Metronomic Chemotherapy in Wilms Tumor (MetroWilms-1906)

Study Overview
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Brief Summary
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This is a multicenter, interventional, non-randomized study among patients with a relapsed or refractory Wilms tumor. The study will aim to assess efficacy of metronomic chemotherapy, in terms of disease control after two cycles of metronomic chemotherapy.

Detailed Description
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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

Official Title
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Phase 1-2 Trial Evaluating Metronomic Chemotherapy in Patients With a Relapsed or Refractory Wilms Tumor

Conditions
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Wilms Tumor

Intervention / Treatment
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* Drug: Vincristine
* Drug: Irinotecan
* Drug: Temozolomide
* Drug: Etoposide
* Drug: Cis-Retinoic acid


Participation Criteria
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Eligibility Criteria
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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 study 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 study drug and for 6 months after stopping the study drug for both female and male patients. Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-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 study drugs, study 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)

Ages Eligible for Study
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Minimum Age: 18 Months
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm - Vincristine + Irinotécan + Témozolomide + Etoposide + Cis-Retinoic acid<br>Metronomic chemotherapy : Vincristine + Irinotécan + Témozolomide + Etoposide + Cis-Retinoic acid | Drug: Vincristine<br>* IV, D1-D22-D43 and D64<br>Drug: Irinotecan<br>* Oral, 5 days/week during W1,W2,W7 and W8 (D1 to D5, D8 to D12, D43 to D47, D50 to D54)<br>Drug: Temozolomide<br>* Oral,3 weeks in a row, twice per cycle (D1 to D21, D43 to D63)<br>Drug: Etoposide<br>* Oral, 3 weeks in a row, twice per cycle (D22 to D42, D64 to D84)<br>Drug: Cis-Retinoic acid<br>* Oral, 2 weeks in a row, thrice per cycle (D15 to D28, D43 to D56, D71 to D84)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control | Complete response, partial response or stable disease after 2 cycles of treatment, measured by the progression-free survival (PFS). | 6 months after inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | The time interval between study entry and date of progression (using RECIST 1.1) | Up to progression, an average of 1 year | 
| Overall survival | The time interval between study entry and death from any cause | Through study completion, an average of 12 months | 
| Tumor response | Using CT-scan or MRI imaging (using RECIST 1.1) | Immediately after each cycle of treatment, up to progression, an average of 1 year | 
| Adverse events | The adverse events (AE) are collected to evaluate the safety of the study treatment. | Through study completion, an average of 12 months (plus 30 days) | 
| The feasibility of evaluated therapy | assessed in terms of frequency of dose reductions or temporary stops of treatment | Through study completion, an average of 12 months | 
| Quality of life of the patient (KindL) | Ravens-Sieberer and Bullinger Quality of Life Questionnaire will be used to measure the quality of life of the patients. The score can go from 0 to 100, and the higher score corresponds to a higher health-related quality of life | Baseline, week 7 and week 13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multidrug chemotherapy, metronomic chemotherapy, Wilms Tumor, Renal cancer