The efficacy and safety of the addition of bevacizumab to conventional induction chemotherapy in high-risk neuroblastoma-: a multicentric randomized controlled phase-3 trial (BRAVEN Trial)
Trial Acronym
BRAVEN Trial
Secondary IDs if Any
Secondary ID
Identifier
NIL
NIL
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr Jagdish Prasad Meena
Designation
Additional Professor
Affiliation
All India Institue of Medical Sciences, New Delhi
Address
Room No 832, 8th Floor, Department of Pediatrics, Mother and Child Blcok, All India Institute of Medical Sciences, New Delhi
New Delhi DELHI 110029 India
Phone
8890139358
Fax
Email
drjpmeena@gmail.com
Details of Contact Person Scientific Query
Name
Dr Jagdish Prasad Meena
Designation
Aditional Professor
Affiliation
All India Institute of Medical sciences, New Delhi
Address
Room No 832, 8th Floor, Department of Pediatrics, Mother and Child Blcok, All India Institute of Medical sciences, New Delhi
New Delhi DELHI 110029 India
Phone
8890139358
Fax
Email
drjpmeena@gmail.com
Details of Contact Person Public Query
Name
Dr Jagdish Prasad Meena
Designation
Additional Professor
Affiliation
All India Institute of Medical sciences, New Delhi
Address
Room No 832, 8th Floor, Department of Pediatrics, Mother and Child Blcok, All India Institute of Medical sciences, New Delhi
New Delhi DELHI 110029 India
Phone
8890139358
Fax
Email
drjpmeena@gmail.com
Source of Monetary or Material Support
Indian Council of Medical Research (ICMR)
Primary Sponsor
Name
Indian Council of Medical Research (ICMR)
Address
Indian Council of Medical Research, V. Ramalingaswami Bhawan, PO Box No. 4911 Ansari Nagar, New Delhi - 110029, India
All India Institute of Medical Sciences (AIIMS), Bhopal
Dr Narendra Chaudhary, Additional Professor, Division of Pediatric Hematology Oncology, All India Institute of Medical Sciences (AIIMS), AIIMS Campus Rd, AIIMS Campus, Saket Nagar, Habib Ganj, Bhopal, Madhya Pradesh 462026 Bhopal MADHYA PRADESH
9443350635
drnarendrapgi@rocketmail.com
Dr Debasish Sahoo
All India Institute of Medical Sciences (AIIMS), Bhubaneswar
Dr Debasish Sahoo, Assistant Professor, Division of Pediatric Hematology Oncology, Department of Medical Oncology, Room no 119, OPD Block, First Floor, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, Orissa, 751019 Khordha ORISSA
8872028232
debasish0712@gmail.com
Dr Jagdish Prasad Meena
All India Institute of Medical Sciences (AIIMS), Delhi
Dr Jagdish Prasad Meena, Room no 832, 8th Floor, Mother and Child Block, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Ansari Nagar, Delhi, 110029 New Delhi DELHI
8890139358
drjpmeena@gmail.com
Dr Shilpa Khanna
Atal Bihari Vajpayee Institute of Medical Sciences and Dr RML Hospital, New Delhi
Dr Shilpa Khanna Arora, Professor, Department of Pediatrics, Room no 201, 2nd Floor, Guest House Building, Atal Bihari Vajpayee Institute of Medical Sciences and Dr RML Hospital, New Delhi, 110001 New Delhi DELHI
9810068078
drshilpakhanna@yahoo.co.in
Dr Maharshi Trivedi
Gujrat Cancer Society(GCS) & Gujrat Cancer & Research Institute(GCRI)
Institute of Medical Sciences, Banaras Hindu University Varanasi
Dr Vineeta Gupta,
Professor & In charge,
Division of Pediatric Hematology-Oncology/BMT Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University Varanasi - 221005
Varanasi UTTAR PRADESH
09415336804
vineetaguptabhu@gmail.com
Dr Nishant Verma
King George Medical University (KGMU), Lucknow
Dr Nishant Verma, Additional Professor, Ground Floor, Department of Pediatrics, King George Medical University (KGMU), Shahmina Road, Lucknow, Uttar Pradesh, 226003 Lucknow UTTAR PRADESH
8765806252
drnishantaiims@gmail.com
Prof Nidhi Chopra and Dr Prashant Prabhakar
Vadhman Mahavir Medical College and Safdarjung Hospital, New Delhi
Dr Nidhi Chopra, Associate Professor and Specialist, Department of Pediatrics, Faculty Room, 2nd Floor, Vadhman Mahavir Medical College and Safdarjung Hospital, New Delhi 110029 New Delhi DELHI
Institute Ethics Committee All India Institute of Medical Sciences Old OT Block, Room No. 102, AIIMS Hospital Ansari Nagar, New Delhi-29 New Delhi South Delhi Delhi
Approved
Gujrat Cancer & Research Institute(GCRI) & Gujrat Cancer Society(GCS) Ethics Committee
Approved
Institutional Ethics Committe,Vardhman Mahavir Medical College and Safdarjung Hospital
Institutional Ethics Committee, Institute of Medical Sciences, Banaras Hindu University Varanasi - 221005
Approved
Institutional Ethics Committee, King Georges Medical University (KGMU), Lucknow - 226003 (UP) India
Approved
Institutional Human Ethics Committee,All India Institute of Medical Sciences Bhopal, Saket Nagar, Bhopal 462 020 Madhya Pradesh, India
Approved
The Institutional Ethics Committee, ABVIMS, DR. RML Hospital, New Delhi
Approved
Regulatory Clearance Status from DCGI
Status
Not Applicable
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: D499||Neoplasm of unspecified behavior of unspecified site,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Bevacizumab arm
This group of patients will receive bevacizumab every two weekly for a total of six doses in addition to conventional induction chemotherapy. The conventional chemotherapy will consist of 8 cycles of Rapid COJEC.
Comparator Agent
Control arm
This group of patients will receive conventional induction chemotherapy. The conventional chemotherapy will consist of 8 cycles of Rapid COJEC.
Inclusion Criteria
Age From
1.00 Day(s)
Age To
18.00 Year(s)
Gender
Both
Details
Children of ≤18 years of age with newly diagnosed high-risk neuroblastoma (HR-NB) will be invited to participate after informed consent
ExclusionCriteria
Details
1. Relapsed cases of neuroblastoma
2. Patients with severe organ dysfunction
3. Known human immunodeficiency virus (HIV), hepatitis B, or hepatitis C virus infection
4. Prior anti-tumor treatment
5. Previous malignant tumours
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
An Open list of random numbers
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
To evaluate the efficacy (O) of the addition of bevacizumab (I) to conventional induction chemotherapy in high-risk neuroblastoma patients (P) compared to conventional induction chemotherapy alone (C)
3-month
Secondary Outcome
Outcome
TimePoints
To investigate the toxicity profile (O) of the bevacizumab addition to the conventional induction chemotherapy (I) compared to induction chemotherapy alone (C) in high-risk neuroblastoma patients (P).
3-month
To compare the minimal residual disease in blood and bone marrow at the end of induction, both groups
3-month
Target Sample Size
Total Sample Size="162" Sample Size from India="162" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Phase of Trial
Phase 3
Date of First Enrollment (India)
01/01/2025
Date of Study Completion (India)
Applicable only for Completed/Terminated trials
Date of First Enrollment (Global)
Date Missing
Date of Study Completion (Global)
Applicable only for Completed/Terminated trials
Estimated Duration of Trial
Years="3" Months="0" Days="0"
Recruitment Status of Trial (Global)
Not Applicable
Recruitment Status of Trial (India)
Not Yet Recruiting
Publication Details
N/A
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - YES
What data in particular will be shared? Response - Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices).
What additional supporting information will be shared? Response - Study Protocol Response - Statistical Analysis Plan Response - Informed Consent Form
Who will be able to view these files? Response - Researchers whose proposed use of the data has been approved by an independent review committee identified for this purpose.
For what types of analyses will this data be available? Response - For individual participant data meta-analysis.
By what mechanism will data be made available? Response (Others) - A link will be provided to view the data.
For how long will this data be available start date provided 01-01-2029 and end date provided 30-12-2033? Response - Beginning 3 months and ending 5 years following article publication.
Any URL or additional information regarding plan/policy for sharing IPD? Additional Information - NIL
Brief Summary
Despite the use of an intensive multimodal approach, combining induction with multi-agent therapy, the 5-year event-free survival (EFS) rates are dismal. The majority of HR-NB patients do not achieve complete response (CR) and 15%–20% develop refractory and early progressive disease (PD) (Stram et al, 1996). Therefore, the induction regimen is the most critical step in the treatment of HR-NB, because resistant clones may arise during induction, and the persistence of residual resistant disease poses a significant problem (Pearson et al, 1992). Further dose escalation of induction chemotherapy and MAC consolidation followed by auto-HSCT will be limited by toxicity (Dufour 2008). Moreover, extended chemotherapy does not improve the survival outcomes in HR-NB (Berthold et al, 2020). Hence, it is important to evaluate the efficacy and toxicity of adding a new tumor-targeted treatment for HR-NB.
The pro-angiogenic vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are thought to play an important role in the start of tumour angiogenesis (Ferrara et al, 2003). Angiogenesis is a key regulator of NB growth, and tumour vascularity is associated with high-risk illness (Peddinti et al, 2007). Expression of VEGF and VEGFR correlates with a higher stage of NB (Komuro et al, 2001) (Sköldenberg et al, 2009). Bevacizumab is a humanized monoclonal VEGF-neutralizing antibody, which was approved by the Food and Drug Administration (FDA) in 2004 for the treatment of metastatic malignancy treatment regimens (Hurwitz 2005), which has revolutionised the therapy paradigm by enhancing overall and/or progression-free survival, making it the standard of care for a variety of advanced malignancies (Garcia et al, 2020).
§Recently, the ITCC-SIOPEN BEACON-Neuroblastoma Trial (age 1-21 years) reported improved overall response rate (ORR) and progression-free survival (PFS) (n=106) with the addition of bevacizumab in relapsed/refractory NB in phase-2 study (Moreno et al, 2017). The BERNIE study evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic soft tissue sarcoma (age 6 months to <18 years) (n=154) and observed that the addition of bevacizumab to chemotherapy was tolerable in patients with metastatic soft tissue sarcoma. There were no treatment-related deaths and no increased incidence of grade 3/4 toxicities with bevacizumab (Chisholm et al, 2017). In another study, De Pasquale et al used bevacizumab in 17 pediatric patients with high-risk malignancies (n=4, stage IV NB) (De Pasquale et al 2011). Modak et al reported a safety profile of bevacizumab in children with refractory/relapsed NB in combination with irinotecan, and temozolomide (Modak et al, 2017).
The main objective of the present study is to investigate an anti-angio-invasive drug with induction regimen in combination. This study aims to evaluate the efficacy and safety of the addition of bevacizumab to conventional induction chemotherapy in patients with high-risk neuroblastoma.