VERITAS
Research type
Research Study
Full title
An international multicenter phase II randomised trial evaluating and comparing two intensification treatment strategies for metastatic neuroblastoma patients with a poor response to induction chemotherapy
IRAS ID
254424
Contact name
Guy Makin
Contact email
Sponsor organisation
Gustave Roussy
Eudract number
2015-003130-27
Clinicaltrials.gov Identifier
Duration of Study in the UK
7 years, 5 months, 30 days
Research summary
Research Summary
High-risk neuroblastoma is one of the major challenges in paediatric oncology, as the outcome remains poor, particularly for patients who respond poorly to initial chemotherapy. High-risk neuroblastoma is not cured by a single treatment. All patients who have become long-term survivors have received sequential treatments with various drugs. This trial compares two sequential treatments, each containing treatments successfully used before, in combination with an experimental component. There is no recognised or accepted standard treatment in this very high-risk patient group and no guidelines exist for poor responders. Eligible patients will receive induction chemotherapy (using irinotecan and temozolomide), and will then be randomised to receive either mIBG radiotherapy with topotecan or high dose thiotepa, followed by autologous stem cell transplant (ASCT). Each randomised treatment will be followed by high dose chemotherapy with busulfan and melphalan (BuMel) and a second ASCT. The two consolidation treatments will be evaluated for success and compared to see which is the better treatment.
Summary of Results
Trial name:
VERITAS: An international multicenter phase II randomised trial evaluating and comparing two intensification treatment strategies for metastatic neuroblastoma patients with a poor response to induction chemotherapy Sponsor Protocol Number: 2015/2294 EudraCT number: 2015-003130-27
Acknowledgment: The research team would like to thank the participating patients and families, whose support and time is gratefully acknowledged.
Abstract:
Purpose of the study: The purpose of this trial was to compare two different treatment regimens to find out which is more effective at treating metastatic neuroblastoma.
What was tested: Patients were randomised in a 1:1 ratio to receive either 131I-mIBG and topotecan (Arm A) or high dose thiotepa (Arm B) People taking part: 34 patients took part in this trial, recruited between 1st October 2018 and 28th November 2022. 9 of these patients were recruited in the UK. 18 patients were randomised to Arm A, receiving treatment with 131I-mIBG and topotecan and 16 were randomised to Arm B, treated with high dose thiotepa.
Results: Overall the study was not able to show if 131I-mIBG with topotecan or high dose thiotepa treatment is more effective at treating high risk metastatic neuroblastoma.
Safety: The number of side effects reported by patents receiving treatment was compared for both arms. In this study, researchers found that there were no safety concerns over the use of 131I-mIBG with topotecan or high dose thiotepa.
Who sponsored this trial?
The trial was sponsored by Gustave Roussy (a cancer centre in France), managed by the Cancer Research UK Clinical Trials Unit based at the University of Birmingham in the UK, and is funded by Cancer Research UK.
General Information about the trial
This study took place in 5 European countries including the UK. Recruitment began in the UK in January 2021. The trial was suspended in Nov 2022 and closed earlier than planned on 3rd July 2023, following the Sponsor’s decision due to a number of different factors including delays in opening countries and sites during and after the COVID-19 pandemic, difficulties in securing access to the trial IMP (131I-mIBG) and issues surrounding low recruitment and data not completed on the eCRF.
Patients with neuroblastoma that has spread to other areas of the body (metastatic neuroblastoma), are initially treated with chemotherapy (in VERITAS this was with 3 cycles of a combination of drugs called temozolomide and irinotecan). In a minority of patients, the disease does not respond well to initial chemotherapy. There is currently no one standard treatment for metastatic neuroblastoma which has not responded well to initial chemotherapy.After initial chemotherapy, patients had their stem cells harvested, before beginning the randomised intensified treatment phase which consisted of either one cycle of 131I-mIBG and topotecan (Arm A) or one cycle of thiotepa (Arm B). All patients then went on to receive consolidation chemotherapy with a combination of drugs called busulphan and melphalan, after which they had their stem cells returned to them. Patients then went on to receive any additional treatment they required.
The main aim of this trial was to evaluate the efficacy of the two treatment arms, and to see which works better for intensive treatment.What patients were included in this trial?
This trial included patients between 1 and 21 years of age, with neuroblastoma that has spread somewhere else in the body, and did not respond well or well enough to initial standard chemotherapy. The median age of patients recruited to this trial was 3 years and 8 months. Of the patients who took part in this trial 19 were male (12 in Arm A and 7 in Arm B) and 15 were female (6 in Arm A and 9 in Arm B).
Patients on this trial also had to be mIBG positive, have adequate organ function and agree to inpatient treatment at a specialist centre.
Which medicines were studied?
Patients on the trial were randomised to receive either 131I-mIBG and topotecan or high dose thiotepa. 131I-mIBG is a radioactive drug which is taken up by and kills neuroblastoma cells. Topotecan works by stopping the chemical which repairs DNA, thereby stopping the tumour cells growing and multiplying, and can make mIBG more effective. Thiotepa interferes with the proteins involved in DNA replication, thereby stopping the tumour cells multiplying.
What were the side effects?
Serious Adverse Events (SAEs) were reported while patients were on trial treatment and for 30 days after they finished treatment. SAEs include any untoward medical occurrences that result in patients being admitted to hospital, are life threatening, result in death, cause long term or significant disability or incapacity or cause birth defects.
Hospitalisations for protocol treatment, events/treatment relating directly to the patients relapse/progression, elective procedures (unless brought forward because of worsening symptoms) or for social reasons (e.g. respite care) were not reported as SAEs.
32 SAEs were reported which were considered related to trial therapy. 0 of these SAEs resulted in death. The most common SAEs reported were 6 instances of decreased lymphocyte count with fever (febrile neutropenia), 4 in Arm A and 2 in Arm B and6 instances of veno occlusive disease (a condition in which some of the veins in the liver become blocked), 3 in each arm.
This trial also collected Adverse Events (AE). These are medical occurrences that are unfavourable and an unintended sign, symptom or disease temporally associated with the use of a drug. AEs include events both related and unrelated to trial treatment. Throughout the trial 27/ 34 patients recruited reported side effects: 15 patients on Arm A and 12 patients on Arm B. There were a total of 87 AE instances reported.The most common AE reported was a decrease in white blood cells, which can increase the risk of developing infections. A reduction in lymphocytes (a type of white blood cell) was reported in 8 instances: 6 instances in patients on Arm A and 2 instances in patients on Arm B. A reduction of neutrophils (another type of white blood cell) accompanied by fever was reported in 14 instances: 5 instances in Arm A and 9 instances in Arm B. Other reported AEs included abdominal pain, reported in 11 instances: 4 in Arm A and 7 in Arm B; and veno occlusive disease (a condition in which some of the veins in the liver become blocked) reported in 5 instances: 3 in Arm A and 2 in Arm B.
What were the overall results of the study?
30/34 patients completed the treatment. 21/30 patients could be evaluated for the disease response after treatment, 11 on Arm A and 10 on Arm B. 1/21 patient (5%) suffered a relapse or progression after treatment (0/11 (0%) Arm A, 1/10 (10%) Arm B). The remainder of patients either showed no change (stable disease) or an improvement (minor response, partial response or complete response) in the disease. There was little difference in the response in the disease after treatment with Arm A compared to Arm B (11/11 were CR, PR, MR or SD in Arm A, 9/10 were CR, PR, MR or SD in Arm B).
The study did not recruit enough participants to be able to demonstrate which treatment has more effect on the disease, or which causes more side effects. Recruitment to the study was stopped in Dec 2022, after the supply of the study drug 131I-mIBG was interrupted in all countries. The recruitment was not reopened once the supply issue was resolved. The Sponsor made the decision to close the trial on 3rd July 2023, due to the low number of participants enrolled. This was attributed partly to delays caused by the COVID-19 pandemic, difficulties reported by recruiting sites in obtaining 131I-mIBG, poor data reporting by sites and also complexities in organizing patient care at the limited trial treatment centres able to carry out the 131I-mIBG treatment.
The intensified consolidation approach was feasible and well tolerated by patients with very-high risk neuroblastoma. The preliminary analyses seem to show a global increase in survival rate compared to historical controls.How has this study helped patients and researchers?
VERITAS has contributed to the evaluation of the benefits related to an intensified consolidation approach in children with very high-risk neuroblastoma. The treatment response will be correlated with clinical and biological features, thus improving our global knowledge of neuroblastoma.
The study has helped inform the design of future studies within this disease area and including radiotherapy. Challenges in radiopharmacy supply and specialised treatment centres have been identified which will be taken into account for future studies.
Are there plans for further studies?
A treatment arm with tandem high-dose chemotherapy is now available for patients with insufficient metastasis response at the end of induction in HR-NBL2 trial. The results of the MINIVAN trial (UK) will add more data to inform the need for future clinical trials including therapeutic MIBG-based approaches.
Where can I find more information about this study?
To learn about this study, you can find more detailed information on the website Clinicaltrials.gov https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fclinicaltrials.gov%252Fstudy%252FNCT03165292%253Ftitles%253DVERITAS%2526page%253D2%2526rank%253D12%2FNBTI%2Fgr24AQ%2FAQ%2Fbfc76095-b2b5-4ce6-babe-b23a94b88d54%2F2%2FKr8p7EziEI&data=05%7C02%7Cedgbaston.rec%40hra.nhs.uk%7Cb887ed2b72144bb5b58f08dceeb3299f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638647700468365623%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=tIdlebYU9evzuW9pZB3BokRzWCjkkNnJ1U8x49zkJTU%3D&reserved=0
A summary is also provided on the Cancer Research UK website.
https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fwww.cancerresearchuk.org%252Fabout-cancer%252Ffind-a-clinical-trial%252Fa-trial-looking-at-two-different-types-intensive-treatment-neuroblastoma-that-has-spread-veritas%2FNBTI%2Fgr24AQ%2FAQ%2Fbfc76095-b2b5-4ce6-babe-b23a94b88d54%2F3%2FXbVZGHAs3K&data=05%7C02%7Cedgbaston.rec%40hra.nhs.uk%7Cb887ed2b72144bb5b58f08dceeb3299f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638647700468379302%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=2TPQfvmlhA1Di9hZHH7HZ2ka1x4ikrEQIQX79VKcduI%3D&reserved=0REC name
West Midlands - Edgbaston Research Ethics Committee
REC reference
19/WM/0143
Date of REC Opinion
14 Jun 2019
REC opinion
Further Information Favourable Opinion