| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Progressive or refractory :
• embryonal brain tumor
• ependymoma
• low-grade glioma
• high-grade glioma (HGG) except diffuse Intrinsic Pontine glioma
(DIPG), Supratentorial Diffuse Midline Glioma K27M mutated are eligible,
• rhabdomyosarcoma
• neuroblastoma
• Ewing sarcoma
• other solid tumors and after approval from coordinators (except DIPG,
osteosarcoma, lymphoma)
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Progressive or refractory paediatric solid tumor |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018338 |
| E.1.2 | Term | Glioma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029260 |
| E.1.2 | Term | Neuroblastoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006153 |
| E.1.2 | Term | Brain tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014967 |
| E.1.2 | Term | Ependymoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039022 |
| E.1.2 | Term | Rhabdomyosarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015560 |
| E.1.2 | Term | Ewing's sarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main 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
Second stage: to estimate and compare the efficacy of the metronomic chemotherapy regimen selected at the end of the previous stage: arm C (cyclophosphamide, capecitabine, vinblastine) with or without Nivolumab in terms of progression-free survival, in children and teenagers with refractory / relapsing solid tumors |
|
| E.2.2 | Secondary objectives of the trial |
1st stage: to evaluate the safety profile of the different combinations of MC in children and teenagers with refractory / relapsing solid tumors over the whole treatment duration
2nd stage:
- To confirm the safety of the drug combination and to estimate the toxicity associated with nivolumab when given in combination with MC, compared to MC alone
- To evaluate the efficacy if nivolumab in terms of tumor response and overall survival, when given in combination with the MC regimen
- To evaluate the efficacy of MC in terms of progression-free survival, on the entire study population first, then separately in "LGG" and "non-LGG" , and in specific histological subgroups, if feasible depending on the number of patients with a similar histology
- To evaluate the feasibility of the drug combination in terms of dose-intensity of each drug
- To describe tumor molecular profile (large scale molecular analysis
performed through MAPPYACTS program or France Genomique 2025, or
others) |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Exploratory objectives of Trans-MetroPD1 study (applicable at second
stage in France and Belgium):
- To evaluate the health-related quality of life (HRQoL) in patients
capable of participating, using the generic KINDL-R questionnaire by self
or proxy-report (in paper format), and to estimate the effect of
treatment group (with versus without nivolumab) on Time Until
Definitive Deterioration (TUDD) of quality of life.
- To investigate the predictive value of circulating progastrin (hPG80) on
disease progression, in regard to PFS evaluation as Metro-PD1 stage 2
main objective
- Immunomonitoring: to characterize B, T, NK, and dendritic cell subsets
and monocyte populations with flow cytometry analysis. |
|
| E.3 | Principal inclusion criteria |
- Histologically proven diagnosis of solid malignant tumor. Confirmed progressive or refractory disease despite standard therapy or for which no effective standard therapy exists.
-Histologically proven diagnosis of:
•embryonal brain tumor,
•ependymoma,
•low-grade glioma (LGG),
• high-grade glioma (HGG) except diffuse Intrinsic Pontine glioma
(DIPG), Supratentorial Diffuse Midline Glioma K27M mutated are eligible,
•rhabdomyosarcoma,
•neuroblastoma,
•Ewing sarcoma,
•and other solid tumors and after approval from coordinators (except
DIPG, osteosarcoma, lymphoma),
and confirmed progressive or refractory disease despite standard
therapy or for which no effective standard therapy exists (this criterion is applicable to stage 2 only)
- Male and female subjects < 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.
- 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):
• RANO criteria for patients with high grade glioma
• RAPNO criteria for patients with low grade glioma
• WHO for other cerebral tumors
• INRC criteria for patients with neuroblastoma (NB),
• RECIST v1.1 for tumors other than cerebral tumors and neuroblastoma
- Performance status: Karnofsky performance status (for patients >16
years of age) or Lansky Play score (for patients ≤16 years of age) ≥
70%.
- Life expectancy ≥ 3 months
- Adequate organ function:
-Hematologic criteria
•Peripheral absolute neutrophil count (ANC) ≥ 1500/mm3
(unsupported)
•White blood cells count ≥ 2500/mm3
•Platelet count ≥ 100,000/mm3 (unsupported)
•Hemoglobin ≥ 8.0 g/dL (transfusion is allowed)
-Cardiac function
•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).
•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
•Serum creatinine < 1.5 x upper limit of normal (ULN) for age
•Total bilirubin < 1.5 x ULN,
•Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) < 3 x ULN;
•-aspartate aminotransferase (AST)/serum glutamic oxaloacetic
transaminase/SGOT < 3 x ULN
- Able to comply with scheduled follow-up and with management of
toxicity.
- Females of child bearing potential must have a negative urine
pregnancy test within seven days prior to initiation of treatment.
- Sexually active patients must agree to use adequate and appropriate contraception while on study drug and for six months after stopping the study drug for young men, and for 12 months after stopping the study
drug for young women
- 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.
- 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.
- Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
- Patients can have received prior treatment with antiPD1 or antiPDL1 if at least SD for six months or PR or CR was obtained.
-Patients with a known partial deficiency of dihydro-pyrimidinedeshydrogenase (DPD) activity are eligible, and must have an uracilemia value ≥16ng/ml and <150ng/ml
- Adult patient (or parents/legal representatives if patient is minor) understand the preparation process of soluble capecitabine, and are able to reconstitute oral solution of capecitabine at home
INCLUSION CRITERIA FOR TRANS-MetroPD1 STUDY:
- Patient or parents/legal representative has/have given written
informed consent to participate to all or part of Trans-MetroPD1 study:
• assessment of HRQoL with generic KINDL-R questionnaire,
• dosage of circulating progastrin,
• immune cells count
- If patient or parents/legal representative agree(s) to participate to the
dosage of circulating progastrin only, patient body weight must be ≥ 8
kg to allow sample collection while respecting blood volume limits in
paediatric population
- If patient or parents/legal representative agrees to participate to
immune cells count only, or both immune cells count and dosage of
circulating progastrin, patient body weight must be ≥ 54 kg to allow
sample collection while respecting blood volume limits in paediatric
population |
|
| E.4 | Principal exclusion criteria |
- Leukemia
- Diagnosis of lymphoma, diffuse intrinsic pontine glioma or
osteosarcoma (for stage 2 only)
- 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.
- 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.
- For patients with CNS tumor:
•Evidence of > Grade 1 recent CNS hemorrhage on the baseline MRI
scan.
• 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 contrastenhanced MRI
iii) Tumor that in the opinion of the investigator, shows significant mass effect
- 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).
- 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)
- Known active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
- Active autoimmune disease requiring immunosuppressive treatment
- Known congenital immunodeficiency
- Presence of any NCI-CTCAE v5 grade ≥ 2 treatment-related extrahematological toxicity with the exception of alopecia, ototoxicity or peripheral neuropathy.
- 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.
- No clinical benefit with previous antiPD1 or antiPDL1 treatment (SD
during a period inferior to 6 months, or PD).
- Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first study drug dose.
- Allogeneic stem cell transplant within 3 months prior to the first study drug dose.
- Patients receiving any agent to treat or prevent graft-versus host
disease (GVHD) post bone marrow transplant are not eligible for this
trial.
- 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).
- Major surgery within 21 days of the first dose. Gastrostomy, ventriculoperitoneal 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.
- Currently taking medications with a known risk of prolonging the QT
interval or inducing Torsades de Pointes.
- Known hypersensitivity to any study drug or component of the
formulation.
- Absence of effective contraception in patients of childbearing age
- Pregnant or nursing (lactating) females.
- Vaccination with live, attenuated vaccines within 4 weeks of the first dose of the study drugs except inactivated vaccines.
- Patients 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 lifethreatening 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
- Patients with galactose intolerance, Lapp lactase deficiency or glucose or galactose malabsorption syndrome (rare hereditary diseases)
- Acute urinary tract infection, pre-existing hemorrhagic cystitis;
obstruction of the urinary tract
- History of organ transplant
- Severe infections requiring parenteral antibiotic therapy
- Active tuberculosis
- History of interstitial lung disease |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1st stage: Dose-limiting toxicity
2nd stage: Progression-free survival (PFS)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1st stage:
DLT is evaluated over the first two 28-day cycles
2nd stage:
PFS is computed as the time interval from the date of randomization to the date of centrally-assessed progression or death from any cause. A central review of all imaging performed over the whole study treatment duration is planned to evaluate tumor response and progressions.
The clinical progression reported by the investigator will be considered as an event if the patient could not have any radiological evaluation to confirm the radiological progression, especially if the patient died of disease progression without radiological evaluation.
PFS-duration of patients alive free of progression at last follow-up will be censored at the date of last visit (3 years after the last inclusion). |
|
| E.5.2 | Secondary end point(s) |
1) Adverse events will be graded according to the NCI CTCAE V5
2) Tumor response will be centrally assessed, using RANO (for stage 1 HGG), RAPNO (for LGG), WHO (other brain tumors), INRC (for NB) or RECIST 1.1 (for all other cases) criteria as appropriate.
The best overall response will be defined as the best response recorded
from randomization over the whole study duration.
3) Overall survival. Survival of patients alive at last follow-up will be censored at the date of last visit (3 years after the last inclusion).
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; RDI will be assessed at both stages of the study.
5) Tumor molecular profile: (large scale molecular analysis is performed on tumor samples through MAPPYACTS program or France Genomique 2025, or others ; when possible, data about the genomic profile and tumor mutational burden (TMB) will be collected for patients treated during Metro-PD1 phase 2.
Trans-MetroPD1 sub-study :
6) Health-Related Quality of Life (HRQoL) is evaluated using KINDL-R questionnaire (self- or proxy-assessment, in paper format)
For each subscale as well as for the resulting total score, we will compute the Time Until Definitive Deterioration (TUDD) defined as the time from randomization to the first observation of a definitive deterioration of KINDL-R score or death. A definitive deterioration of quality of life is defined by a score decrease by more than 10 points as compared with the score at baseline, without later improvement superior to 10 points as compared with baseline (or if the patient dropped out of the study resulting in missing data).
7) Progastrin (hPG80) dosage is performed on plasma samples at
different times, and should allow to explore:
- predictive value for progression of single hPG80 measurement before treatment
- predictive value for progression of single hPG80 measurement at tumor
assessment
- predictive value for progression of hPG80 variations measurement and hPG80 variations
8) Immune cells count is performed is performed at different times by flow cytometry, to describe the evolution of immune cells before and during the treatment
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) AE, DLT, SAE: during treatment or in the 28 days after end of treatment.
After the end of the treatment, only SAE related to the study treatment will be recorded.
2) Tumor assessment: every 2 cycles during treatment.
3) OS : time interval from the date of randomization to the date of death from any cause, or the date of last visit (3 years after the last inclusion).
4) RDI : at the end of treatment, for all patients, at both stages of the study
Trans-MetroPD1 sub-study :
5) HQRoL: at baseline, and each tumor assessment (until progression or end of treatment).
6) Progastrin dosage: on plasma samples collected the same day as Imaging (until progression or end of treatment).
7) Immune cells count: at D0, D8, D15, D28, D42, and at disease progression |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| feasibility trial to evaluate the safety of the combination of Nivolumab + metronomic chemotherapy |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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