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    Summary
    EudraCT Number:2018-000096-32
    Sponsor's Protocol Code Number:METRO-PD1-1708
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-04-10
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2018-000096-32
    A.3Full title of the trial
    Metro-PD1: a phase I/II trial evaluating anti-PD1 (Nivolumab) in combination with metronomic chemotherapy in children and teenagers with refractory /relapsing solid tumors or lymphoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Metro-PD1: a phase I/II trial evaluating anti-PD1 (Nivolumab) in combination with metronomic chemotherapy in children and teenagers with refractory /relapsing solid tumors or lymphoma
    A.3.2Name or abbreviated title of the trial where available
    METRO-PD1
    A.4.1Sponsor's protocol code numberMETRO-PD1-1708
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03585465
    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 SponsorCentre Oscar Lambret
    B.1.3.4CountryFrance
    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 supportAnticancer Fund
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportBristol Myers Squibb
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Ghent
    B.5.2Functional name of contact pointHiruz
    B.5.3 Address:
    B.5.3.1Street AddressCorneel Heymanslaan 10
    B.5.3.2Town/ cityGhent
    B.5.3.3Post code9890
    B.5.3.4CountryBelgium
    B.5.4Telephone number00329332 05 15
    B.5.5Fax number00329332 05 20
    B.5.6E-mailhiruz.ctu@uzgent.be
    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.3.2Product code BMS-936558
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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.2.1.1.1Trade name ENDOXAN
    D.2.1.1.2Name of the Marketing Authorisation holderBAXTER SA
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 namecyclophosphamide
    D.3.4Pharmaceutical form Coated 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 INNcyclophosphamide
    D.3.9.1CAS number 50-18-0
    D.3.9.3Other descriptive nameANHYDROUS CYCLOPHOSPHAMIDE
    D.3.9.4EV Substance CodeSUB121739
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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.2.1.1.1Trade name CYCLOPHOSPHAMIDE SANDOZ
    D.2.1.1.2Name of the Marketing Authorisation holderSANDOZ
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 namecyclophosphamide
    D.3.4Pharmaceutical form Powder for injection
    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 INNcyclophosphamide
    D.3.9.1CAS number 50-18-0
    D.3.9.3Other descriptive nameANHYDROUS CYCLOPHOSPHAMIDE
    D.3.9.4EV Substance CodeSUB121739
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 Vinblastine TEVA
    D.2.1.1.2Name of the Marketing Authorisation holderTeva Pharma Belgium NV
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 nameVinblastine
    D.3.4Pharmaceutical form Powder for solution for injection
    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 INNVINBLASTINE SULFATE
    D.3.9.1CAS number 143-67-9
    D.3.9.4EV Substance CodeSUB05098MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    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 CAPECITABINE MEDAC
    D.2.1.1.2Name of the Marketing Authorisation holderMEDAC
    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 namecapecitabine
    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 INNcapecitabine
    D.3.9.3Other descriptive nameCAPECITABINE
    D.3.9.4EV Substance CodeSUB12474MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number600
    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
    Progressive or refractory :
    • high grade glioma
    • neuroblastoma
    • other cerebral tumors
    • lymphoma
    E.1.1.1Medical condition in easily understood language
    Progressive or refractory solid brain tumors or lymphoma
    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 PT
    E.1.2Classification code 10018338
    E.1.2Term Glioma
    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 PT
    E.1.2Classification code 10029260
    E.1.2Term Neuroblastoma
    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 10006153
    E.1.2Term Brain tumor
    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 HLGT
    E.1.2Classification code 10025323
    E.1.2Term Lymphomas NEC
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    First stage: to identify between the three considered metronomic chemotherapy regimens (Cyclophosphamide-Vinblastine / Capecitabin / Cyclophosphamide-Vinblastine + Capecitabin), the one deemed feasible and safe when given in combination with Nivolumab in children and teenagers with refractory / relapsing solid tumors or lymphomas

    Second stage: to estimate and compare the efficacy of the metronomic chemothapy regimen selected at the end of the previous stage with or without Nivolumab in terms of progression-free survival, in children and teenagers with refractory / relapsing solid tumors or lymphoma
    E.2.2Secondary objectives of the trial
    First stage: to evaluate the safety profile of the different combinations of metronomic chemotherapy in children and teenagers with refractory / relapsing solid tumors over the whole treatment duration

    Second stage:
    - To confirm the safety of the drug combination and to estimate the toxicity associated with nivolumab when given in combination with metronomic chemotherapy, compared to metronomic chemotherapy alone
    - To evaluate the efficacy if nivolumab in terms of tumor response and overall survival, when given in combination with the metronomic chemotherapy regimen
    - To evaluate the feasibility of the drug combination in terms of dose-intensity of each drug
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1- Histologically proven diagnosis of solid malignant tumor, or lymphoma. Confirmed progressive or refractory disease despite standard therapy or for which no effective standard therapy exists
    2- Male and female subjects > 4 to < 18 years of age at inclusion; patients 18 years and older may be included after discussion with the sponsor if they had a pediatric recurrent/refractory malignancy diagnosed before the age of 18.
    3- Evaluable or measurable disease as defined by adequate standard imaging criteria for each patient’s tumor type (see corresponding appendices for definition of evaluable and/or measurable lesions):
    3a- RANO criteria for patients with high grade glioma (HGG or midline diffuse glioma),
    3b- WHO for other cerebral tumors
    3c- INRC criteria for patients with neuroblastoma (NB),
    3d- RECIST v1.1 for tumors other than cerebral tumors and neuroblastoma
    3e- Standard response criteria for lymphoma (depending on lymphoma type),
    4- Performance status: Karnofsky performance status (for patients >16 years of age) or Lansky Play score (for patients ≤16 years of age) ≥ 70%. Patients who are unable to walk because of paralysis or stable neurological disability, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
    5- Life expectancy ≥ 3 months
    6- Adequate organ function:
    -Hematologic criteria
    6a-Peripheral absolute neutrophil count (ANC) ≥ 1500/mm3 (unsupported)
    6b-White blood cells count ≥ 2500/mm3
    6d-Platelet count ≥ 100,000/mm3 (unsupported)
    6e-Hemoglobin ≥ 8.0 g/dL (transfusion is allowed)
    -Cardiac function
    6f-Shortening fraction (SF) >29% and left ventricular ejection fraction (LVEF) ≥50% at baseline, as determined by echocardiography (mandatory only for patients who have received cardiotoxic therapy or mediastinal irradiation).
    6g-Absence of QTc prolongation (QTc > 450 msec on baseline ECG, using the Fridericia correction [QTcF formula]) or other clinically significant ventricular or atrial arrhythmia.
    -Renal and hepatic function
    6h-Serum creatinine < 1.5 x upper limit of normal (ULN) for age
    6i-Total bilirubin < 1.5 x ULN,
    6j-Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) < 3 x ULN;
    6k-aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT < 3 x ULN
    7- Able to comply with scheduled follow-up and with management of toxicity.
    8- Females of child bearing potential must have a negative urine pregnancy test within seven days prior to initiation of treatment.
    9- Sexually active patients must agree to use adequate and appropriate contraception while on study drug and for six months after stopping the study drug.
    10- Patient able to comfortably swallow capsules.
    11- Patients on stable doses of corticosteroids (≤ 0.25 mg/kg prednisolone or equivalent) for at least seven days prior to receiving study drug may be included.
    12- Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific screening procedures are conducted according to local, regional or national guidelines.
    13- Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
    14- Patients can have received prior treatment with antiPD1 or antiPDL1 if at least SD for six months or PR or CR was obtained.
    15- Patients with a known partial deficiency of dihydro-pyrimidine-deshydrogenase (DPD) activity are eligible, and must have an uracilemia value of ≥ 16 ng/ml and <150 ng/ml
    E.4Principal exclusion criteria
    1- Any hematopoietic neoplasm
    2- Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or require increasing doses of corticosteroids or local CNS directed therapy to control their CNS disease.
    3- Patients requiring high doses of corticosteroids >0.25mg/kg prednisolone or equivalent) or increasing doses of corticosteroids during the seven days prior to receiving study drug.
    4- For patients with CNS tumor:
    4a- Evidence of > Grade 1 recent CNS hemorrhage on the baseline MRI scan.
    4b- Participants with bulky tumor on imaging are ineligible; bulky tumor is defined as:
    - i) Tumor with any evidence of uncal herniation or severe midline shift
    - ii) Tumor with diameter of > 6 cm in one dimension on contrast-enhanced MRI
    - iii) Tumor that in the opinion of the investigator, shows significant mass effect
    5- Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
    6- Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within twelve months of screening)
    7- Known active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
    8- Active autoimmune disease requiring immunosuppressive treatment
    9- Known congenital immunodeficiency
    10- Presence of any NCI-CTCAE v5 grade ≥ 2 treatment-related extra-hematological toxicity with the exception of alopecia, ototoxicity or peripheral neuropathy.
    11- Systemic anticancer therapy within 21 days of the first study dose or 5 times its half-life, whichever is less, 6 weeks in case of nitrosourea.
    12- No clinical benefit with previous antiPD1 or antiPDL1 treatment (SD during a period inferior to 6 months, or PD).
    13- Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first study drug dose.
    14- Allogeneic stem cell transplant within 3 months prior to the first study drug dose.
    15- Patients receiving any agent to treat or prevent graft-versus host disease (GVHD) post bone marrow transplant are not eligible for this trial.
    16- Radiotherapy (non-palliative) within 21 days prior to the first dose of drug (or within six weeks for therapeutic doses of MIBG or craniospinal irradiation).
    17- 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.
    18- Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes.
    19- Known hypersensitivity to any study drug or component of the formulation.
    20- Absence of effective contraception in patients of childbearing age
    21- Pregnant or nursing (lactating) females.
    22- Vaccination with live, attenuated vaccines within 4 weeks of the first dose of the study drugs except inactivated vaccines.
    23- Patient with a known complete absence of DPD activity ; it is known that patients carrying some homozygous or heterozygous mutations of DPYD responsible for the complete or almost complete absence of enzymatic activity of DPD, are exposed to a maximum risk of life-threatening or fatal toxicity ; patients with a complete deficiency of DPD activity (uracilemia ≥150ng/ml) should not be included in the trial neither treated with capecitabine
    24- Patients with galactose intolerance, Lapp lactase deficiency or glucose or galactose malabsorption syndrome (rare hereditary diseases)
    25- Acute urinary tract infection, pre-existing hemorrhagic cystitis; obstruction of the urinary tract
    26- History of organ transplant
    27- Severe infections requiring parenteral antibiotic therapy
    28- Active tuberculosis
    29- History of interstitial lung disease
    E.5 End points
    E.5.1Primary end point(s)
    1st stage: Dose-limiting toxicity
    2nd stage: Progression-free survival (PFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1st stage: over the first two 28-day cycles

    2nd stage: from the date of randomization to the date of centrally-assessed progression (RANO criteria for patients with high-grade glioma or midline diffuse glioma, WHO criteria for patient with other brain tumors, INRC criteria for patients with neuroblastoma, RECIST v1.1 criteria in all other cases ; standard response criteria for lymphoma (depending on lymphoma type)) or death from any cause. A central review of all imaging is planned to evaluate tumor response and progressions. PFS-duration of patients alive free of progression at last follow-up will be censored at the date of last visit.
    E.5.2Secondary end point(s)
    1) Adverse events (type, grade) graded according to the NCI CTCAE V5
    2) Tumor response, centrally assessed, using RANO / WHO / INRC / RECIST1.1 or lymphoma criteria as appropriate (cf. hereinabove). The best overall response will be defined as the best response recorded from randomization until disease progression.
    3) Overall survival. Survival of patients alive at last follow-up will be censored at the date of last visit.
    4) Relative dose-intensity of the different drugs estimated for each drug as the ratio between the computed dose-intensity (cumulative dose expressed in mg/m² divided by the study duration and expressed in mg/m²/week) and the protocol dose intensity.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) per 28-day cycle and over the whole treatment duration. All AE occurring during treatment or in the 28 days after end of treatment will be reported, regardless of reported causal relationship, except symptoms related to the underlying disease or disease progression. DLT and SAEs will be reported directly to the sponsor over the whole treatment duration plus 28 days, for all patients, in both arms. After the end of the treatment, only SAE (Serious Adverse Event) related to the study treatment will be recorded
    2) every 2 cycles during treatment.
    3) from the date of randomization to the date of death from any cause.
    4) at the end of treatment
    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 No
    E.6.7Pharmacodynamic No
    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
    feasibility trial to evaluate the safety of the combination of Nivolumab + metronomic chemotherapy
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years5
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    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: 92
    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: 46
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 46
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    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
    young children
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state36
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 102
    F.4.2.2In the whole clinical trial 102
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    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 BSPHO
    G.4.3.4Network Country Belgium
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-05-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-08
    P. End of Trial
    P.End of Trial StatusOngoing
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