SIOPEN Clinical trials
SIOPEN High Risk Neuroblastoma Study 2 (HR-2)
Chief Investigator: Dr Dominique Valteau-Couanet
Sponsor: Institut Gustave Roussy, Paris
This study aims to improve the outcome for patients with newly diagnosed high-risk neuroblastoma.
The treatment of high-risk neuroblastoma is complex, and involves a number of phases:
- Initial “induction” chemotherapy
- Surgery to remove the primary tumour
- "Consolidation" with high-dose chemotherapy followed by autologous stem cell rescue (ASCR)
- Radiotherapy to the site of the primary tumour
- Maintenance therapy with anti-GD2 immunotherapy and retinoic acid.
The SIOPEN HR-2 study aims to answer several questions:
- To compare two different induction chemotherapy regimens: Rapid-COJEC and the GPOH.
- To investigate the impact of giving more intensive consolidation: comparing standard single course of Busulfan-Melphalan (Bu-Mel) with two courses of high dose chemotherapy (Thiotepa followed by Bu-Mel), autologous stem each course being supported by ASCR
- In patients with a macroscopic residue disease before radiotherapy, to evaluate the benefit of a radiotherapy boost to the residue ( total 36 Gy) in comparison to the standard 21 Gy dose delivered to the site of the primary tumour.
All patients enrolled in the trial must have newly diagnosed High Risk Neuroblastoma
The study opened in France in 2020, and aims to recruit 800 patients over 6 years. Other countries are in set up, with a plan to open in 26 countries: Germany, Austria, Belgium, Denmark, Greece, Ireland, Israel, Italy, The Netherlands, Poland, Spain, Switzerland, united Kingdom, Australia and New Zealand; Croatia; Finland; Hungary; Lithuania; Norway; Portugal; Czech Republic; Slovakia; Slovenia and Sweden.
There are no results available from the study yet.
Further details about the trial can be found at clinicaltrials.gov database:
https://clinicaltrials.gov/ct2/show/NCT04221035
SIOPEN Low and Intermediate Risk Neuroblastoma European Study (LINES)
Chief Investigator: Dr Adele Canete
Sponsor: Instituto de Investigacion Sanitaria La Fe, Valencia
This study aims to improve the outcome for patients with newly diagnosed low and intermediate -risk neuroblastoma.
The study stratifies patient’s treatment according to biological and clinical markers in order to:
• Minimize the treatment burden in those low-risk patients who in previous studies were shown to have an excellent long-term outcome
• Intensify treatment in those patients with biologically unfavourable (but not MYCN amplified) neuroblastoma to improve outcome.
The LINES trial includes ten separate therapeutic groups, in one of these (Group 1) the treatment is randomised. The study is also collecting data on patients with neonatal adrenal masses (NAM) in infants below 3 months are also registered and observed, without initial surgery.
The study opened in July 2011, and is open in Italy, France, Austria, Denmark, Norway, Israel, Ireland, Sweden, Belgium, Switzerland, Ireland, Australia and Portugal.
Further details about the trial can be found at clinicaltrials.gov database:
https://clinicaltrials.gov/ct2/show/NCT01728155
VERITAS (Trial Evaluating and Comparing Two Intensification Treatment Strategies for Metastatic Neuroblastoma Patients With a Poor Response to Induction Chemotherapy)
Chief Investigator: Dr Dominique Valteau-Couanet
Sponsor: Institut Gustave Roussy, Paris
This study aims to improve the outcome for patients with high risk neuroblastoma which is refractory to induction chemotherapy
The trial is a prospective, open-label, randomised, multi-centre phase 2 trial. It aims to evaluate the efficacy of two intensified consolidation strategies:
• high dose 131I-mIBG therapy with topotecan, followed by high dose Busulfan-Melphalan (Bu-Mel)
• High dose thiotepa followed by high dose Bu-Mel
Each phase of the intensified treatment is supported by autologous stem cell rescue (ASCR).
The trial opened in October 2018, and aims to recruit 150 patients, with 75 patients randomly allocated to each treatment arm.
The study is open in France, Spain, The Netherlands, Italy and the UK, and it is planned to open in Austria, Germany and Israel .
No results are available from the study yet
Further details about the trial can be found at clinicaltrials.gov database:
https://clinicaltrials.gov/ct2/show/NCT03165292
A randomised phase IIb trial of BEvACizumab added to Temozolomide ± IrinOtecan for children with refractory/relapsed Neuroblastoma (The BEACON trial)
Chief Investigator: Dr Lucas Moreno (Vall d’Hebron Hospital, Barcelona, Spain)
Sponsor: University of Birmingham (UK)
This study aims to improve the outcome of children with relapsed or refractory neuroblastoma.
The trial is a collaboration between Innovative Therapies for Children with Cancer (ITCC) and the European Neuroblastoma Research Group (SIOPEN) consortia.
The study is open to children and young adults aged 1 to 21 years of age with relapsed/refractory neuroblastoma.
The trial opened initially in 2013 to evaluate the role of bevacizumab, irinotecan and topotecan added to temozolomide-based chemotherapy in 160 patients. Bevacizumab, irinotecan and topotecan randomisations have now closed. These results have been presented at ASCO and SIOP meetings in 2019 and 2020:
https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.10001?af=R
https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.10501
In 2019, the new dinutuximab beta randomisation was opened planning to recruit 64 patients. 43 sites are participating in BEACON Immuno trial, with 40 currently open for recruitment to the dinutuximab beta randomisation. The trial is now open in the UK, Denmark, Spain, Belgium, Ireland, Switzerland, Austria Netherlands and France. Approvals for Italy are awaited. It is expected that recruitment for this randomisation will be achieved during Q1 2021.
Further details about the trial can be found at clinicaltrials.gov database (NCT02308527):
https://clinicaltrials.gov/ct2/show/NCT02308527
Spinal cord compression
Chief Investigators : Dr. Shifra Ash and Dr Riccardo Haupt.
Sponsor: Associazione Italiana Ematologia-Oncologia Pediatrica (AIEOP), Italy
This study aims to collect information about the outcome of patients with neuroblastoma and spinal cord compression.
It is the first prospective registry collecting clinical, pathological, biological, therapeutic and follow-up data on symptomatic and asymptomatic patients with spinal cord involvement.
The primary aim is:
• to describe the natural history and treatments given for patients with peripheral neuroblastic tumours presenting with spinal cord involvement, in order, to evaluate the combined effects of risk factors and to develop treatment guidelines.
Secondary aims are:
• to correlate the pathologic and biological characteristics with the clinical features, response to therapy and sequelae
• to share the diagnostic and therapeutic approaches adopted in the participating centres
• to increase the communication regarding patients with a peripheral neuroblastic tumour presenting with spinal cord involvement
• to develop common guidelines for the management of children with any peripheral neuroblastic tumour presenting with spinal cord involvement.
There are also two parallel studies:
• Neuroradiological review and Scoring by a neuroradiology panel
• Data collection study on infant patients with Peripheral Neuroblastic Tumours presenting with Spinal Canal Involvement
The study is recruiting all patients younger than 18years of age, with the diagnosis of peripheral neuroblastic tumour (neuroblastoma, ganglioneuroblastoma, ganglioneuroma) presenting with either symptomatic or asymptomatic spinal cord involvement. Patients can be enrolled for study at at initial diagnosis or relapse/progression can be enrolled, providing that they have not had previous chemotherapy, except corticosteroids, in the last 6 months
The study opened in June 2014 and expected to complete recruitment in June 2021. It is currently open in Italy, Israel, Ireland, The Netherlands, Poland, Slovakia, Norway, Spain, France, Sweden, Russia, Japan, Germany, Portugal, Belgium, Switzerland, Australia and Austria.
A Phase I study of 131-1 mIBG followed by Nivolumab and Dinutuximab beta Antibody in children with relapsed/refractory Neuroblastoma. (The MINIVAN trial)
Chief Investigator: Dr Juliet Gray
This is a phase I trial investigating combining 131-I mIBG therapy, anti-PD-1 antibody (Nivolumab) and anti-GD2 antibody (dinutuximab beta) in children with relapsed or refractory neuroblastoma.
The study is jointly funded by the charities Solving Kids Cancer (UK and US), Joining against Cancer in Kids (J.A.C.K) and Band of Parents, through the INBRACED initiative. It is a collaborative transatlantic study, led by Dr Juliet Gray and Dr Mark Gaze (UK), Professor Paul Sondel and Dr Ken Desantes (Madison, US) and Professor Holger Lode (Greiswald, Germany).
The study is based on pre-clinical (laboratory) results suggesting that this combination of treatments work effectively together to kill neuroblastoma and generate immunity to the tumour. Although each of the treatments has been widely used in children, they have not previously been used in combination. The study is designed primarily at the side effects and tolerability of this new combination of treatments in children with neuroblastoma, but is also looking for evidence that this treatment is effective at treating neuroblastoma and also to investigate the immune effects.
The study has 3 cohorts (groups) of patients. The first cohort of patients only received 131-I mIBG therapy and Nivolumab. This was well tolerated with no unexpected side effects, so the second cohort of patients are now receiving 131-I mIBG therapy, Nivolumab and a 50% dose of dinutuximab beta. If the patients in cohort two, tolerated this treatment well, then a final, third cohort of patients will receive all three treatments at the full dose.
The trial is open to most patients with relapsed or refractory neuroblastoma who have MIBG positive disease on scans. For more details about specific eligibility criteria, please see:
https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-of-mibg-nivolumab-and-dinutuximab-beta-for-neuroblastoma-minivan
The study opened in the UK (Southampton Children’s Hospital and UCLH London) in July 2018, and in the US (Madison Children’s Hospital) in September 2020. It is hoped it will open in Greifswald in Germany very soon.
For more details about the study, please contact Dr Juliet Gray (jcgray@soton.ac.uk) or see: https://www.solvingkidscancer.org.uk/minivan
Multimodal Molecular Targeted Therapy to Treat Relapsed or Refractory High-risk Neuroblastoma (RIST-rNB-2011)
Chief Investigator: Selim Corbacioglu
Sponsor: University of Regensburg
This study aims to improve the outcome of patients with relapsed or refractory neuroblastoma
Further details about the trial can be found at clinicaltrials.gov database:
https://clinicaltrials.gov/ct2/show/NCT01467986
Prospective multicentre clinical trial for risk estimation and treatment stratification in low and intermediate risk neuroblastoma patients (NB2015-LR)
Chief Investigator: Thorsten Simon
Sponsor: University of Cologne
This study aims to improve the outcome of patients with low and intermediate risk neuroblastoma. The study is evaluating the use RNA expression array based treatment stratification algorithm. The primary objectives of the trial are:
• the improvement of event free survival for Group B patients with intensified treatment
• maintainance of event free survival of group C patients with reduced treatment after treatment allocation by gene expression-based risk stratification compared to patients of group A.
The study is open at sites across Germany.
For more details about the trials, please see: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004883-37/DE
A phase II trial of 177Lutetium-DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma (LuDO-N Trial)
Chief investigator: Dr Jakob Stenman
Sponsor: Karolinska University Hospital, Stockholm
The prognosis for children with relapsed or refractory high-risk neuroblastoma is dismal with very few survivors. As neuroblastoma is known to be a relatively radiosensitive tumor, targeted intravenous radiotherapy is an attractive treatment option and 131I-mIBG treatment has been used in a relapse setting, since the 1980’s. Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE, targeted at somatostatin receptors, has recently evolved, as a possibly less myelotoxic alternative to 131I-mIBG treatment, and this treatment has been both effective and well tolerated in the second line treatment of neuroendocrine tumors in adults. Building on the experience from the first pediatric trial on 177Lu-DOTATATE (LuDO Trial, UCLH, London) we aim to perform a multicenter, stage II clinical trial to evaluate the response to single agent 177Lu-DOTATATE treatment in children with relapsed or refractory high-risk neuroblastoma.
In the LuDO-N trial, an intensified dosing schedule will be utilized to administer 177Lu-DOTATATE in two doses, two weeks apart. The aim is to achieve a cumulative whole-body radiation dose of 2,4 Gy over two courses and not exceeding a cumulative renal dose of 23 Gy, in order to avoid renal toxicity. A weight based activity of 200 MBq kg-1 will be used for the first dose and the activity of the second dose will be based on dosimetry. Due to the risk of myelotoxicity, autologous peripheral blood stem cells will be available for all included study subjects, in order to allow for stem cell transplantation, if needed. Response evaluation will be performed at 1 and 4 months after end-of-treatment.
The study will be led and coordinated by the Karolinska University Hospital in Stockholm, Sweden. Patients will initially be recruited from the Nordic countries, Lithuania and from the The Netherlands. Study centers will be established in all participating countries and the 177Lu-DOTATATE (Lutathera®) treatment will be given at the Karolinska University Hospital and at the Prinses Máxima Centrum. The LuDO-N Trial is scheduled to open on May 19, 2021in Sweden, Norway and Denmark, with Finland and Lithuania soon to follow and in The Netherlands later during 2021. The UK has expressed an interest in joining the Trial in 2022. Recruitment is estimated to continue over a period of 3-5 years. Follow-up of patients will continue until 5 years after treatment of the last patient.
For more details about the trials, please see: https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-004445-36/NO
