Siop Randomet 2017

Overview

Sponsor-declared trial summary

Key facts

Sponsor

GPOH gGmbH

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Dec 2019 → ongoing

Decision date (initial)

2024-05-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Stiftung Deutsche Krebshilfe

External identifiers

EU CT number

2023-508926-91-00

EudraCT number

2018-000533-13

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

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).

Secondary objectives 9

1. To investigate acute toxicity (grade and duration) of preoperative chemotherapy of 6 weeks of VAD as compared to VCE in stage 4 renal tumours
2. To investigate the histological composition and the local stage distribution of the primary tumour of upfront 6 weeks of VAD as compared to VCE in stage 4 WT.
3. To investigate the primary tumour volume reduction of upfront 6 weeks of VAD as compared to VCE in stage 4 renal tumours.
4. To investigate the number of patients needing radiotherapy (local and/or metastatic site) in both randomized arms
5. To investigate the 2 years and 5 years EFS and OS of upfront 6 weeks of VAD versus VCE
6. To investigate short-term (haematological, mucositis, hepatic) and long-term side (auditive, cardiac, hepatic) effects of upfront 6 weeks of VAD versus VCE followed by a response-, histology- and stage-based adjuvant therapy in stage 4 renal tumours. long-term toxicity (auditive, cardiac, and hepatic) will predominantly be studied with an add-on study to this protocol, enabling a sufficiently long follow-up. This will give rise to a separate study and funding.
7. Investigating the role of molecular markers: o Gain of 1q
8. To prospectively asses and review the standard imaging criteria in use for pulmonary metastases in order to better define what is considered a lung metastasis
9. Investigating the imaging characteristics of lung metastasis (maximum size, number, lungs (lobes) involved) in routine chest imaging in correlation with outcome (EFS/OS after two years)

Conditions and MedDRA coding

Stage IV childhood renal tumour with pulmonary +/- non-pulmonary metastasis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Age <18 years >3 months
2. Patient 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. Metastatic disease must be confirmed by central review.
3. Understand and voluntarily provide permission (subjects and when applicable, parental/legal representative(s)) to the ICF prior to conducting any study related assessments/procedures
4. Able to adhere to the study visit schedule and other protocol requirements
5. No pre-existing and ongoing cardiac malfunction disease
6. No pre-existing and ongoing liver function deficiency which is not controllable by substitution
7. Metastatic childhood renal tumour must be confirmed by central review.

Exclusion criteria 17

1. Patient and/or parental/legal representative(s) denied randomization
2. primary nephrectomy
3. inability to be followed until two years after treatment
4. other chemotherapy prior to enrolment
5. other histology than nephroblastoma at diagnosis
6. Pregnancy or lactating
7. Fertile female with child bearing potential and fertile male subjects who deny the use of highly effective contraceptive measures
8. Treated by any investigational agent in a clinical study within previous 4 weeks
9. 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).
10. pre-existing health impairment that significantly hazards the safe treatment according to the study
11. unwillingness to follow adequate supportive measures including transfusion of blood products if medically needed
12. 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
13. Active, uncontrolled life threatening Infection (e.g. Acute Hepatitis, Pneumonia, AIDS, Varizella)
14. known chromosomal instability/susceptibility (e.g. Fanconi Anemia, Nijmegen Breakage Syndrome)
15. participation in other interventional trials (registration in observational noninterventional studies is acceptable)
16. age at start of treatment <3 months or >18 years
17. any other medical condition incompatible with the protocol treatment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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)

Secondary endpoints 27

1. Percentage of patients after 6 weeks of preoperative chemotherapy achieving a CR after surgery of metastasis at time of nephrectomy
2. Percentage of patients with complete response +/- VGPR of (pulmonary) metastasis of nephroblastoma after 6 weeks of preoperative chemotherapy + 9 weeks adjuvant chemotherapy.
3. Percentage of patients with complete response +/- VGPR of (pulmonary) metastasis of nephroblastoma after preoperative chemotherapy + 9 weeks adjuvant chemotherapy + metastasectomy
4. Percentage of patients with remaining metastatic disease after surgery that achieve a CR at week 9 of adjuvant chemotherapy
5. Percentage of patients with complete response +/- VGPR of (pulmonary) metastasis of nephroblastoma at the end of adjuvant chemotherapy ± metastasectomy ± RT
6. 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
7. Primary tumour volume shrinkage after 6 weeks of preoperative chemotherapy
8. Primary tumour volume after 6 weeks of preoperative chemotherapy
9. Number of metastases at diagnosis and after preoperative treatment
10. Maximum diameters of the largest metastases at diagnosis and after preoperative treatment
11. Stage distribution of local tumour
12. Histologic subtype distribution of local tumour (LR, IR, HR)
13. Histologic subtype distribution of resected nodules/metastasis (LR, IR, HR)
14. Percentage of blastema and blastemal residual volume in local tumour
15. Percentage of patients with <10 ml of blastemal residual volume in resected nephroblastoma after 6 weeks of preoperative chemotherapy
16. Percentage of necrosis in local tumour
17. Percentage of patients with complete necrosis in resected nodules
18. Percentage of patients with 1q gain being in CR/VGPR in both arms.
19. Percentage of patients requiring pulmonary radiotherapy in first line
20. Percentage of patients suffering Grade 3 or 4 ALAT or bilirubin increase during preoperative treatment
21. Percentage of patients suffering from SOS during preoperative treatment according to EBMT criteria
22. Percentage of patients suffering any Grade 4 or grade 5 toxicity during preoperative chemotherapy
23. Overall duration of preoperative treatment per arm as determined as interval D1 – date of nephrectomy
24. Delay in timing of nephrectomy: % of patients with more than 8 weeks since start of preoperative chemotherapy because of toxicity
25. Percentage of (peri-)operative complications (haemorrhage, rupture, thromboembolism)
26. Event-free survival at 2 and 5 years for the whole cohort and according to study arm (VAD/VCE) and according to 1qGain
27. Overall survival at 2 and 5 years for the whole cohort and according to study arm (VAD/VCE) and according to 1qGain

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

GPOH gGmbH

Sponsor organisation

GPOH gGmbH

Address

Chausseestrasse 128-129, Mitte Mitte

City

Berlin

Postcode

10115

Country

Germany

Scientific contact point

Organisation

GPOH gGmbH

Contact name

Prof. Rhoikos Furtwängler

Public contact point

Organisation

GPOH gGmbH

Contact name

Prof. Dirk Reinhardt

Third parties 3

Locations

10 EU/EEA countries · 110 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 134 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications