Metronomic Chemotherapy in Wilms Tumor (MetroWilms-1906)

The main aim of this study is to assess efficacy of metronomic chemotherapy, in terms of disease control after two cycles of metronomic chemotherapy .

Other objectives of the study include:

• To evaluate disease control obtained with metronomic chemotherapy, in terms of progression-free survival (PFS) and overall survival (OS).
• Evaluating early response after one cycle of treatment of metronomic treatment;
• Evaluating best tumor response over the whole metronomic treatment duration;
• Evaluating safety of the proposed metronomic chemotherapy;
• Evaluating the feasibility of the proposed metronomic chemotherapy.
• To evaluate quality of life using Kindl® Quality of Life questionnaire at baseline (before start of treatment), and approximately at weeks 7 and 13 of treatment

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 include the trial molecules) or after 1 line for high risk relapse for which there would not be any curative therapy. If 1 line for high risk relapse, the enrolment should be confirmed by coordinators.
• Radiologically measurable or evaluable disease (visible, target or non-target-lesion on MRI or CT-scan)
• Performance status: Karnofsky performance status (for patients >16 years of age) or Lansky 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 be confirm by assessment of cystatin )
• Females of childbearing potential must have a negative seric pregnancy test within 7 days 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 of contraception), 1 month before beginning of treatment while on trial drug and for 7 months after stopping the trial drug for female patients and after 6 months for male patients.
• Written informed consent from parents/legal representative, patient, and age-appropriate assent before any trial-specific screening procedures according to national 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) infection or any other uncontrolled infection.
• Known hypersensitivity to dacarbazine (DTIC), isotretinoin or to any of the trial drugs, 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 or psychological reasons)