| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Wilms tumor |
| Tumeur de Wilms |
|
| E.1.1.1 | Medical condition in easily understood language |
| Renal cancer/ Nephroblastoma |
| Tumeur du rein/ Néphroblasatome |
|
| 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 | 10029145 |
| E.1.2 | Term | Nephroblastoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate efficacy of metronomic chemotherapy in patients with a relapsed or refractory Wilms tumor, in terms of disease control after two cycles of metronomic chemotherapy (approximately 6 months). |
| Evaluer l’efficacité de la chimiothérapie métronomique sur des patients atteints d’une tumeur de Wilms réfractaire ou en rechute en termes de contrôle de la maladie après 2 cycles de chimiothérapie métronomique (environ 6 mois). |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate disease control obtained with metronomic chemotherapy, in terms of progression-free survival (PFS) and overall survival (OS).
- To evaluate early response after one cycle of treatment of metronomic treatment.
- To evaluate best tumor response over the whole metronomic treatment duration.
- To evaluate safety of the proposed metronomic chemotherapy.
- To evaluate the feasibility of the proposed metronomic chemotherapy.
- To evaluate quality of life using kidKindl® Quality of Life questionnaire at baseline (before start of treatment), and approximately at weeks 7 and 13 of treatment. |
- Evaluer le contrôle de la maladie en termes de survie sans progression (PFS) et survie globale (OS)
- Evaluer la réponse précoce après un cycle de traitement du traitement métronomique
- Evaluer la meilleure réponse tumorale sur la durée du traitement métronomique
- Evaluer la tolérance de la chimiothérapie métronomique proposée
- Evaluer la faisabilité de la chimiothérapie métronomique proposée
- Evaluer la qualité de vie avant et en cours de traitement avec le questionnaire KidKindl à la Baseline (avant le début du traitement), puis à environ 7 et 13 semaines de traitement. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Patient ≥18 months old and ≤ 35 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. |
|
| E.4 | Principal 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) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Disease control (complete response, partial response or stable disease) after 2 cycles of treatment, measured by the progression-free survival (PFS), approximately 6 months after inclusion, based on central review using RECIST 1.1 criteria. Tumor response will be evaluated by the treating physician using RECIST 1.1 (appendix 2). A radiological central review will be performed in real time (72h after receiving the images) for doubtful cases to discuss whether study treatment should be continued or not. A central review is also planned for all cases.
If imaging is not performed due to clinical progression or death from any cause, it will be classified as a failure. A patient will be deemed not evaluable for the main criteria analysis if she/he receives a second line systemic treatment before a confirmed disease progression, in particular if a second line treatment is administered after early stop of study treatment for a reason other than disease progression. Local treatment will not be considered as a reason for censoring if the local treatment was deemed feasible because of response to study treatment.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| after 2 cycles of treatment, approximately 6 months after inclusion |
|
| E.5.2 | Secondary end point(s) |
-Progression free survival, computed as the time interval between study entry and date of progression (according to central review, and using RECIST 1.1) or death from any cause. Patients still alive without evidence of disease progression at the time of their last visit will be censored at that date. We will use similar rules for censoring as for the primary endpoint.
-Overall survival, computed as the time interval between study entry and death from any cause. Patients still alive at the time of their last visit will be censored at that date.
-Tumor response based on CT-scan or MRI imaging, using the same method over the whole study period, and evaluated by central radiological review, using RECIST 1.1 criteria after each cycle of treatment (every 3 months approximately). The early response is based on the evaluation after one cycle. The best response is measured over the whole treatment duration. Radiological evaluations that would be performed after the initiation of another line of systemic treatment will not be considered for the evaluation of response.
-Adverse events occurring from start of treatment until the end of study treatment (plus 30 days) will be reported and graded using the NCI-CTCAE v5.0 classification, excluding those unequivocally related to the underlying disease or its progression. All AE will be analyzed, and described according to the reported causal relationship. An AE will be classified as Severe AE if grade is equal or higher than 3 for extra-hematological AE and grade 4 for hematological AE.
-The feasibility of evaluated therapy will be assessed in terms of frequency of dose reductions or temporary stops of treatment, summarized by the relative dose intensity for each drug, and reasons for permanent termination.
-Quality of life will be assessed using kidKindl® Quality of Life questionnaires (Ravens-Sieberer and Bullinger, 1998), with three time points (baseline and approximately at weeks 7 and 13). |
|
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 17 |
| 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
|
| end of the trial = 12 months after the end of treatment of the last patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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