Randomized multi-centre open-label non-inferiority phase 3 clinical trial for patients with a stage IV childhood renal tumour comparing upfront Vincristine, Actinomycin-D and Doxorubicin (VAD, standard arm) with upfront Vincristine, Carboplatin and Etoposide (VCE, experimental arm)

Childhood renal tumours are among the most frequent childhood tumours and
represent about 6% of all childhood tumours. Nephroblastomas (Wilms tumour, WT)
account for >85% of all renal tumours of childhood. Their treatment consists of
neoadjuvant chemotherapy, (partial) nephrectomy and risk-based adjuvant
chemotherapy ± irradiation[76]. For localized tumours, overall survival is >85%
except in case of high risk histology. European patients with nephroblastoma
have been treated for > 40 years according to SIOP protocols (International
Society of Pediatric Oncology) since 1972 with currently 267 centres
collaborating internationally within the SIOP Renal Tumour Study Group
[SIOP-RTSG].
Recently SIOP-RTSG has published a standard of care treatment guideline
SIOP-RTSG Umbrella.

Childhood renal tumours treated according to SIOP protocols are classified and
staged according the SIOP Working classification of childhood renal tumours.
Children presenting with metastasis at diagnosis are termed Stage IV.
Nephroblastoma metastasize predominantly to the lung (95%) and/or the liver
(12%) and only in rare cases to the bones or other extra-abdominal sites (<5%)
[Furtwängler R., Oral Presentation, GPOH Scientific Summer Meeting 2008].
Pulmonary metastases are visible on conventional imaging in at least 10-13% of
nephroblastoma patients, with an additional 4-13% of patients having suspicious
nodules on CT-scan only. The treatment of metastatic nephroblastoma consists of
neoadjuvant 3-drug chemotherapy (including Actinomycin D, Vincristine and
Doxorubicin), nephrectomy, possibly metastasectomy and risk-based adjuvant
chemotherapy ± radiotherapy to the flank and/or metastases. With this
multimodality treatment long-term survival reaches more than 80%, and is best
in the 48-67% of patients with complete resolution of metastasis after
preoperative treatment. However, these promising results are bought at the
price of a relevant risk of cardiac and pulmonary sequelae due to the use of
doxorubicin ± concomitant RT. Ongoing research shows 4-17% of congestive heart
failure rates and a not yet reached plateau of subclinical cardiac changes up
to 25% in patients treated with higher doses of anthracyclins. Furthermore,
hepatic toxicity due to the use of actinomycin-D can be life threatening in
form of a sinusoidal obstruction syndrome (SOS).

This study has been transitioned to CTIS with ID 2023-508926-91-00 check the CTIS register for the current data.

To determine non-inferiority of preoperative 6 weeks of VCE to VAD in the
overall metastatic rapid response rate (MetRR) in newly diagnosed stage 4
childhood renal tumours. The MetRR will include the pulmonary response rate
(PRR) and the response rate on non-pulmonary metastasis (NPRR).

This is a randomized multi-centre open-label non-inferiority phase 3 clinical
trial for patients with a stage IV renal tumor comparing upfront Vincristine,
Actinomycin-D and Doxorubicin (VAD, standard arm) with upfront Vincristine,
Carboplatin and Etoposide (VCE, experimental arm).

If the study achieves its primary objective, that the VCE arm is non-inferior
to the VAD arm in terms of Metastatic Rapid Responders, non-inferiority and
superiority tests on secondary endpoints will be used as supportive evidence.
Power might be too low to show a beneficial effect for these secondary
endpoints convincingly.

If the primary objective is not achieved but a beneficial effect is found for
certain secondary endpoints, further studies might help support this indication
of a benefit. The study may be stopped e.g. for safety concerns if the VCE arm
has unacceptably unfavourable results for (part of) the study endpoints.

Randomization between VAD and VCE treatment

Blastemal type nephroblastoma represents a subtype which has already been shown
to benefit from intensive treatment in SIOP 2001 [77,82]. This highlights the
need to identify *high risk*, chemo resistant blastema in order to avoid
unnecessary failure of first line therapy. Hence, one aim of the study is to
optimise the definition of high risk, *blastemal type* Wilms tumour, which is
currently defined according to the crude proportion of resistant blastemal
cells that survived pre-operative chemotherapy.

If the primary objective is not achieved but a beneficial effect is found for
certain secondary endpoints, further studies might help support this indication
of a benefit.The study may be stopped e.g. for safety concerns if the VCE arm
has unacceptably unfavourable results for (part of) the study endpoints.

The sponsor and coordinating Investigators will set up an independent data
monitoring committee as part of the trial management to ensure appropriate and
safe conduct of the trial. For this purpose, the IDSMC will continuously review
the trial data and assess the progress, safety data and critical efficacy
endpoints of the trial. It will perform risk-benefit assessments in order to
weigh possible safety disadvantages against a possible gain in efficacy.