E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Stage IV childhood renal tumours |
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E.1.1.1 | Medical condition in easily understood language |
Metastasized childhood tumours in kidneys |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine non-inferiority of upfront 6 weeks of VCE to VAD in the overall metastatic response rate (MetRR) in newly diagnosed stage 4 WT. The MetRR will include the pulmonary response rate (PRR) and the response rate on non-pulmonary metastasis (NPRR). |
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E.2.2 | Secondary objectives of the trial |
- acute toxicitiy of preoperative chemotherapy
- histological composition and local stage distribution of the primary tumour
- tumour volume reduction
- EFS and OS after 2 and 5 years
- short term and long term effects
- role of molecular markers
- assess and review the standard imaging criteria in use of pulmonary matastases
- investigating the imaging characteristics of lung metastasis in routine chest imaging in correlation with outcome |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The substudy are part of
1. Histologic and molecular response to preoperative treatment and outcome
- Investigating the role of remaining blastema after pre-treatment wit VCE or VAD
- Investigating the role of molecular markers
2. Exploration of outcome and risk factor
- To investigate a potential difference in outcome between males and females in both treatment arms at 2 and 5 years.
- To investigate the potential difference in outcome for children <2 years, 2-4 years and >4 years in both treatment arms.
- Investigating risk factors/Clinical outcome after treatment:
3. Long term and acute sude effects
- Percentage of patients suffering febrile grade 4 neutropenia during postoperative treatment
- Percentage of patients suffering Grade 3 or 4 ALAT or bilirubin increase during postoperative treatment
- Percentage of patients suffering from SOS during postoperative treatment according to EBMT criteria [48]
- Percentage of patients with persistent CTCAE grade 3 and 4 ototoxicity (at the end of treatment and/or at 2 years after end of treatment) (=>= 30dB hearing loss in 2-4 kHZ area)
- Percentage of patients with > grade I CTCAE left ventricular dysfunction at the end of treatment 2, 5 and 10 years (for 5 and 10 years)
- Percentage of patients with second malignancy (within 2 years after end of treatment)
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E.3 | Principal inclusion criteria |
- Children <18 years at date of diagnosis and >3months
- Patients suffering from metastatic renal tumour at initial diagnosis, having at least one circumscript, non-calcified (pulmonary) nodule (or other lesion highly suspicious of metastasis according to criteria for metastatic disease) ≥3 mm as determined by chest CT-scan and abdominal CT-scan/MRI (for radiological details please refer to section 12.8).
- Metastatic childhood renal tumour must be confirmed by central review.
- Signed informed consent form(s) prior to study entry according to national guidelines and GCP guidelines
- Understand and voluntarily provide permission (subjects and when applicable, parental/legal representative(s)) to the ICF prior to conducting any study related assessments/procedures
- Able to adhere to the study visit schedule and other protocol requirements
- No pre-existing and ongoing cardiac malfunction disease (insufficiency, malign arrhythmias)
- No pre-existing and ongoing liver function deficiency that is not controllable by substitution |
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E.4 | Principal exclusion criteria |
- inability to be followed until two years after treatment
- other chemotherapy prior to enrolment
- Patient and/or parental/legal representative(s) denied randomization
- primary nephrectomy
- histology other than nephroblastoma if confirmed by upfront tumour biopsy/cutting needle biopsy
- pregnancy or lactation
- Fertile female with child bearing potential and fertile male subjects who refuse using highly effective contraceptive measures
- Treated by any investigational agent in a clinical study within previous 4 weeks
- hypersensitivity to the active substances or other excipients contained in the investigational medical products listed in the summary of product characteristics (SmPC) or Investigators Brochure (IB).
- unwillingness to follow adequate supportive measures including transfusion of blood products if medically needed
- inability to receive chemotherapy according to the protocol, this is particulary true for:
a. acute kidney failure needing dialysis treatment
b. pre-existing peripheral neuropathy
- Active, uncontrolled life threatening Infection (e.g. Acute Hepatitis, Pneumonia, AIDS, Varizella)
- known chromosomal instability/susceptibility (e.g. Fanconi Anemia, Nejjmegen Breakage Syndrome)
- participation in other interventional trials (registration in observational non-interventional studies is acceptable)
- age at start of treatment <3 months or >18 years
- any other medical condition incompatible with the protocol treatment |
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E.5 End points |
E.5.1 | Primary end point(s) |
Percentage of patients with radiologic complete response (CR) of any metastasis and/or Very Good Partial Response (VGPR) of lung metastasis of childhood renal tumours after 6 weeks of preoperative chemotherapy (Section 12.5 for definitions of metastatic response) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
6 weeks after start of preoperative chemotherapy of the last patient |
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E.5.2 | Secondary end point(s) |
- Radiologic response to preoperative treatment:
Metastatic response assessment:
- Percentage of patients after 6 weeks of preoperative chemotherapy achieving a CR after surgery of metastasis at time of nephrectomy
- Percentage of patients with complete response +/- VGPR of (pulmonary) metastasis of nephroblastoma after 6 weeks of preoperative chemotherapy + 9 weeks adjuvant chemotherapy.
- Percentage of patients with complete response +/- VGPR of (pulmonary) metastasis of nephroblastoma after preoperative chemotherapy + 9 weeks adjuvant chemotherapy + metastasectomy
- Percentage of patients with remaining metastatic disease after surgery that achieve a CR at week 9 of adjuvant chemotherapy
- Percentage of patients with complete response +/- VGPR of (pulmonary) metastasis of nephroblastoma at the end of adjuvant chemotherapy ± metastasectomy ± RT
- Percentage of patients with radiologic complete response (CR) of any metastasis or Very Good Partial Response (VGPR) of lung metastasis of nephroblastoma after 6 weeks of preoperative chemotherapy of patients with remaining metastatic disease after surgery that achieve a CR at week 9 of adjuvant chemotherapy
- Primary tumour volume shrinkage after 6 weeks of preoperative chemotherapy
- Primary tumour volume after 6 weeks of preoperative chemotherapy
- Number of metastases at diagnosis and after preoperative treatment
- Maximum diameters of the largest metastases at diagnosis and after preoperative treatment
- Histologic & molecular response to preoperative treatment:
- Stage distribution of local tumour
- Histologic subtype distribution of local tumour (LR, IR, HR)
- Histologic subtype distribution of resected nodules/metastsis (LR, IR, HR)
- Percentage of blastema and blastemal residual volume in local tumour
- Percentage of patients with <10 ml of blastemal residual volume in resected nephroblastoma after 6 weeks of preoperative chemotherapy
- Percentage of necrosis in local tumour
- Percentage of patients with complete necrosis in resected nodules
- Percentage of patients with 1q gain being in CR/VGPR in both arms.
- Treatment burden, complications, side effects and toxicity:
- Percentage of patients requiring pulmonary radiotherapy in first line
- Percentage of patients suffering Grade 3 or 4 ALAT or bilirubin increase during preoperative treatment
- Percentage of patients suffering from SOS during preoperative treatment according to EBMT criteria [48]
- Percentage of patients suffering any Grade 4 or grade 5 toxicity during preoperative chemotherapy.
- Overall duration of preoperative treatment per arm as determined as interval D1 – date of nephrectomy
- Delay in timing of nephrectomy: % of patients with more than 8 weeks since start of preoperative chemotherapy because of toxicity
- Percentage of (peri-)operative complications (haemorrhage, rupture, thromboembolism)
- Outcome:
- Event-free survival at 2 and 5 years for the whole cohort and according to study arm (VAD/VCE) and according to 1qGain
- Overall survival at 2 and 5 years for the whole cohort and according to study arm (VAD/VCE) and according to 1qGain
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
after surgery (6 weeks), 9 weeks after initiation of postoperative treatment (if applicable), at the end of overall treatment, 2 years and 5 years (if applicable) |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 47 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Brazil |
Czech Republic |
Denmark |
France |
Germany |
Greece |
Holy See (Vatican City State) |
Hungary |
Ireland |
Italy |
Netherlands |
Norway |
Poland |
Portugal |
Spain |
Sweden |
Switzerland |
United Kingdom |
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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
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Last subject last visit, it is anticipated to be at the date patients were last known alive for two years after end of the treatment or date of death |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 8 |