Evaluation of Temozolomide, Topotecan, and Dinutuximab Beta in High-Risk Relapsed Neuroblastoma: A Multi-Arm, Multi-Stage Platform Trial
- Trial ID
- 2024-516115-24-00
- Protocol
- RG_22-136
- Sponsor
- The University Of Birmingham
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the BEACON 2 trial is to test **novel treatments** against the current best available treatment in patients with relapsed **neuroblastoma**. This is clinically relevant as it aims to improve therapeutic outcomes for patients with high-risk relapsed neuroblastoma, a condition characterized by its aggressive nature and poor prognosis. Identifying more effective treatment options could significantly impact survival rates and quality of life for these patients.
Secondary objectives include evaluating the safety of the treatment regimens, assessing the anti-tumor response, and examining longer-term outcomes and quality of life. These objectives are crucial for understanding the broader implications of the novel treatments, ensuring they are not only effective but also safe and beneficial in the long term for patients' overall well-being.
Participants
The clinical trial involves a total of **52 participants** diagnosed with high-risk relapsed **neuroblastoma**, as defined by the International Neuroblastoma Staging System (INSS). The study population includes both male and female subjects, with an age range starting from 1 year and above. Participants were selected based on specific inclusion criteria, including histologically proven neuroblastoma, measurable disease by cross-sectional imaging, and adequate performance and organ function. The trial population is considered vulnerable, and lifestyle factors such as diet and physical activity are not specified. Key health status requirements include normal liver function, controlled blood pressure, and stable coagulation parameters. Participants must have a life expectancy of at least 12 weeks and meet specific bone marrow and renal function criteria. The trial does not specify any particular lifestyle considerations or habits beyond the medical criteria outlined.
Plans and Procedures
The clinical trial is designed to evaluate novel treatments against the current best available treatment for **high-risk relapsed neuroblastoma**. This trial is structured as a multi-arm, multi-stage platform trial, incorporating both phase I and phase II components. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial extends until June 30, 2032, with recruitment anticipated to commence on June 1, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as histologically proven neuroblastoma and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments of progression-free survival, overall survival, and quality of life, among other endpoints. The trial will conclude with an end-of-study visit to evaluate the long-term outcomes and any adverse events experienced during the study.
The expected length of participant involvement in the trial is contingent upon the treatment arm and individual response, with a minimum life expectancy requirement of 12 weeks. Conditions that may lead to early termination from the study include significant disease progression, unacceptable toxicity, or withdrawal of consent. The trial aims to define a safe and tolerable combination regimen and assess the best objective response, clinical benefit, and incidence of adverse events. Participants will be monitored closely to ensure adherence to the protocol and to address any safety concerns promptly.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, routes, and frequencies of administration. **Temozolomide** is utilized in multiple formulations, including a hard capsule and an oral suspension. The hard capsule form of Temozolomide is administered orally, with the frequency of administration determined by the study protocol. The oral suspension, marketed as Kimozo 40 mg/ml, is also administered orally. Both forms contain the active substance Temozolomide, which is of chemical origin. The oral suspension is noted for its cytotoxic properties and is designated as an orphan drug.
**Topotecan** is provided as a powder for concentrate for solution for infusion. This formulation is administered intravenously. The active substance, Topotecan, is of chemical origin, and the administration schedule is defined by the trial protocol to ensure optimal therapeutic outcomes.
**Dinutuximab beta**, marketed as Qarziba 4.5 mg/mL concentrate for solution for infusion, is administered intravenously. This protein-based therapeutic is used in the trial to evaluate its efficacy in the treatment of relapsed neuroblastoma. The administration schedule is carefully monitored to maintain participant safety and compliance.
**Bevacizumab** is provided as a concentrate for solution for infusion and is administered intravenously. The active substance, Bevacizumab, is a protein of other origin. The dosing schedule is determined by the trial protocol, and participant compliance is closely monitored to ensure adherence to the treatment regimen.
**Irinotecan** is also included in the trial as a concentrate for solution for infusion, administered intravenously. The active substance, Irinotecan, is of chemical origin. The trial protocol specifies the dosing schedule, and compliance is monitored to ensure the integrity of the study results.
Throughout the trial, participant compliance with the dosing schedules is monitored through regular assessments and documentation. The trial aims to evaluate the efficacy of these experimental treatments against the current best available treatment for relapsed neuroblastoma, with a focus on safety and therapeutic outcomes.
Efficacy
Efficacy in the clinical trial for relapsed **neuroblastoma** will be assessed using both primary and secondary endpoints. The primary endpoints include Progression-Free Survival time, as defined by the International Neuroblastoma Response Criteria (INRC) 2017, for Tier 1 randomised comparison, and the definition of a safe and tolerable combination regimen for Tier 2 dose expansion-confirmation cohorts. Secondary endpoints encompass a range of measures: Best objective response (complete and partial response) during the trial treatment of 12 cycles, clinical benefit (complete, partial, and minor response and stable disease) as per INRC 2017, time response to progression for responders, overall survival time, quality of life assessed by Peds-QL questionnaires, and the incidence and severity of adverse events (AEs).
The efficacy parameters will be collected and analyzed at specified intervals throughout the trial duration, which is estimated to conclude by June 30, 2032. The trial will employ validated scales and criteria, such as the INRC 2017, to ensure consistent and reliable measurement of outcomes. The quality of life will be specifically measured using the Peds-QL questionnaires, providing a comprehensive assessment of the impact of the treatment on patients' well-being. The trial is designed to rigorously evaluate the efficacy of novel treatments against the current best available treatment in relapsed neuroblastoma, with a focus on both survival outcomes and quality of life.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Disease specific: Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS) definition
- Disease Specific: High risk relapsed neuroblastoma (relapsed or progressed after being defined as High Risk at any time following diagnosis or progressed/relapsed as high-risk neuroblastoma)
- Disease Specific: Measurable disease by cross sectional imaging or evaluable disease (uptake on MIBG or FDG PET/CT/MRI scan with or without bone marrow histology), as per INRC [2, 3]. Participants with only bone marrow detectable disease (bone marrow aspirate or trephine) are NOT eligible for the study
- General: Age ≥1 year
- General: Signed informed consent from participant, parent or guardian
- Performance and organ function: Performance Status - Lansky (for patients ≤12 years of age) or Karnofsky (for those >12) ≥ 50%, (Participants who are unable to walk because of paralysis, but who are able to sit upright unassisted in a wheelchair, will be considered ambulatory for the purpose of assessing performance score)
- Performance and organ function: Life expectancy of ≥12 weeks
- Performance and organ function: Bone marrow function (within 72 hours prior to randomisation) - Platelets ≥ 50 x 109/L (unsupported for 72 hours), ANC ≥ 0.50 x 109/L (no G-CSF support for 72 hours) and Haemoglobin > 8 g/dL (transfusions allowed)
- Performance and organ function: Renal function (within 72 hours prior to randomisation) - Absence of clinically significant proteinuria (either early morning urine dipstick ≤ 2+) or if dipstick urinalysis shows > 2+ proteinuria, protein: creatinine (Pr/Cr) ratio must be < 0.5 or a 24 hour protein excretion must be < 0.5g and Serum creatinine ≤ 1.5 ULN for age, if higher, a measured GFR (radioisotope or 24 hour urine calculated creatinine clearance) must be ≥ 60 ml/min/1.73 m2
- Performance and organ function: Liver function (within 72 hours prior to randomisation) - Absence of clinically significant signs of liver dysfunction. AST or ALT ≤ 3.0 ULN and total bilirubin ≤ 1.5 ULN. In patients with liver metastases, AST or ALT ≤ 5 ULN and total bilirubin ≤ 2.5 ULN is allowed
- Performance and organ function: Coagulation - Participants must not have an active uncontrolled coagulopathy. Anticoagulation is permitted as long as the INR or APTT is within therapeutic limits (according to the medical standard of the institution) and the participant has been on a stable dose of anticoagulants for at least two weeks at the time of study enrolment.
- Performance and organ function: Blood pressure below 95th centile for age and sex. Participants ≥18 years of age should have a blood pressure ≤150/90 mmHg (within 72 hours prior to randomisation). Use of antihypertensive medication is permitted.
- Tier 2 Specific Inclusion Criteria: More than one relapse event or ineligible for Tier 1. NB - The following previous treatments are allowed provided that the principal investigator expects a favourable benefit/risk assessment (e.g. patients could derive potential benefit from the Tier 2 combination): bevacizumab, any anti-GD2 antibody given with chemotherapy (‘chemo-immunotherapy’) and previous treatment with temozolomide with irinotecan
Exclusion Criteria
- Known contraindication or hypersensitivity to: Any study drug or component of the formulation, Chinese hamster ovary products or other recombinant human or humanised antibodies and Participants with mild previous hypersensitivity reactions to anti-GD2 antibodies may be included, but those with severe (or G4) hypersensitivity reactions to anti-GD2 antibodies will be excluded.
- Clinically significant neurological toxicity, uncontrolled seizures or objective peripheral neuropathy (> grade 2). (Unresolved neurological deficits from previous spinal cord compression or surgeries are acceptable). Participants with previous ≥ Grade 3 motor neurotoxicity secondary to anti-GD2 are excluded, even if recovered.
- Prior severe arterial thrombo-embolic events (e.g. cardiac ischemia, cerebral vascular accident, peripheral arterial thrombosis) or any ongoing arterial thrombo-embolic events
- A history of (noninfectious) pneumonitis requiring steroids, or current pneumonitis.
- Patients that are allergic to all therapies for Pnemocystis jirovecii pneumonia and can thus not receive prophylaxis for PJP.
- Uncontrolled infection
- Inadequate recovery from prior surgery with ongoing ≥ Grade 3 surgical complications. Grade ≥ 2 wound dehiscence.
- Recent surgical procedures (at start of trial treatment). Patient can be randomised up to 48hr prior to these periods being completed provided that trial treatment only starts after complying with all of them: Core biopsies within previous 24hr, Open excisional biopsies within previous 48hr, Major surgery within previous 2 weeks, Bone marrow aspirates/trephines, within previous 48hr and Tunnelled central line insertion within previous 48hr
- Washout from prior treatments (at start of trial treatment): Chemotherapy within previous 2 weeks (1 week for oral metronomic chemotherapy regimens), Any anti-GD2 therapy within previous 2 weeks, Craniospinal radiotherapy or MIBG therapy within previous 6 weeks, Radiotherapy to the tumour bed within previous 2 weeks (no washout for palliative radiotherapy), Myeloablative therapy with haematopoietic stem cell rescue (autologous stem cell transplant) within previous 8 weeks, Allogeneic stem cell transplant within previous 12 weeks (with absence of active ≥ G2 acute GVHD) and 14 days or 5 half-lives (whichever occurs later) from last administration of an IMP in an IMP-trial
- Bleeding metastases (participants with CNS metastases can be enrolled as long as the metastases are not bleeding). At least 6 months from any ≥ G3 haemoptysis or pulmonary haemorrhage
- Use of enzyme inducing anticonvulsants within 72hr of start of trial treatment
- Conditions that increase the risk of bevacizumab-related toxicities: History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation), History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to study enrolment and Current chronic intestinal inflammatory disease/bowel obstruction
- Intolerance to galactose and fructose, lactase deficiency, and/or defect of absorption of galactose and fructose
- Males or females of reproductive potential may not participate unless they agree to use a highly effective method of birth control, i.e. with a failure rate of less than 1% per year, (e.g. implants, injectables, combined oral contraceptives, IUDs, sexual abstinence or vasectomised partner), for the duration of study therapy and for up to 6 months after the last dose of trial drugs. A negative urine or serum pregnancy test must be obtained within 72 hours prior to dosing in females who are post-menarche.
- Pregnant or lactating participant
- Live or live-attenuated vaccines given within previous 28 days prior to study enrolment
- Any uncontrolled medical condition that poses an additional risk to the participant
- Tier 1 Specific Exclusion Criteria: More than one relapse event after the start of high risk neuroblastoma therapy
- Tier 1 Specific Exclusion Criteria: Previous treatments that are not allowed - Bevacizumab for relapsed neuroblastoma. Patients who have received BIT for refractory disease are not excluded, providing no progression of disease during this treatment occurred and Treatment with any anti-GD2 antibody given with chemotherapy (‘chemo-immunotherapy’) for treatment of relapsed neuroblastoma. Prior treatment with chemo-immunotherapy for refractory disease is allowed, provided no disease progression during this therapy.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Yet Recruiting | 01 Jun 2025 | 3 |
 Belgium | Not Yet Recruiting | 01 Jun 2025 | 5 |
 Denmark | Recruiting | 01 Jun 2025 | 4 |
 France | Not Yet Recruiting | 01 Jun 2025 | 25 |
 Germany | Not Yet Recruiting | 01 Jun 2025 | 24 |
 Italy | Not Yet Recruiting | 01 Jun 2025 | 7 |
 The Netherlands | Not Yet Recruiting | 01 Jun 2025 | — |
 Norway | Not Yet Recruiting | 01 Jun 2025 | 2 |
 Spain | Not Yet Recruiting | 01 Jun 2025 | 18 |
 Sweden | Not Yet Recruiting | 01 Jun 2025 | 4 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TEMOZOLOMIDE | Test | — | ORAL USE | — | — | SUB10889MIG |
TOPOTECAN | Test | — | INTRAVENOUS USE | — | — | SUB11191MIG |
TEMOZOLOMIDE | Test | — | ORAL USE | — | — | SUB10889MIG |
TEMOZOLOMIDE | Test | — | ORAL USE | — | — | SUB10889MIG |
IRINOTECAN | Test | — | INTRAVENOUS USE | — | — | SUB08295MIG |
TEMOZOLOMIDE | Test | — | ORAL USE | — | — | SUB10889MIG |
TEMOZOLOMIDE | Test | — | ORAL USE | — | — | SUB10889MIG |
Kimozo 40 mg/ml, suspension buvable | Test | SUSPENSION BUVABLE | ORAL USE | — | — | PRD9834544 |
TEMOZOLOMIDE | Test | — | ORAL USE | — | — | SUB10889MIG |
TOPOTECAN | Test | — | INTRAVENOUS USE | — | — | SUB11191MIG |