NIVOLUMAB for Pediatric solid tumor | Glioma | Brain tumor | Neuroblastoma | Rhabdomyosarcoma | Ependymoma | Ewing sarcoma | Lymphoma

Inclusion criteria

• {"criterion_text":"- 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 (this criterion is applicable to stage 1 only)"}
• {"criterion_text":"- Sexually active patients must agree to use adequate and appropriate contraception while on study drug and for 6 months after stopping the study drug for young men, and for 12 months after stopping the study drug for young women"}
• {"criterion_text":"- Patients on stable doses of corticosteroids (< 0.25mg/kg/d prednisolone or equivalent) during the 7 days prior to receiving study drugs"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Patient affiliated to a social security regimen or beneficiary of the same according to local requirements."}
• {"criterion_text":"- Patients can have received prior treatment with anti-PD1 or anti-PDL1 if at least SD for 6 months or PR or CR was obtained."}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Trans-MetroPD1 study: -\tPatient or parents/legal representative has/have given written informed consent to participate to all or part of Trans-MetroPD1 study: -\tassessment of HRQoL with generic KINDL-R questionnaire, -\tdosage of circulating progastrin, -\timmune cells count NB: if this criterion is not applicable, the patient is still eligible to principal study"}
• {"criterion_text":"- If patient or parents/legal representative agrees 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"}
• {"criterion_text":"- 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 NB: According ETHICAL CONSIDERATIONS FOR CLINICAL TRIALS ON MEDICINAL PRODUCTS CONDUCTED WITH THE PAEDIATRIC POPULATION, the trial-related blood loss per-individual should not exceed 3 % of the total blood volume during a period of four weeks and should not exceed 1% at any single time. In the rare case of simultaneous trials, the recommendation of 3% remains the maximum. The total volume of blood is estimated at 80 to 90 ml/kg body weight; 3% is 2.4 ml blood per kg body weight. Consequently, exploratory studies that needs blood sample can be performed on patients within a certain weight range, in order to respect blood volume limits in paediatric population (see appendix 11 for weight calculation)"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- 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 have a pediatric recurrent/refractory malignancy diagnosed before the age of 18 years."}
• {"criterion_text":"- Evaluable or measurable disease as defined by standard imaging criteria for the patient’s tumor type (see corresponding appendices for definition of evaluable and/or measurable lesions: •\tRANO criteria for patients with HGG (appendix 3), •\tRAPNO criteria for patients with LGG (appendix 13) •\tWHO for other cerebral tumors (appendix 4), •\tINRC criteria for patients with NB (appendix 5), •\tRECIST v1.1 for tumors other than cerebral tumors and neuroblastoma (appendix 6)"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Life expectancy ≥ 3 months"}
• {"criterion_text":"- 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 or mediastinal irradiation). - 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"}
• {"criterion_text":"- Able to comply with scheduled follow-up and with management of toxicity."}
• {"criterion_text":"- Females of child bearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment."}

Exclusion criteria

• {"criterion_text":"- Leukemia"}
• {"criterion_text":"- Known congenital immunodeficiency"}
• {"criterion_text":"- Presence of any NCI-CTCAE v5 grade ≥ 2 treatment-related extra-hematological toxicity with the exception of alopecia, ototoxicity or peripheral neuropathy."}
• {"criterion_text":"- Systemic anticancer therapy within 21 days of the first study dose, 6 weeks in case of nitrosourea or 5 times its half-life, whichever is less, 6 weeks in case of nitrosourea."}
• {"criterion_text":"- No clinical benefit with previous antiPD1 antiPDL1 treatment (SD during a period inferior to 6 months, or PD)."}
• {"criterion_text":"- Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first study drug dose."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Radiotherapy (non-palliative) within 21 days prior to the first dose of drug (or within 6 weeks for therapeutic doses of MIBG or craniospinal irradiation)."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes."}
• {"criterion_text":"- Known hypersensitivity to any study drug or component of the formulation."}
• {"criterion_text":"- Diagnosis of lymphoma, diffuse intrinsic pontine glioma or osteosarcoma (for stage 2 only)."}
• {"criterion_text":"- Absence of effective contraception in patients of childbearing age"}
• {"criterion_text":"- Pregnant or nursing (lactating) females."}
• {"criterion_text":"- Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug except inactivated vaccines."}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Patients with galactose intolerance, Lapp lactase deficiency or glucose or galactose malabsorption syndrome (rare hereditary diseases)"}
• {"criterion_text":"- Acute urinary tract infection, pre-existing hemorrhagic cystitis; obstruction of the urinary tract"}
• {"criterion_text":"- History of organ transplant"}
• {"criterion_text":"- Severe infections requiring parenteral antibiotic therapy"}
• {"criterion_text":"- Active tuberculosis"}
• {"criterion_text":"- History of interstitial lung disease"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Patients requiring high doses of corticosteroids (> to 0.25mg/kg/d prednisolone or equivalent) or increasing doses of corticosteroids during the 7 days prior to receiving study drugs."}
• {"criterion_text":"- For patients with CNS tumor: o\tEvidence of > Grade 1 recent CNS hemorrhage on the baseline MRI scan. o\tParticipants 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"}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months of screening)"}
• {"criterion_text":"- Known active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection."}
• {"criterion_text":"- Active autoimmune disease requiring immunosuppressive treatment"}

Primary endpoints

• {"endpoint_text":"- First stage : The Dose-Limiting Toxicity (DLT) will be assessed over the first two 28-day cycles, according to the NCI CTCAE V5","definition_or_measurement_approach":"DLT assessed over the first two 28-day cycles according to NCI CTCAE V5"}
• {"endpoint_text":"- Second stage : Progression-free survival (PFS) computed as the time interval from the date of randomization to the date of centrally-assessed progression or death from any cause","definition_or_measurement_approach":"PFS defined as time from randomization to centrally-assessed progression or death from any cause"}

Secondary endpoints

• {"endpoint_text":"- •\tAdverse events (type, grade) graded according to the NCI CTCAE V5. All AE occurring during treatment or in the 28 days after end of treatment will be reported, regardless of reported causal relationship, except symptoms unequivocally 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. Liver-related laboratory abnormalities (DILI) will be reported.","definition_or_measurement_approach":"AE type and grade graded per NCI CTCAE v5; all AEs during treatment and within 28 days after end of treatment reported; DLT and SAEs reported to sponsor during treatment plus 28 days; liver-related lab abnormalities reported"}
• {"endpoint_text":"- •\tTumor response during treatment, centrally assessed, using RANO (for stage 1) or RAPNO (for LGG)/ WHO / INRC / RECIST 1.1 as appropriate (cf. hereinabove). The best overall response will be defined as the best response recorded from randomization over the whole study treatment duration.","definition_or_measurement_approach":"Tumor response centrally assessed using RANO, RAPNO, WHO, INRC or RECIST v1.1 as appropriate; best overall response is best recorded from randomization during treatment"}
• {"endpoint_text":"- •\tOverall survival, computed as the time interval from the date of randomization to the date of death from any cause. Survival of patients alive at last follow-up will be censored at the date of last visit (3 years after last inclusion).","definition_or_measurement_approach":"Overall survival measured from randomization to death; survivors censored at last visit (3 years after last inclusion)"}
• {"endpoint_text":"- •\tRelative 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.","definition_or_measurement_approach":"RDI = (computed cumulative dose mg/m² divided by study duration expressed mg/m²/week) / protocol dose-intensity; assessed at both stages"}
• {"endpoint_text":"- •\tRelevant molecular alterations like specific gene mutations or fusions will be described for each patient treated during phase 2.","definition_or_measurement_approach":"Descriptive reporting of molecular alterations (mutations/fusions) from molecular analyses performed (e.g., MAPPYACTS/France Genomique)"}
• {"endpoint_text":"- • Ancillary : Trans-MetroPD1 study : Health Related Quality of Life (HRQoL) HRQoL of Life is evaluated using the age-appropriate KINDL-R questionnaire (self- and proxy-assessment in paper format) before the start of treatment (ideally within 2 weeks), at each tumor assessment during the whole course of treatment, then at disease progression or just before the start of a new treatment if end of MetroPD1 treatment is not motivated by progressive disease.","definition_or_measurement_approach":"HRQoL evaluated using age-appropriate KINDL-R questionnaire (self and proxy), at baseline (ideally within 2 weeks), at each tumor assessment during treatment, and at progression or before new treatment"}
• {"endpoint_text":"- • Ancillary: Progastrin (hPG80) dosage is performed on plasma samples collected the same day as the following exams: baseline imaging, tumor assessment during the whole course of treatment (until progression or end of treatment). The measurement at different times: - predictive value for progression of single hPG80 measurement before treatment, - of single hPG80 measurement at tumor assessment - of hPG80 variations measurement and hPG80 variations","definition_or_measurement_approach":"hPG80 measured in plasma at baseline and at tumor assessments during treatment; analyses include predictive value of baseline hPG80, hPG80 at assessments, and hPG80 variation over time"}

Other endpoints

• {"endpoint_text":"- Ancillary Trans-MetroPD1 exploratory objective: To evaluate the health-related quality of life (HRQoL) in patients capable of participating, using the generic KINDL-R questionnaire by self and proxy-report, and to estimate the effect of treatment group (with versus without nivolumab) on Time Until Definitive Deterioration (TUDD) of quality of life.","definition_or_measurement_approach":"HRQoL measured with KINDL-R; effect on Time Until Definitive Deterioration (TUDD) compared between treatment groups"}
• {"endpoint_text":"- Exploratory: To investigate the predictive value of circulating progastrin (hPG80) on disease progression, in regard to PFS evaluation as Metro-PD1 stage 2 main objective","definition_or_measurement_approach":"Circulating hPG80 measured in plasma at baseline and at tumor assessments; evaluated for predictive value on progression and relation to PFS"}

France

Earliest CTIS Part Ii Submission Date

20-06-2024

Latest Decision Or Authorization Date

18-11-2025

Processing Time Days

516

Number Of Sites

6

Number Of Participants

63

Primary sponsor

Full Name

Centre Oscar Lambret

Organisation Type

Pharmaceutical company

Country Of Registered Address

France