Metronomic Chemotherapy in Wilms Tumor (MetroWilms-1906)

Inclusion Criteria:

• Patient ≥18 months old and ≤ 17 years old

• Relapsed or refractory Wilms tumor, histologically proven at diagnosis

• After at least 2 lines of chemotherapy (conventional or high dose, which may includethe trial molecules) or after 1 line for high risk relapse for which there would notbe any curative therapy. If 1 line for high risk relapse, the enrolment should beconfirmed by coordinators.

• Radiologically measurable or evaluable disease (visible, target or non-target-lesionon MRI or CT-scan)

• Performance status: Karnofsky performance status (for patients >16 years of age) orLansky Play score (for patients ≤16 years of age) ≥ 70%.

• Able to take oral medication or nasal gastric tube or authorized gastrostomy

• Adequate biological criteria:

• Neutrophils > 1000/mm3 ; Platelets > 75 000/mm3

• Transaminases (ALT/ AST) ≤ 3 times ULN (or ≤ 6 times ULN if liver metastasis);total bilirubin ≤ 2 ULN (except in case of Gilbert's disease)

• Creatinine ≤ 1,5 ULN or clearance ≥ 60 mL/ min/ 1,73m2 (In case of doubt, to beconfirm by assessment of cystatin )

• Females of childbearing potential must have a negative seric pregnancy test within 7days prior to initiation of treatment.

• Sexually active patients must agree to use adequate and appropriate contraception (at least one highly effective contraception or two complementary methods ofcontraception), 1 month before beginning of treatment while on trial drug and for 7months after stopping the trial drug for female patients and after 6 months for malepatients.

• Written informed consent from parents/legal representative, patient, andage-appropriate assent before any trial-specific screening procedures according tonational guidelines.

• Patient covered by the French "Social Security" regime

Exclusion Criteria:

• Prior history of other cancer within 5 years

• Chemotherapy or radiotherapy of target lesion within 3 weeks prior to inclusion

• Target therapy within less than 5 * half-life of the substance prior to inclusion

• Major surgery within 15 days prior to inclusion

• Presence of any NCI-CTCAE v5 grade ≥ 2 cardiac, hepatic, pulmonary or renal toxicity

• Severe myelosuppression

• Severe peripheral neuropathy (grade ≥ 2)

• Fructose intolerance

• Inflammatory bowel chronic disease and/or intestinal obstruction

• Patients with demyelinating form of Charcot-Marie-Tooth disease

• Known active viral hepatitis or known human immunodeficiency virus (HIV) infectionor any other uncontrolled infection.

• Known hypersensitivity to dacarbazine (DTIC), isotretinoin or to any of the trialdrugs, trial drug classes, excipients in the formulation

• Hyperlipidemia and hypervitaminosis A

• Vaccination with a live attenuated vaccine within 1 month prior to inclusion

• Pregnant or breastfeeding patients

• Inability to comply with medical follow-up of the trial (geographical, social orpsychological reasons)