesta (DR), la tasa de control de la enfermedad (TCE), el tiempo hasta la respuesta (TR), la supervivencia global (SG) y la supervivencia libre de progresión (SLP) de ribociclib en combinación con trametinib.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ● Written informed consent must be obtained prior to any study specific screening procedures.
    ● Patient is an adult male/female ≥ 18 years of age at the time of informed consent.
    ● Patient has histologically and/or cytologically confirmed malignancies:
    Phase Ib:
    ● Patients with advanced or metastatic solid tumors who have failed at least one prior line of systemic antineoplastic therapy in the advanced setting without a standard of care treatment option available;
    Phase II:
    ● Advanced or metastatic pancreatic adenocarcinoma who have failed at least one prior systemic antineoplastic therapy in the advanced setting
    ● Advanced or metastatic KRAS-mutant CRC who have failed at least two prior systemic antineoplastic therapies in the advanced setting without a standard of care treatment option
    available. Testing for KRAS mutation in patients with CRC using locally approved diagnostic kit will be used for eligibility.
    ● Phase II only: patient must have measurable disease, i.e., at least one measurable lesion as per response evaluation criteria in solid tumors (RECIST) 1.1 criteria (Tumor lesions previously irradiated or subjected to other locoregional therapy will only be considered measurable if disease progression at the treated site after completion of prior therapy is clearly documented).
    ● Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
    ● Patient has adequate bone marrow and organ function as defined by the following laboratory values within 2 weeks prior to Cycle 1 Day 1 as assessed by local laboratory for eligibility
    ● Absolute neutrophil count ≥ 1.5 × 109/L (without administration of white blood cell growth factor for at least 2 weeks prior to Cycle 1 Day 1)
    ● Platelets ≥ 100 × 109/L (without platelet infusion / transfusion for at least 2 weeks prior to Cycle 1 Day 1)
    ● Hemoglobin ≥ 9.0 g/dL
    ● INR ≤ 1.5
    ● Serum creatinine <1.5 mg/dL
    ● Total bilirubin <ULN except for patients with Gilbert’s syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN.
    ● Aspartate aminotransferase (AST) must be within normal range, except for patients with liver metastasis, who are only included if the AST is <2.5 × ULN
    ● Alanine aminotransaminase (ALT) must be within normal range, except for patients with liver metastasis, who are only included if the ALT is <2.5 × ULN
    ● Albumin ≥ 3.0 g/dL
    ● Patient must have the following laboratory values within normal limits or corrected to within normal limits with supplements before the first dose of study medication on Cycle 1
    Day 1:
    ● Sodium
    ● Potassium
    ● Magnesium
    ● Phosphorus
    ● Total Calcium (corrected for serum albumin)
    ● Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed by the central ECG reading
    ● QTcF interval at screening <450 msec (using Fridericia’s correction)
    ● Resting heart rate 50-90 bpm

    Further inclusion criteria and details are described in the protocol.
    -El consentimiento informado por escrito deberá obtenerse antes de cualquier procedimiento de selección específico del estudio.
    -Pacientes adultos hombres/mujeres >/=18 años de edad en el momento del consentimiento informado.
    - Pacientes con neoplasias malignas histológica y/o citológicamente confirmadas.
    Fase Ib:
    -Pacientes con tumores sólidos metastásicos o avanzados que hayan fracasado al menos a una línea previa de terapia antineoplásica sistémica en el estadío avanzado, sin una opción terapéutica estándar disponible.
    Fase II:
    -Adenocarcinoma pancreático metastásico o avanzado que haya fracasado al menos a una terapia antineoplásica sistémica previa en el estadío avanzado.
    -CCR metastásico o avanzado con mutación KRAS que haya fracasado al menos a dos terapias antineoplásicas sistémicas previas en el estadío avanzado, sin una opción terapéutica estándar disponible. Para la elegibilidad se utilizará el análisis de mutación de KRAS en pacientes con CCR utilizando el kit diagnóstico aprobado localmente.
    Sólo fase II: los pacientes deberán presentar enfermedad medible, es decir, por lo menos una lesión medible según los criterios de evaluación de respuesta (RECIST 1.1) (las lesiones del tumor irradiadas previamente o sujetas a otra terapia locorregional sólo serán consideradas medibles si se documenta claramente progresión de la enfermedad en la zona tratada, después de la finalización de la terapia previa).
    - Pacientes con un estado funcional del Grupo de Oncología Cooperativo del Este (ECOG) de 0 ó 1.
    -Pacientes con una función orgánica y de la médula ósea adecuada definido con los siguientes valores de laboratorio dentro de 2 semanas antes del día 1 del ciclo 1, determinado por el laboratorio local para elegibilidad.
    - Recuento absoluto de neutrófilos >/= 1.5 × 109/L (sin administración de factor de crecimiento leucocitario durante por lo menos 2 semanas antes del día 1 del ciclo 1)
    -Plaquetas>/= 100 × 109/L (sin infusión/transfusión de plaquetas durante por lo menos 2 semanas antes del día 1 del ciclo 1)
    -Hemoglobina >/= 9.0 g/dL
    - INR </= 1.5
    -Creatinina sérica < 1.5 mg/dL
    -Bilirrubina total < LSN, excepto en pacientes con síndrome de Gilbert que sólo pueden ser incluidos si la bilirrubina total es </= 3.0 × LSN o la bilirrubina directa </= 1.5 × LSN.
    -Los valores de aspartato aminotransferasa (AST) deberán encontrarse dentro del rango de normalidad, excepto para pacientes con metástasis hepáticas, que sólo se incluirán si la AST es < 2.5 × LSN.
    -Los valores de alanina aminotransferasa (ALT) deberán encontrarse dentro del rango de normalidad, excepto para pacientes con metástasis hepáticas, que sólo se incluirán si la ALT es < 2.5 × LSN.
    -Albúmina >/= 3.0 g/dL
    -El paciente deberá presentar los siguientes valores de laboratorio dentro de los límites de normalidad o corregidos dentro de los límites de normalidad con suplementos antes de la primera dosis de la medicación del estudio el día 1 del ciclo 1:
    .Sodio
    .Potasio
    .Magnesio
    .Fósforo
    .Calcio total (corregido para albúmina sérica)
    -Valores de ECG estándar de 12 derivaciones definido como la media de los ECGs triplicados y evaluado por el laboratorio de ECG central
    -Intervalo QTcF en la selección < 450 ms (utilizando la corrección de Fridericia)
    -Frecuencia cardíaca en reposo 50-90 ppm.

    Otros criterios de inclusión y más detalles están descritos en el protocolo.
    E.4Principal exclusion criteria
    Phase II only:
    ● Patient has received prior treatment with a MEK inhibitor or a CDK4/6 inhibitor.
    Phase Ib and Phase II:
    ● Patient with a known hypersensitivity to the study drugs or any of the excipients of ribociclib or trametinib.
    ● Patient is concurrently using other anti-cancer therapy.
    ● Patient has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to Cycle 1 Day 1, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia) and/or from whom ≥ 25% (Ellis 1961) of the bone marrow was irradiated.
    ● Limitation of local therapy in liver lesions (localized liver therapy)
    ● Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, or vaccine therapy) within 28 days prior to Cycle 1 Day 1, or chemotherapy without delayed toxicity within the last 2 weeks preceding the first dose of study treatment with no more than grade 1 treatment related AEs.
    ● Prior therapy with anthracyclines at cumulative doses of 450 mg/ m2 or more for doxorubicin or 900 mg/m2 or more for epirubicin.
    ● Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.
    Patient has a concurrent malignancy or malignancy within 3 years prior to Cycle 1 Day 1, with the exception of adequately treated basal or squamous cell carcinoma or curatively resected cervical cancer.
    ● Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
    ● At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment.
    ● Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases.
    ● Patient has impairment of GI function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting,
    diarrhea, malabsorption syndrome, or small bowel resection).
    ● History of interstitial lung disease or pneumonitis.
    ● History of liver disease as follow :
    ● Cirrhosis
    ● Autoimmune hepatitis
    ● Portal Hypertension
    ● Drug-induced liver steatosis
    ● Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:
    ● History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry
    ● Documented cardiomyopathy
    ● Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
    ● Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
    ● Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
    ● Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting study drug)
    ● Inability to determine the QTcF interval
    ● Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
    ● Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy
    ● Systolic Blood Pressure (SBP) >160 or <90 mmHg
    ● Patient is currently receiving any of the following substances and cannot be discontinued 7 days prior to Cycle 1 Day 1:
    ● Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pomelos, star-fruit, and Seville oranges.
    ● Substances that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
    ● Herbal preparations/medications, dietary supplements.
    ● History of deep vein thrombosis or pulmonary embolism within 6 months
    ● Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment.
    Note: The following uses of corticosteroids are permitted: short term use less than one week, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).
    ● History of retinal vein occlusion (RVO)

    Further exclusion criteria and details are described in the protocol.
    Sólo fase II: Pacientes que hayan recibido tratamiento (tto.) previo con un inhibidor de MEK o un inhibidor de CDK4/6.
    Fase Ib y fase II:
    Pacientes con una hipersensibilidad conocida a las medicaciones del estudio o a alguno de los excipientes de ribociclib o de trametinib.
    Pacientes que estén utilizando actualmente otra terapia antineoplásica.
    Pacientes que hayan recibido radioterapia </=4 semanas o radiación de campo limitado para paliación </= 2 semanas antes del día 1 del ciclo 1 y que no se hayan recuperado a grado 1 o mejor de los efectos secundarios relacionados de dicha terapia (excepción de alopecia) y/o cuya médula ósea haya sido irradiada ≥ 25% (Ellis 1961).
    Limitación de terapia local en lesiones hepáticas (véase Apartado 5.3).
    Tto. antineoplásico sistémico previo dentro de los 28 días antes del día 1 del ciclo 1 o quimioterapia sin toxicidad retardada dentro de las últimas 2 semanas anteriores a la primera dosis del tratamiento del estudio con AAs como máximo de grado 1 relacionados con el tto.
    Terapia previa con antraciclinas a dosis acumuladas de 450 mg/m² o más para doxorrubicina o de 900 mg/m² o más para epirrubicina.
    Pacientes que actualmente reciban warfarina u otro anticoagulante derivado cumarínico para tratamiento, profilaxis o por otro motivo. Se permite la terapia con heparina, LWMH o fondaparinux.
    Pacientes con una neoplasia maligna concurrente o neoplasia maligna dentro de los 3 años antes del día 1 del ciclo 1, con la excepción de carcinoma cutáneo escamoso o basal adecuadamente tratado o cáncer del cuello del útero extirpado curativamente.
    Pacientes con afectación del SNC, excepto que cumplan TODOS los criterios siguientes:
    Por lo menos 4 semanas desde la finalización de la terapia previa (incluyendo radiación y/o cirugía) hasta el inicio del tto. del estudio.
    Tumor en el SNC clínicamente estable en el momento de la selección y que no reciban esteroides y/o medicaciones antiepilépticas inductoras de enzimas para las metástasis cerebrales.
    Pacientes con deterioro de la función gastrointestinal (GI) o enfermedad GI que pueda alterar significativamente la absorción de las medicaciones del estudio (por ejemplo, enfermedades ulcerosas, náuseas incontroladas, vómitos, diarrea, síndrome de mala absorción o resección del intestino delgado).
    Antecedentes de enfermedad pulmonar intersticial o neumonitis.
    Antecedentes de las siguientes enfermedades hepáticas:
    . Cirrosis
    . Hepatitis autoinmune
    . Hipertensión portal
    . Esteatosis hepática inducida por fármacos
    Pacientes con enfermedad cardiaca incontrolada y/o anomalía de repolarización cardíaca clínicamente significativas, que incluya alguna de las siguientes :
    .Antecedentes de MI, angina de pecho, pericarditis sintomática, bypass coronario arterial por injerto dentro de los 6 meses antes de la inclusión en el estudio
    .Cardiomiopatía documentada
    .LVEF < 50%, determinada con MUGA o ECO
    .Síndrome de QT prolongado o antecedentes familiares de muerte súbita idiopática o de síndrome de QT prolongado congénito, o algo de lo siguiente:
    .Factores de riesgo de TdP incluyendo hipocalemia o hipomagnesemia no corregida, antecedentes de insuficiencia cardíaca o antecedentes de bradicardia sintomática/clínicamente significativa
    .Medicación concomitante con un riesgo conocido de prolongación del intervalo QT y/o que se conozca que causa(n) TdP, que no pueda ser suspendida o sustituida por medicación alternativa segura (ej: dentro de 5 semividas o 7 días antes de iniciar la medicación del estudio).
    .Incapacidad para determinar el intervalo QTcF
    -Arritmias cardíacas clínicamente significativas (por ejemplo, taquicardia ventricular), bloqueo completo de rama izquierda, bloqueo AV de grado alto (EJ: bloqueo bifascicular, tipo II de Mobitz y bloqueo AV de 3º grado).
    -HPTA refractaria a tratamiento definida como una presión arterial sistólica > 140 mmHg y/o diastólica > 90 mm Hg que no pueda ser controlada con terapia antihipertensiva.
    -PAS > 160 o < 90 mmHg
    Pacientes que actualmente estén recibiendo alguna de las siguientes sustancias y que no puedan ser suspendidas 7 días antes del día 1 del ciclo 1:
    .Inductores o inhibidores potentes conocidos de CYP3A4/5, incluyendo pomelo, híbridos del pomelo, toronjas, fruta estrella y naranjas de Sevilla.
    .Sustancias que posean un estrecho índice terapéutico y que sean metabolizadas predominantemente por CYP3A4/5.. Preparaciones/medicaciones herbales, suplementos dietéticos.
    .Antecedentes de trombosis venosa profunda o de embolismo pulmonar dentro de los 6 meses.
    -Pacientes que actualmente reciban o hayan recibido corticosteroides sistémicos ≤ 2 semanas antes del inicio del tto. del estudio o que no se hayan recuperado completamente de los efectos 2arios. de dicho tto.
    Nota: Se permiten los siguientes usos de corticosteroides: uso a corto plazo, menos de una semana, aplicaciones tópicas, inhaladores,colirios o inyecciones locales.
    -Historial de OVR.
    Más detalles en el protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Phase Ib
    ● Frequency of dose limiting toxicities (DLTs) at each dose level associated with administration of ribociclib and trametinib in a 28 day cycle

    Phase II
    ● Overall response rate (ORR) defined as the proportion of patients with a best overall confirmed response of complete response (CR) or partial response (PR) as assessed per response evaluation criteria in solid tumors (RECIST) 1.1 by investigator assessment
    Fase Ib
    Frecuencia de dosis limitante tóxicas (DLTs) en cada nivel de dosis asociado a una administración de ribociclib y trametinib en un ciclo de 28 días.

    Fase II
    Tasa de respuesta global (TRG) definida como la proporción de pacientes con una mejor respuesta global de RC o RP confirmada, evaluado según los RECIST 1.1 por el investigador.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase Ib
    Safety will be monitored by the assessments described below as well as collecting of the adverse events at every visit (see Table 7-1 of the protocol).

    Phase II
    Imaging assessments will be performed at screening within 28 days prior to Cycle 1 Day 1 and subsequently every 6 weeks during the first 12 months and every 12 weeks thereafter.
    Fase Ib
    La seguridad será monitorizada por la evaluación descrita arriba y también por la recogida de los eventos adversos en cada visita (ver Tabla 7-1 del protocolo).

    Fase II
    Las evaluaciones por imagen serán realizadas en el cribado dentro de los 28 días previos al ciclo 1 día 1 y después cada 6 semanas durante los primeros 12 meses y tras ello, cada 12 semanas.
    E.5.2Secondary end point(s)
    Phase Ib and II
    ● Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity.
    ● PK parameters such as but not limited to Cmax, Tmax, and AUC and Cmin for ribociclib (and metabolite LEQ803) and trametinib

    Phase Ib
    ● Progression disease rate defined as the proportion of patients with a progression disease as assessed per RECIST 1.1 by investigator assessment
    ● PFS, defined as time from first dose of study drug to progression or death due to any cause

    Phase II
    ● Duration of response (DOR), calculated as the time from the date of the first documented CR or PR to the first documented progression or death due to any cause
    ● Disease control rate (DCR), time to response (TTR) calculated as the time from first dose to first documented response (CR+PR)
    ● Progression free survival (PFS)
    ● Overall survival (OS), defined as time from first dose of study drug to death due to any cause
    Fase Ib y II
    Eventos Adversos (AEs), Eventos Adversos serios (SAEs), cambios en los valores hematológicos y químicos, signos vitales, electrocardiogramas (ECGs), interrupciones de dosis, reduciones e intensidad de dosis.
    Parámetros PK tales como , pero no limitado, Cmax, Tmax, y AUC y Cmin for ribociclib (y su metabolito LEQ803) y trametinib

    Fase Ib
    Tasas de progresión de la enfermedad definida como la proporción de pacientes con una progresión de la enfermedad evaluado según los RECIST 1.1 por el investigador.
    PFS, se define como el tiempo desde la primera dosis de la medicación de estudio hasta la progresión o muerte por cualquier causa.

    Fase II
    Duración de la respuesta (DR), calculada como el tiempo desde la fecha de la primera dosis documentada CR o PR a la primera documentación de progresión o muerte por cualquier causa.
    Tasa de control de la enfermedad (TCE), tiempo hasta la respuesta (TR) calculados como el tiempo desde la primera dosis hasta la primera respuesta documentada (CR+PR).
    Supervivencia libre de progresión (SLP)
    Supervivencia global (SG) definido como el tiempo desde la primera dosis de la medicación de estudio hasta la muerte por cualquier causa.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase Ib and II
    Safety will be monitored by the assessments described below as well as collecting of the adverse events at every visit (see Table 7-1 of the protocol).

    Phase Ib
    Imaging assessments will be performed at screening within 28 days prior to Cycle 1 Day 1 and subsequently every 8 weeks during the first 12 months and every 12 weeks thereafter.

    Phase II
    Imaging assessments will be performed at screening within 28 days prior to Cycle 1 Day 1 and subsequently every 6 weeks during the first 12 months and every 12 weeks thereafter.
    Fase Ib y II
    La seguridad será monitorizada por la evaluación descrita arriba y también por la recogida de los eventos adversos en cada visita (ver Tabla 7-1 del protocolo).

    Fase Ib
    Las evaluaciones por imagen serán realizadas en el cribado dentro de los 28 días previos al ciclo 1 día 1 y después cada 8 semanas durante los primeros 12 meses y tras ello, cada 12 semanas.
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase Ib/II
    Fase Ib/II
    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 Yes
    E.8.1.7.1Other trial design description
    Phase Ib open label, dose escalation part followed by open-label two-arm non-randomized Phase II
    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 trial2
    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 EEA6
    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
    Australia
    Belgium
    Canada
    Germany
    Hong Kong
    Netherlands
    Russian Federation
    Spain
    Taiwan
    Turkey
    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
    LVLS ( Última visita último paciente)
    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 days24
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months7
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 34
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 15
    F.4.2.2In the whole clinical trial 69
    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)
    N/A
    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 Decision2017-09-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-14
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2019-05-03
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