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    Summary
    EudraCT Number:2018-000127-14
    Sponsor's Protocol Code Number:NCT-2017-0516
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-03-18
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-000127-14
    A.3Full title of the trial
    INFORM2 exploratory multinational phase I/II combination study of Nivolumab and Entinostat in children and adolescents with refractory high-risk malignancies
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    INFORM2 NivEnt, an european clinical trial to determine a safe dose and signs of efficacy of the combination treatment of novolumab and entinostat in children and adolescents with refractory high-risk malignancies
    A.3.2Name or abbreviated title of the trial where available
    INFORM2 NivEnt
    A.4.1Sponsor's protocol code numberNCT-2017-0516
    A.5.4Other Identifiers
    Name:BMS Trial CodeNumber:CA209-9JH
    Name:Syndax Trial CodeNumber:SNDX-275-0209
    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 SponsorHeidelberg University Hospital
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGerman Cancer Research Center (DKFZ)
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportBristol-Myers Squibb Pharma EEIG
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportSyndax Pharmaceuticals Inc.
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportGerman Cancer Aid (DKH)
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
    B.5.2Functional name of contact pointKiTZ Clinical Trial Unit
    B.5.3 Address:
    B.5.3.1Street AddressIm Neuenheimer Feld 130/3
    B.5.3.2Town/ cityHeidelberg
    B.5.3.4CountryGermany
    B.5.6E-mailinform2@kitz-heidelberg.de
    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 Opdivo
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNivolumab
    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.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEntinostat
    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.3.9.1CAS number 209783-80-2
    D.3.9.3Other descriptive nameENTINOSTAT
    D.3.9.4EV Substance CodeSUB33300
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEntinostat
    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.3.9.1CAS number 209783-80-2
    D.3.9.3Other descriptive nameENTINOSTAT
    D.3.9.4EV Substance CodeSUB33300
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    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.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
    This trial investigates a novel combination treatment regimen using immune checkpoint inhibition and epigenetic therapy in children with relapsed/refractory/progressive high-risk solid tumors or CNS tumors. Thus, this trial focuses on the pediatric population in 4 biomarker-defined cohorts, for which there is no standard of care treatment available.
    E.1.1.1Medical condition in easily understood language
    Children and adolescents with refractory/relapsed/progressive high-risk solid tumors or CNS tumors with no standard of care treatment available
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase I
    To determine the recommended phase II dose (RP2D) of the combination treatment with nivolumab and entinostat administered to adolescents 12-21 years with progressive, relapsed, refractory high-risk solid tumors and CNS tumors
    To determine the recommended phase II dose (RP2D) of the combination treatment with nivolumab and entinostat administered to children 6-11 years with progressive, relapsed, refractory high-risk solid tumors and CNS tumors

    Phase II
    To evaluate activity of the combination treatment with nivolumab and entinostat in children and adolescents with refractory/relapsed/progressive high-risk solid tumors and CNS tumors with:
    Group A: a high mutational load (> 100 somatic SNVs/exome)
    Group B: high PD-L1 mRNA expression (RPKM by RNA-Seq > 3)
    Group C: Focal MYC(N) amplification
    Group D: Patients with biomarker low tumors according to the definitions of group A-C.
    E.2.2Secondary objectives of the trial
    • Comparison of patient outcomes in group D (biomarker low) with all biomarker positive groups A, B and C (pooled and separately)
    • Comparison of patient outcomes in group A-D with matching groups of the INFORM registry (pooled and separately)
    • Evaluation of somatic SNV count as a predictive biomarker: relation of patient outcomes to the level of somatic SNVs
    • Evaluation of PD-L1 mRNA expression as a predictive biomarker: relation of patient outcomes to the level of PD-L1 mRNA expression
    • Evaluation of the level of MYC(N) amplification as a predictive biomarker: relation to patient outcomes
    • Evaluate activity using immune related response evaluation methods
    • Entinostat plasma PK (CSF if appropriate)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Children and adolescents with refractory/relapsed/progressive high-risk
    -CNS tumors: medulloblastoma, ependymoma, ATRT, ETMR, pediatric high grade glioma (including DIPG) or other pediatric embryonal CNS tumors
    OR
    -solid tumors: neuroblastoma, nephroblastoma, rhabdoid tumor, embryonal or alveolar rhabdomyosarcoma or other embryonal small round blue cell tumors including pediatric type (bone) sarcoma
    OR
    Children and adolescents with newly diagnosed high grade glioma (HGG) in the context of a constitutional mismatch repair deficiency syndrome
    - No standard of care treatment available
    - Age at registration ≥ 6 to ≤ 21 years.
    - Molecular analysis for biomarker identification (SNV load, PDL1 mRNA expression, MYC/N amplification) in laboratories complying with DIN EN ISO/IEC 17025 or similar via INFORM molecular diagnostic platform or equivalently valid molecular pipeline.
    - Biomarker determined using whole exome sequencing (SNV load), RNA-sequencing (PDL1 mRNA expression) and whole genome sequencing (MYC/N amplification).
    - In case molecular analysis was not performed via INFORM Registry molecular pipeline: transfer of molecular data (whole exome and RNA sequencing)
    - Time between biopsy/puncture/resection of the current refractory/relapsed/progressive tumor and registration ≤ 12 weeks
    - Disease that is measurable as defined by RANO criteria or RECIST v1.1 (as appropriate).
    - Life expectancy > 3 months, sufficient general condition score (Lansky ≥ 70 or Karnofsky ≥ 70). Transient states like infections can be accepted, and also stable disabilities resulting from disease/surgery (hemiparesis, amputations etc.) can be accepted and will not be considered for Lansky/Karnofsky assessments.
    - Laboratory requirements:
    - Hematology: absolute granulocytes ≥ 1.0 × 109/l (unsupported)
    platelets ≥ 100 × 109/l
    hemoglobin ≥ 8 g/dl or ≥ 5,6 nmol/L
    - Biochemistry: Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
    AST(SGOT) ≤ 3.0 x ULN
    ALT(SGPT) ≤ 3.0 x ULN
    serum creatinine ≤ 1.5 x ULN for age
    - ECG: normal QTc interval ≤ 480 msec
    - Patient is able to swallow oral study medication
    - Ability of patient and/or legal representative(s) to understand the character and individual consequences of clinical trial
    - Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment. Sexually active women of childbearing potential must agree to use acceptable and appropriate contraception during the study and for at least 6 months after the last study treatment administration. Sexually active male patients must agree to use a condom during the study and for at least 7 months after the last study treatment administration.
    - Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
    - Before patient screening and registration, written informed consent, also concerning data and blood transfer, must be given according to ICH/GCP, and national/local regulations.
    - No prior therapy with the combination of immune checkpoint inhibitors and HDACi
    - BSA ≥ 0.9m2
    - Phase I: molecular analysis performed and biomarker status known (mutational load, PD-L1 mRNA expression AND MYC(N) amplification status).
    - Phase II: molecular analysis performed, biomarker status known (mutational load, PD-L1 mRNA expression AND MYC(N) amplification status) and stratification according to the following criteria:
    - Group A: high mutational load (defined as > 100 somatic SNVs/exome) based on whole exome sequencing
    OR
    - Group B: high PD-L1 mRNA expression (defined as reads per million total reads per kilobase of exon model (RPKM) > 3) based on RNA sequencing
    OR
    - Group C: Focal MYC(N) amplification based on whole genome sequencing
    OR
    - Group D: Patients with biomarker low tumors according to the definitions of group A-C.
    E.4Principal exclusion criteria
    - Patients with CNS tumors or metastases who are neurologically unstable despite adequate treatment (e.g. convulsions).
    - Patients with low-grade gliomas or tumors of unknown malignant potential are not eligible
    - Evidence of > Grade 1 recent CNS hemorrhage on the baseline MRI scan.
    - Participants with bulky CNS tumor on imaging are ineligible; bulky tumor is defined as:
    - Tumor with any evidence of uncal herniation or severe midline shift
    - Tumor with diameter of > 6 cm in one dimension on contrast-enhanced MRI
    - Tumor that in the opinion of the investigator, shows significant mass effect
    - Previous allogeneic bone marrow, stem cell or organ transplantation
    - Diagnosis of immunodeficiency
    - Diagnosis of prior or active autoimmune disease
    - Evidence of interstitial lung disease
    - Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the investigator, would preclude adequate absorption.
    - Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative]). Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA test must be performed in these patients prior to study treatment. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
    - Clinically significant, uncontrolled heart disease
    - Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48 hour interval must be maintained before the first dose of the investigational drug is administered.
    - Any anticancer therapy (e.g., chemotherapy, HDACi (including valproic acid), DNA methyltransferase inhibitors, other immunotherapy, targeted therapy, biological response modifiers, endocrine anticancer therapy or radiotherapy) within 4 weeks or at least 5 half-lives (whichever is longer) of study drug administration.
    - Radiologically confirmed radiotherapy induced pseudoprogression in CNS tumors
    - Traditional herbal medicines; these therapies are not fully studied and their use may result in unanticipated drug-drug interactions that may cause or confound the assessment of toxicity. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product. For information on CYP substrates and P-gp inhibitors or inducers see section 5.8.
    - History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form (including benzamide) of the investigational medicinal product
    - Participation in other ongoing clinical trials.
    - Pregnant or lactating females.
    - Presence of underlying medical condition (e.g. gastrointestinal disorders or electrolyte disturbances) that in the opinion of the Investigator or Sponsor could adversely affect the ability of the subject to comply with or tolerate study procedures and/or study therapy, or confound the ability to interpret the tolerability of combined administration of entinostat and nivolumab in treated subjects
    - Patients receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids (up to 5 mg/m2/day prednisone equivalent) may be approved after consultation with the Sponsor.
    No patient will be allowed to enroll in this trial more than once.
    E.5 End points
    E.5.1Primary end point(s)
    Phase I: Dose Limiting Toxicity (DLT) of the combination treatment
    Phase II: Best response (CR or PR) will be based on RANO criteria for all primary CNS tumors and RECIST for non-CNS tumors, defined for each patient as the best response under study combination therapy during the first 6 cycles (assessment every 2 cycles)
    E.5.1.1Timepoint(s) of evaluation of this end point
    DLT: continuously
    Response: every 2 cycles
    E.5.2Secondary end point(s)
    • Duration of Response (DOR)
    • Disease Control Rate (DCR)
    • Stable disease (SD)
    • Progression-free survival (PFS)
    • Time to Response (TTR)
    • Overall Survival (OS)
    • Immune related Response Rate (RR) measured by iRECIST criteria and iRANO criteria
    • Entinostat plasma PK on 1 day, 1 week and 5 weeks after initiation of therapy
    E.5.2.1Timepoint(s) of evaluation of this end point
    Response: every 2 cycles
    Pharmakokinetik (Entinostat): on 1 day, 1 week and 5 weeks after initiation of therapy
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) 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
    dosefinding of the combination of nivolumab and entinostat in children and adolescents
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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: 106
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 45
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 61
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 22
    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 No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    children and adolelscents
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 48
    F.4.2.2In the whole clinical trial 128
    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)
    Patients having reached end of treatment including patients with formal confirmed radiological progression are allowed to continue combination treatment if they are experiencing a clinical benefit for a maximum of 12 months or until end of study, whatever comes first, at the discretion of the investigator. Patients continuing treatment beyond progression or planned EOT will stay on study and adhere to the study visit plan.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-02-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-27
    P. End of Trial
    P.End of Trial StatusOngoing
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