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    The EU Clinical Trials Register currently displays   43935   clinical trials with a EudraCT protocol, of which   7309   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2021-005617-14
    Sponsor's Protocol Code Number:CLEE011Q12101
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-07-01
    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 number2021-005617-14
    A.3Full title of the trial
    Phase I/II multicenter study to assess efficacy and safety of ribociclib (LEE011) in combination with topotecan and temozolomide (TOTEM) in pediatric patients with relapsed or refractory neuroblastoma and other solid tumors
    Estudio de fase I/II multicéntrico en el que se evalúan la eficacia y la seguridad de ribociclib (LEE011) en combinación con topotecán y temozolomida (TOTEM) en pacientes pediátricos con neuroblastoma recidivante o refractario y otros tumores sólidos
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess safety and identify dose of ribociclib in combination of temozolomide and topotecan (TOTEM) in patients (12 months – 21 years old) with relapsed or refractory solid tumors (Phase I), and further assess efficacy and safety in patients (12 months – 21 years old) with relapsed or refractory neuroblastoma (Phase II)
    Estudio para evaluar la seguridad e identificar la dosis de ribociclib en combinación con temozolomida y topotecán (TOTEM) en pacientes (12 meses - 21 años) con tumores sólidos recidivantes o refractarios (Fase I) y evaluar la eficacia y seguridad en pacientes (12 meses - 21 años) con neuroblastoma recidivante o refractario (Fase II)
    A.4.1Sponsor's protocol code numberCLEE011Q12101
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/020/2022
    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 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 pointTrial Monitoring Organization (TMO)
    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 number+34930353036
    B.5.5Fax number+34932479903
    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 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 nameribociclib
    D.3.2Product code LEE011
    D.3.4Pharmaceutical form Powder for oral solution
    D.3.4.1Specific paediatric formulation Yes
    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.3.9.1CAS number 1374639-75-4
    D.3.9.2Current sponsor codeLEE011
    D.3.9.4EV Substance CodeSUB180246
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number204.082
    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 Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nametemozolomida 5 mg cápsulas duras
    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 INNTemozolomide
    D.3.9.3Other descriptive nameTemozolomide
    D.3.9.4EV Substance CodeSUB10889MIG
    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: 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 Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nametopotecan
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTOPOTECAN HYDROCHLORIDE
    D.3.9.1CAS number 119413-54-6
    D.3.9.3Other descriptive nameTopotecan
    D.3.9.4EV Substance CodeSUB04921MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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: 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.2.5The 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 nametemozolomida 20 mg cápsulas duras
    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 INNTemozolomide
    D.3.9.3Other descriptive nameTemozolomide
    D.3.9.4EV Substance CodeSUB10889MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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.2.5The 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 nametemozolomida 100 mg cápsulas duras
    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 INNTemozolomide
    D.3.9.3Other descriptive nameTemozolomide
    D.3.9.4EV Substance CodeSUB10889MIG
    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: 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.2.5The 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 nametemozolomida 140 mg cápsulas duras
    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 INNTemozolomide
    D.3.9.3Other descriptive nameTemozolomide
    D.3.9.4EV Substance CodeSUB10889MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number140
    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 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.2.5The 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 nametemozolomida 180 mg cápsulas duras
    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 INNTemozolomide
    D.3.9.3Other descriptive nameTemozolomide
    D.3.9.4EV Substance CodeSUB10889MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number180
    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: 8
    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.2.5The 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 nametemozolomida 250 mg cápsulas duras
    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 INNTemozolomide
    D.3.9.3Other descriptive nameTemozolomide
    D.3.9.4EV Substance CodeSUB10889MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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
    relapsed or refractory neuroblastoma and other solid tumors (including medulloblastoma, high grade glioma, malignant rhabdoid tumors, and rhabdomyosarcoma) in patients from 12 months to 21 years old
    neuroblastoma recidivante o refractario y otros tumores sólidos (incluyendo meduloblastoma, glioma de alto grado, tumores rabdoides malignos y rabdomiosarcoma) en pacientes con edades comprendidas entre los 12 meses y los 21 años
    E.1.1.1Medical condition in easily understood language
    Recurrent solid tumors in patients from 12 months to 21 years old
    Tumores sólidos recurrentes en pacientes con edades comprendidas entre los 12 meses y los 21 años
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase I - part A: To determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of ribociclib in combination with TOTEM.
    Phase I - part B: To evaluate antitumor activity as assessed by Overall Response Rate (ORR) of ribociclib in combination with TOTEM.
    Phase II: To evaluate the treatment effect as assessed by ORR of ribociclib in combination with TOTEM versus placebo plus TOTEM.
    Fase I – parte A: determinar la dosis máxima tolerada (MTD) y/o dosis recomendada para la fase II (RP2D) de ribociclib en combinación con TOTEM.
    Fase I – parte B: evaluar la actividad antitumoral según la tasa de respuesta global (ORR) de ribociclib en combinación con TOTEM.
    Fase II: evaluar el efecto del tratamiento según la ORR de ribociclib en combinación con TOTEM frente a placebo y TOTEM.
    E.2.2Secondary objectives of the trial
    Phase I – part A:
    • to characterize the safety and tolerability of ribociclib in combination with TOTEM (ribociclib+TOTEM)
    • to characterize the pharmacokinetics (PK) of ribociclib+TOTEM
    Phase I – part B:
    • to assess the antitumor activity of ribociclib+TOTEM as assessed by Duration of response (DOR), PFS, Time to response (TTR), and OS.
    • to characterize the safety and tolerability of ribociclib+TOTEM
    • to characterize the PK of ribociclib+TOTEM
    Phase II:
    • to assess the treatment effect of ribociclib+TOTEM as assessed by PFS and DOR versus placebo plus TOTEM.
    • to assess the treatment effect of ribociclib+TOTEM as assessed by TTR, Clinical Benefit Rate, and OS versus placebo plus TOTEM.
    • to characterize the PK of ribociclib+TOTEM.
    • to characterize the safety and tolerability of ribociclib+TOTEM.
    • to describe the effect of ribociclib+TOTEM on Patient Reported Outcomes (PRO).
    Fase I – parte A:
    - Caracterizar la seguridad y la tolerabilidad de ribociclib en combinación con TOTEM (ribociclib+TOTEM)
    - Caracterizar la farmacocinética (PK) de ribociclib+TOTEM
    Fase I – parte B:
    - Evaluar la actividad antitumoral de ribociclib+TOTEM según la duración de respuesta (DOR), la supervivencia libre de progresión (PFS), el tiempo hasta la respuesta (TTR) y la supervivencia global (OS).
    - Caracterizar la seguridad y la tolerabilidad de ribociclib+TOTEM.
    - Caracterizar la PK de ribociclib+TOTEM
    Fase II:
    - Evaluar el efecto del tratamiento con ribociclib+TOTEM según la PFS y la DOR frente a placebo y TOTEM.
    - Evaluar el efecto del tratamiento con ribociclib+TOTEM según la TTR, la tasa de beneficio clínico (CBR) y la OS frente a placebo y TOTEM.
    - Caracterizar la PK de ribociclib+TOTEM.
    - Caracterizar la seguridad y la tolerabilidad de ribociclib+TOTEM.
    - Describir el efecto de ribociclib+TOTEM sobre los resultados comunicados por el paciente (PRO).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Signed informed consent/assent must be obtained prior to participation in the study. Participants and/or guardian must have the ability to understand and the willingness to sign a written informed consent document.
    2.Age >/= 12 months and </= 21 years at the time of signing consent form.
    3.Histologically or cytologically confirmed solid tumors listed below that have progressed despite standard therapy or for which no effective standard therapy exists.
    a. Neuroblastoma (NB) (Phase I and Phase II)
    i. Histologically proven NB as per International Neuroblastoma Staging System (INSS)
    ii. Relapsed: any relapsed or progressed high-risk (HR)-NB
    iii. Refractory high-risk disease: lack of adequate response to frontline therapy that precludes the participant from proceeding to consolidation therapies (e.g. myeloblative chemotherapy)
    iv. Measurable disease by cross sectional imaging and/or evaluable disease (uptake on MIBG scan or FDG PET with or without bone marrow histology) per International Neuroblastoma Response Criteria (INRC).
    v. Imaging confirmed disease recurrence or progression
    vi. Participants must have an available MYCN amplification status before screening.
    b. Medulloblastoma (MB) (Phase I) regardless of genetic status (i.e. Groups 3 or 4 WNT-activated or non-WNT, SHH-activated or non-SHH).
    c. High-grade glioma (HGG) (Phase I): Note: excluding any low grades (grade I or grade II) such as astrocytoma, oligodendroglioma, or mixed glioneuronal tumors
    i. HGG, not otherwise specified (NOS), WHO Grade III or Grade IV
    ii. Glioblastoma, IDH-wildtype, or IDH-mutant
    iii. Anaplastic astrocytoma, IDH mutant
    iv. Anaplastic oligodendroglioma, IDH mutant
    v. Anaplastic pleomorphic xanthoastrocytoma
    vi. Diffuse midline gliomas, H3 K27-altered
    vii. Diffuse hemispheric glioma, H3 G34-mutant
    viii. Diffuse pediatric-type HGG, H3-wildtype and IDH-wildtype
    d. Malignant rhabdoid tumor (MRT) (Phase I): includes diagnoses of atypical teratoid/rhabdoid tumor (AT/RT), and rhabdoid tumor of the kidney (RTK), and other soft tissues as defined by 2 of the 3 following criteria; either (i)+(ii) or (i)+(iii):
    i. Morphology and immunophenotypic panel consistent with rhabdoid tumor
    ii. Loss of SMARCB1 confirmed by immunohistochemistry
    iii. Molecular confirmation of tumor-specific bi-allelic SMARCB1 loss/mutation is encouraged in cases where SMARCB1 immunohistochemistry is equivocal and required if SMARCB1 immunohistochemistry is not available.
    e. Rhabdomyosarcoma (RMS) (Phase I) independent of fusion status and subtype.
    4.Participants with central nervous system (CNS) disease who are on corticosteroids should take stable doses for at least 7 days prior to first dose of ribociclib with no plans for escalation. Note: participants with symptomatic CNS disease who are neurologically unstable or require local CNS-directed therapy to control their CNS disease are not eligible for the study.
    5.Measurable disease per Revised Assessment in Neuro-Oncology (RANO) criteria for participants with HGG and per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for MB, MRT and RMS.
    6.Performance status: participants who are unable to walk because of paralysis, but who are able to sit upright unassisted in a wheelchair, will be considered ambulatory for the purpose of assessing performance score
    a.</= 16 years: Lansky Play score >/= 50%
    b.>16 years: Karnofsky performance status >/= 50% or ECOG < 3
    7.Life expectancy of >/= 12 weeks at the time of enrollment.
    8.Adequate bone marrow function (bone marrow may be involved with tumor) and organ function defined as:
    a. Peripheral absolute neutrophil count (ANC) >/= 1000/mm3 without growth factor support within 7 days of the test
    b. Platelet count >/= 75,000/mm3 without support within 7 days of the test
    c. Hemoglobin >/= 8.0 g/dL (transfusion allowed)
    d. Total bilirubin </= 1.5 x ULN for age (in case of Gilbert’s syndrome, </= 3.0 x ULN or direct bilirubin </= 1.5 x ULN for age)
    e. Adequate liver function, defined as total serum bilirubin </= 1.5 x ULN AND alanine aminotransferase (ALT) / aspartate aminotransferase (AST) </= 2.5 x ULN (in case of liver metastases, AST / ALT ≤ 5 x ULN)
    f. Adequate renal function, defined as serum creatinine </= 1.5 x ULN based on age/gender normal. In participants with serum creatinine > 1.5 x ULN for age/gender normal, a calculated glomerular filtration rate (GFR) must be >/= 60 mL/min/1.73 m2.
    g. Adequate cardiac function, defined as corrected QTc interval using Fridericia’s correction (QTcF) </=450 ms and shortening fraction (SF) > 29% (> 35% for participants < 3 years) and left ventricular ejection fraction (LVEF) >/= 50% on echocardiogram
    h. The following laboratory values within normal limits or corrected to within normal limits with supplements before first dose of study medication:
    i. Potassium
    ii. Magnesium
    iii. Total calcium (corrected for serum albumin)
    - Other protocol-defined inclusion criteria may apply
    1.Se deberá obtener el consentimiento/asentimiento informado firmado antes de la participación en el estudio. Los participantes o el tutor deben ser capaces de comprender y tener la voluntad de firmar un documento de consentimiento informado por escrito.
    2.Edad comprendida entre >/=12 meses y </=21 años en el momento de la firma del consentimiento.
    3.Los tumores sólidos confirmados histológica o citológicamente indicados a continuación que hayan progresado a pesar del tratamiento estándar o para los que no exista un tratamiento estándar efectivo.
    a.Neuroblastoma (NB) (fase I y fase II)
    i.NB confirmado histológicamente conforme al Sistema Internacional de Estadificación del Neuroblastoma (INSS).
    ii.Recidivante: cualquier NB recidivante o avanzado de alto riesgo.
    iii.Enfermedad refractaria de alto riesgo: falta de respuesta adecuada al tratamiento de primera línea que impida al participante proceder a las terapias de consolidación (p. ej., quimioterapia mieloablativa).
    iv.Enfermedad medible mediante imagen transversal o enfermedad evaluable (imagen con captación de MIBG o FDG-PET con o sin histología de médula ósea) según los criterios INRC.
    v.Recurrencia o progresión de la enfermedad confirmada mediante estudio de diagnóstico por imagen.
    vi.Se debe haber determinado el estado de amplificación de MYCN de los participantes antes de la selección.
    b.Meduloblastoma (MB) (fase I) independientemente del estado genético (es decir, grupos 3 o 4, WNT activado o no WNT, SHH activado o no SHH).
    c. Glioma de alto grado (fase I): Nota: Se excluyen cualquier glioma de bajo grado (grado I o grado II) como astrocitoma, oligodendroglioma o tumores glioneuronales mixtos
    i.GAG NOS de grado III o grado IV según la OMS
    ii. Glioblastoma con o sin mutación de isocitrato deshidrogenasa (IDH)
    iii.Astrocitoma anaplásico con mutación de IDH
    iv.Oligodendroglioma anaplásico con mutación de IDH
    v. Xantoastrocitoma pleomórfico anaplásico
    vi.Gliomas difusos de la línea media con alteración de H3 K27
    vii.Glioma hemisférico difuso con mutación de H3 G34
    viii.GAG difuso de tipo pediátrico, sin mutación de H3 y sin mutación de IDH
    d.El tumor rabdoide maligno (fase I) incluye diagnósticos de un tumor teratoide atípico/rabdoide (TA/TR) y un tumor rabdoide del riñón (TRR) y otros tejidos blandos según lo definido por 2 de estos 3 criterios; bien (i)+(ii) o (i)+(iii):
    i.Perfil morfológico e inmunofenotípico que coincide con el tumor rabdoide
    ii.Pérdida de SMARCB1 confirmada por inmunohistoquímica
    iii.La confirmación molecular de una pérdida/mutación bialélica de SMARCB1 específica del tumor está recomendada en caso de que la inmunohistoquímica de SMARCB1 sea equívoca y es obligatoria en caso de que no se disponga de una inmunohistoquímica de SMARCB1.
    e.Rabdomiosarcoma (fase I) independiente del estado y subtipo de fusión.
    4.Los participantes con una enfermedad del sistema nervioso central (SNC) que estén recibiendo corticosteroides deberán tomar dosis estables durante al menos los 7 días anteriores a la primera dosis de ribociclib sin intención de escalada. Nota: los participantes con una enfermedad sintomática del SNC que sean neurológicamente inestables o que requieran tratamiento local dirigido al SNC para controlar su enfermedad no son elegibles para participar en el estudio.
    5.Enfermedad medible según los criterios RANO en los participantes con GAG y según los criterios de evaluación de la respuesta en tumores sólidos (RECIST) 1.1 en los participantes con MB, TRM y RMS.
    6.Estado funcional: los participantes que no puedan caminar debido a una parálisis, pero que puedan sentarse erguidos sin ayuda en una silla de ruedas serán considerados ambulatorios con el fin de evaluar la puntuación del estado funcional
    a.</=16 años: puntuación de Lansky Play >/=50 %
    b.>16 años: estado funcional de Karnofsky >/=50 % o ECOG <3
    7.Esperanza de vida >/=12 semanas en el momento del reclutamiento.
    8.Función adecuada de la médula ósea (la médula ósea puede estar afectada por el tumor) y de los órganos, definida como:
    a.Recuento absoluto de neutrófilos (RAN) periféricos >/=1000/mm3 sin tratamiento de apoyo con factores de crecimiento durante los 7 días anteriores a la prueba
    b.Recuento de plaquetas </=75 000/mm3 sin tratamiento de apoyo durante los 7 días anteriores a la prueba
    c.Hemoglobina >/=8,0 g/dl (transfusión permitida)
    d.Bilirrubina total </=1,5 x límite superior de normalidad (LSN) para la edad (en caso de síndrome de Gilbert, </=3,0 x LSN o bilirrubina directa </=1,5 x LSN para la edad)
    e.Función hepática adecuada, definida como bilirrubina sérica total </=1,5 x LSN Y alanino aminotransferasa (ALT)/aspartato aminotransferasa (AST) </=2,5 x LSN (en caso de metástasis hepáticas, AST/ALT </=5 x LSN)

    -Pueden aplicarse otros criterios de inclusión definidos por el protocolo
    E.4Principal exclusion criteria
    1. Known hypersensitivity to any of the excipients of ribociclib or topotecan or temozolomide.
    2. Not recovered from clinical and laboratory acute toxicities related to prior anti-cancer therapies.
    3. Concurrent severe and/or uncontrolled concurrent medical conditions that in the Investigator's judgement could compromise their ability to tolerate or absorb protocol therapy or would interfere with the study procedures or results.
    4. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality.
    5. History of QTcF prolongation (i.e. QTcF interval of > 450 ms) or QTcF > 450 ms on screening ECG.
    6. Currently taking medications with a known risk to prolong the QT interval or induce TdP that cannot be discontinued or replaced by safe alternative medication.
    7. Currently taking medications that are known strong inducers or inhibitors of CYP3A4/5 cannot be discontinued at least 7 days or 5 half-lives.
    8. Currently taking medications that are mainly metabolized by CYP3A4/5 with a narrow therapeutic index that cannot be discontinued at least 7 days or 5 half-lives.
    9. Vaccinated with live, attenuated vaccines within 4 weeks.
    10. Participated in a investigational study within 30 days or 5 half-lives.
    11. Received prior treatment with a CDK4/6 inhibitor.
    12. Received anticancer therapy (including experimental) within 4 weeks.
    13. Received myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks.
    14. Received allogeneic stem cell transplant within 3 months.
    15. Has radiation within 4 weeks (or 2 weeks if radiation therapy is given for palliation), or within 6 weeks of MIBG treatment.
    16. Major surgery within 2 weeks and not recovered fully from the side effects.
    - Other protocol-defined exclusion criteria may apply
    1.Participantes con hipersensibilidad conocida a cualquiera de los excipientes
    de ribociclib, topotecán o temozolomida.
    2.No haberse recuperado de toxicidades clínicas y analíticas agudas relacionadas con los tratamientos previos contra el cáncer.
    3.Enfermedades graves o no controladas concurrentes que, según el criterio del investigador, pudieran poner en riesgo la capacidad de tolerar o absorber el tratamiento del protocolo o que pudieran interferir en los procedimientos o resultados del estudio.
    4. Enfermedad cardíaca clínicamente significativa no controlada o anomalía en
    la repolarización cardíaca.
    5.Antecedentes de prolongación del QTcF (es decir, intervalo del QTcF >450 ms) o QTcF >450 ms en el electrocardiograma (ECG) de selección.
    6.Medicación que tiene un riesgo conocido de prolongar el intervalo QT o
    inducir TdP que no puede discontinuarse ni cambiarse por otra medicación segura.
    7.Participantes que estén recibiendo alguna de las siguientes sustancias y que
    no puedan discontinuarse al menos 7 días o 5 veces la vida media de
    eliminación.
    8.Participantes que estén tomando medicación que sea principalmente
    metabolizada por CYP3A4/5 con un índice terapéutico estrecho que no pueda
    discontinuarse al menos 7 días o 5 veces la vida media de eliminación.
    9.Participantes vacunados con vacunas vivas atenuadas durante las
    4 semanas anteriores.
    10.Haber participado en un estudio de investigación previo dentro de los 30
    días anteriores a la inclusión o dentro de las 5 del producto en
    investigación.
    11.Haber recibido tratamiento previo con un inhibidor de CDK4/6.
    12.Haber recibido la última dosis de un tratamiento contra el cáncer (incluido
    uno experimental) durante las 4 semanas anteriores.
    13.Tratamiento mieloablativo previo con rescate autólogo de células madre
    hematopoyéticas durante las 8 semanas anteriores.
    14.Trasplante alogénico de células madre durante los 3 meses anteriores a la
    primera dosis.
    15.Haber tenido la última fracción de radiación durante las 4 semanas
    anteriores.
    16.Cirugía mayor durante las 2 semanas anteriores y no haberse recuperado totalmente de los efectos secundarios.
    -Pueden aplicarse otros criterios de exclusión definidos por el protocolo
    E.5 End points
    E.5.1Primary end point(s)
    Phase I – part A: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28-Day cycle)
    Phase I – part B: ORR (percentage of participants with confirmed best overall of CR or PR) as assessed by Blinded Independent Review Committee (BIRC) per Revised Assessment in Neuro-Oncology (RANO) criteria for participants with high-grade glioma (HGG), International Neuroblastoma Response Criteria (INRC) for participants with neuroblastoma (NB), response evaluation criteria in solid tumors (RECIST) version 1.1 for participants with medulloblastoma (MB), malignant rhabdoid tumor (MRT) and rhabdomyosarcoma (RMS)
    Phase II: ORR (percentage of participants with confirmed best overall confirmed CR or PR) as assessed by BIRC using INRC
    Fase I – parte A: incidencia de las toxicidades limitantes de dosis
    (DLT) en el ciclo 1 (28 días ciclo)
    Fase I – parte B: ORR(porcentaje de participantes con mejor respuesta
    global confirmada RC o RP), evaluada por el Comité
    Ciego de Revisión Independiente (BIRC) conforme a los Criterios de la Evaluación de respuesta en neurooncología (RANO) en los
    participantes con glioma de alto grado (GAG), los Criterios
    internacionales de respuesta del neuroblastoma (INRC) en los participantes con neuroblastoma (NB), y los Criterios de evaluación de respuesta en tumores sólidos (RECIST) 1.1 para los participantes con meduloblastoma (MB), tumores rabdoides malignos (TRM) y rabdomiosarcoma (RMS)
    -Fase II:ORR (porcentaje de
    participantes con mejor respuesta global confirmada de RC o RP) evaluada por el BIRC mediante los criterios INRC
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I – part A: 9 months from trial start until declaring MTD/RP2D
    Phase I – part B: 15 months from the Phase IB trial start till completion of Phase IB
    Phase II: 40 months from the Phase II trial randomization till completion of Phase II (including 6 months from the last patient enrolled)
    Fase I – parte A: 9 meses desde el inicio del ensayo hasta la declaración de la dosis máxima tolerada (MTD)/dosis recomendada para la fase II (RP2D)
    Fase I - parte B: 15 meses desde el inicio del ensayo de Fase IB hasta la finalización de la Fase IB
    Fase II: 40 meses desde el inicio de la Fase II aleatorizada del ensayo hasta la finalización de la Fase II (incluidos 6 meses desde el último paciente inscrito)
    E.5.2Secondary end point(s)
    Phase I – part A:
    - Safety: Incidence, type, and severity of adverse events (AEs) per common terminology criteria for adverse events (CTCAE) version 5.0 including changes in laboratory values, performance status, vital signs, liver assessments, cardiac assessments, and incidence of DLTs in Cycle 1.
    -Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all treatment components.
    - Plasma concentrations of ribociclib and derived PK parameters such as AUC, Cmax, Tmax.
    Phase I – part B:
    - DOR, PFS, TTR per RANO criteria for participants with HGG, INRC for participants with NB, RECIST 1.1 for participants with MB, MRT and RMS as assessed by BIRC assessment, and OS.
    - Safety: Incidence, type, and severity of AEs per CTCAE version 5.0 including changes in laboratory values, performance status, vital signs, liver assessments, cardiac assessments and incidence of DLTs in Cycle 1.
    -Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all treatment components.
    - Plasma concentrations of ribociclib and derived PK parameters such as AUC, Cmax, Tmax.
    Phase II:
    - PFS and DOR using INRC as assessed by BIRC (key secondary endpoints).
    - TTR, CBR using INRC as assessed by BIRC and OS.
    - Plasma concentrations of ribociclib, topotecan, temozolomide and derived PK parameters of ribociclib such as AUC and Cmax.
    - Safety: Incidence, type, and severity of adverse events per CTCAE version 5.0 criteria including changes in laboratory values, performance status, vital signs, liver assessments and cardiac assessments.
    -Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all treatment components.
    -PRO as measured by the Pediatric Quality of Life Inventory (PedsQL) questionnaire.
    Fase I – parte A:
    -Seguridad: incidencia, tipo y gravedad de los acontecimientos adversos (AA) según los criterios de terminología común de acontecimientos adversos (CTCAE) versión 5.0 incluidos cambios en los valores de laboratorio, estado funcional, signos vitales, evaluaciones hepáticas, evaluaciones cardíacas e incidencia de las toxicidades limitantes de dosis (DLTs) en el ciclo 1.
    -Tolerabilidad: interrupciones de dosis, reducciones, intensidad de la dosis y duración de la exposición para todos los componentes del tratamiento.
    -Concentraciones plasmáticas de ribociclib y parámetros farmacocinéticos (PK) derivados como AUC, Cmax, Tmax.
    Fase I – parte B:
    - DOR, PFS, TTR según los criterios RANO para participantes con GAG, los INRC para participantes con NB, los RECIST 1.1 para participantes con MB, MRT y RMS evaluados por BIRC y OS.
    -Seguridad: incidencia, tipo y gravedad de los AEs según CTCAE versión 5.0, incluidos cambios en los valores de laboratorio, estado funcional, signos vitales, evaluaciones hepáticas, evaluaciones cardíacas e incidencia de las DLTs en el ciclo 1.
    -Tolerabilidad: interrupciones de dosis, reducciones, intensidad de la dosis y duración de la exposición para todos los componentes del tratamiento.
    -Concentraciones plasmáticas de ribociclib y parámetros PK derivados como AUC, Cmax, Tmax.
    Fase II:
    -PFS y DOR usando los criterios INRC evaluado por BIRC (principales variables secundarias de evaluación)
    -TTR, CBR usando los criterios INRC evaluado por BIRC y OS
    -Concentraciones plasmáticas de ribociclib, topotecan, temozolomida y parámetros de PK derivados de ribociclib como AUC y Cmax.
    - Seguridad: incidencia, tipo y gravedad de los AEs según CTCAE versión 5.0, incluidos cambios en los valores de laboratorio, estado funcional, signos vitales, evaluaciones hepáticas y evaluaciones cardíacas.
    -Tolerabilidad: interrupciones de dosis, reducciones, intensidad de la dosis y duración de la exposición para todos los componentes del tratamiento.
    -PRO medido mediante el cuestionario Pediatric Quality of Life Inventory Version PedsQLTM
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase I – part A: 9 months from trial start until declaring MTD/RP2D
    Phase I – part B: 15 months from the Phase IB trial start till completion of Phase IB
    Phase II: 40 months from the Phase II trial randomization till completion of Phase II (including 6 months from the last patient enrolled)
    Fase I – parte A: 9 meses desde el inicio del ensayo hasta la declaración de la dosis máxima tolerada (MTD)/dosis recomendada para la fase II (RP2D)
    Fase I - parte B: 15 meses desde el inicio del ensayo de Fase IB hasta la finalización de la Fase IB
    Fase II: 40 meses desde el inicio de la Fase II aleatorizada del ensayo hasta la finalización de la Fase II (incluidos 6 meses desde el último paciente inscrito)
    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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Acceptability, palatability, PRO
    Aceptabilidad, palatabilidad, PRO
    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 I/II in new population and indication
    Fase I/II en una nueva población e indicación
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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
    Singapore
    United States
    France
    Netherlands
    Spain
    Germany
    Italy
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    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
    Study completion is defined as when the last patient finishes their Study Completion visit and any repeat assessments associated with this visit have been documented and followed-up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision.
    La finalización del estudio se define cuando el último paciente finaliza su visita de finalización del estudio y el investigador documenta y realiza un seguimiento adecuado de las evaluaciones asociadas con esta visita o, en el caso de una decisión de finalización anticipada del estudio, la fecha de esa decisión.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days26
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months9
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 230
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 23
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 150
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 55
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 2
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Minors
    Menores
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 230
    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)
    Novartis will make every effort to supply ribociclib to participants who may benefit from continued treatment as per the Investigator’s opinion. After completion of 12 cycles of treatment, in case of ongoing clinical benefit (i.e. stable disease or better) with acceptable toxicity, participants may continue to receive ribociclib alone at the same dose as received in combination with TOTEM until disease progression or occurrence of unacceptable toxicity that precludes any further treatment.
    NVS hará todo lo posible para suministrar ribociclib a ptes que puedan beneficiarse de continuar el tto según la opinión del investigador.Después de completar 12 ciclos de tto,en caso de beneficio clínico continuo (es decir, enfermedad estable o mejor) con toxicidad aceptable, los ptes pueden continuar recibiendo ribociclib solo en la misma dosis que recibieron en comb. con TOTEM hasta la progresión de la enfermedad o la aparición de toxicidad inaceptable que imposibilita cualquier tto posterior
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Innovative Therapies for Children with Cancer (ITCC)
    G.4.3.4Network Country France
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-10-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-07-27
    P. End of Trial
    P.End of Trial StatusOngoing
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