| Eligibility |
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 of 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 (HGG), who are eligible at
stage 1 only
- 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 >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.
- 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% (>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).
- 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 serum or urine pregnancy test
within 7 days prior to initiation of treatment.
- 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
- Patients on stable doses of corticosteroids (=0.25 mg/kg prednisolone or equivalent)
for at least 7 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
6 months or PR or CR was obtained.
- Patients with a known partial deficiency of dihydro-pyrimidine-deshydrogenase (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
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 7 days prior to
receiving study drug.
- For patients with CNS tumor:
o Evidence of > Grade 1 recent CNS hemorrhage on the baseline MRI scan.
o 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
- 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 12 months of screening)
- 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 extra-hematological 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 6 weeks for therapeutic doses of MIBG or craniospinal irradiation).
- 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.
- 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.
- 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
- 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
INCLUSION CRITERIA FOR TRANS-METROPD1
- Patient or parents/legal representative has/have given written informed consent to
participate to all or part of Trans-MetroPD1 study
- 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
- 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
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