| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Progressive or refractory :
• high grade glioma
• neuroblastoma
• other cerebral tumors
• lymphoma
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Progressive or refractory solid brain tumors or lymphoma |
|
| 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 | HLGT |
| E.1.2 | Classification code | 10025323 |
| E.1.2 | Term | Lymphomas NEC |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 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.2.2 | Secondary 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.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 >12 years of age) or Lansky Play score (for patients ≤12 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% (>35% for children < 3 years) and left ventricular ejection fraction (LVEF) ≥50% at baseline, as determined by echocardiography (mandatory only for patients who have received cardiotoxic therapy).
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 serum or 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. |
|
| E.4 | Principal 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- 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- Known absence of dihydro-pyrimidine-deshydrogenase (DPD) activity; although a DPD deficiency can’t be precisely defined, 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 and should not be 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 |
|
| 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: 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.5.2 | Secondary 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.5.2.1 | Timepoint(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.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 | 4 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
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