BEACON: A randomised phase IIb trial of BEvACizumab added to Temozolomide ± IrinOtecan for children with refractory/relapsed Neuroblastoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

The University Of Birmingham

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 May 2014 → 29 Apr 2026

Decision date (initial)

2024-11-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Cancer Research UK · F. Hoffman-La Roche Ltd · Imagine for Margo · Recordati Rare Disease Ltd · Solving Kids Cancer

External identifiers

EU CT number

2024-518931-12-00

EudraCT number

2012-000072-42

ClinicalTrials.gov

NCT02308527

ISRCTN

ISRCTN40708286

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Pharmacogenomic, Therapy, Safety, Efficacy

- To test whether bevacizumab added to a backbone chemotherapy regimen (temozolomide, irinotecan, temozolomide or
topotecan-temozolomide) demonstrates activity in children with relapsed or refractory neuroblastoma
- To test whether the addition of irinotecan to temozolomide increases the activity of chemotherapy in children with
relapsed or refractory neuroblastoma
- To test whether the addition of topotecan to temozolomide increases the activity of chemotherapy in children with
relapsed or refractory neuroblastoma

Secondary objectives 1

1. To evaluate the safety of the above therapy regimens and to compare how the combinations influence the frequency of relapsing and prolong the survival of treated patients

Conditions and MedDRA coding

Neuroblastoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS) (Brodeur et al. 1988) definition
2. Relapsed or refractory neuroblastoma o Relapsed: any relapsed or progressed high-risk neuroblastoma o Refractory high risk disease: Lack of adequate response to frontline therapy that precludes the patient from proceeding to consolidation therapies (e.g. myeloablative chemotherapy)
3. Measurable disease by cross sectional imaging (RECIST) or evaluable disease (uptake on MIBG scan with or without bone marrow histology). Patients with only bone marrow detectable disease (bone marrow aspirate or trephine) are NOT eligible for the study
4. Age ≥1 to ≤21 years
5. Informed consent from patient, parent or guardian
6. Performance Status: o Lansky ≥ 50%, Karnofsky ≥ 50% or ECOG ≤3 o (Patients 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)
7. Bone marrow function (prior to 72 hours of planed randomisation date): o No bone marrow disease:  Platelets ≥ 75 x 109/L (unsupported for 72 hours)  ANC ≥ 0.75 x 109/L (no G-CSF support for 72 hours)  Haemoglobin > 7.5 g/dL (transfusions allowed) o Bone marrow disease:  Platelets ≥ 50 x109/L (unsupported for 72 hours)  ANC ≥0.5 x 109/L (no G-CSF for 72 hours)  Haemoglobin > 7.5 g/dL (transfusions allowed) Dinutuximab beta arm only: • Bone marrow function (within 72 hours of randomisation): o No bone marrow disease:  Platelets ≥75 x 109/L (unsupported for 72 hours)  ANC ≥ 0.75 x109/L (no G-CSF support for 72 hours)  Haemoglobin ≥ 8 g/dL (transfusions allowed) o Bone marrow disease:  Platelets ≥ 50 x109/L (unsupported for 72 hours)  ANC ≥ 0.5 x 109/L (no G-CSF for 72 hours)  Haemoglobin ≥ 8 g/dL (transfusions allowed)
8. Renal function (prior to 7 days of randomisation date):Serum creatinine ≤ 1.5 ULN for age, if higher, a calculated GFR (radioisotope or 24 hour urine calculated creatinine clearance) must be ≥ 60 ml/min/1.73 m2
9. Liver function (prior to 72 hours of randomisation date): AST or ALT ≤3 ULN and total bilirubin ≤1.5 ULN. In case of liver metastases, AST or ALT ≤5 ULN and total bilirubin ≤2.5 ULN.
10. Cardiac function, measured using echocardiogram prior to 4 weeks of randomisation date or 12 weeks if patient has not received anthracyclines or cardiotoxics. Shortening fraction ≥29% on echocardiogram
11. Adequate lung function; no dyspnoea at rest and pulse oximetry > 94% in room air
12. Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to initiation of treatment. Sexually active women of childbearing potential must agree to use acceptable and appropriate contraception during the study and for at least 6 months after the last study treatment administration. Sexually active males patients must agree to use condom during the study and for at least 6 months after the last study treatment administration.
13. Availability and willingness to place a double central venous access if needed for trial treatment and supportive care in case of treatment with chemo-immunotherapy

Exclusion criteria 14

1. Previous treatment with temozolomide drugs
2. Previous treatment with chemotherapy in combination with anti-GD2 directed therapy (“chemo-immunotherapy”) with any anti-GD2 antibody. Prior treatment with anti-GD2 directed therapy alone with/without cytokines is allowed provided a 4 week wash-out period is met
3. Known hypersensitivity to: o Any study drug or component of the formulation
4. Patients with mild previous hypersensitivity reactions to anti-GD2 antibodies may be included, but those with severe (or G4) hypersensitivity reactions to antiGD2 antibodies will be excluded Clinically significant neurological deficit, uncontrolled seizures or objective peripheral neuropathy (>grade 2). (Unresolved neurological deficits from previous spinal cord compression are acceptable)
5. Uncontrolled infection
6. Inadequate recovery from prior surgery with no ongoing ≥Grade 3 surgical complications. For core biopsies, no less than 24 hours; for open excisional biopsies, no less than 48 hours; for major surgery, no less than 2 weeks Patient less than (at point of planned date of randomisation):  Two weeks from prior chemotherapy. One week from prior oral metronomic chemotherapy (i.e. oral etoposide or oral cyclophosphamide).Six weeks from prior craniospinal radiotherapy or MIBG therapy and two weeks from radiotherapy to the tumour bed. No washout is required for palliative radiotherapy  Eight weeks from prior high dose chemotherapy with autologous haematopoietic stem cell rescue  Three months from prior allogeneic stem cell transplant, no ongoing treatment with immunosuppressive agents and no signs of ≥grade 2 acute graft versus host disease  14 days or 5 half-lives (whichever occurs later) from last administration of an IMP in an IMP-trial.  14 days or 5 half-lives (whichever occurs later) from last administration of any other biological/targeted anticancer agent
7. Bleeding metastases (Patients with CNS metastases can be enrolled as long as the metastases are not bleeding)  Pregnant or lactating patient  Any uncontrolled medical condition that poses an additional risk to the patient  Low probability of treatment compliance
8. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation) (Bevacizumab randomisation only)
9. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to study enrolment (Bevacizumab randomisation only)
10. Current chronic intestinal inflammatory disease/bowel obstruction (Bevacizumab randomisation only)
11. Known intolerance to galactose and fructose, lactase deficiency, and/or defect of absorption of galactose and fructose (Bevacizumab randomisation only)
12. Pregnant or lactating patient
13. Any uncontrolled medical condition that poses an additional risk to the patient (i.e. haemoptysis, non-healing, bone fracture, wound/ulcer)
14. Low probability of treatment compliance

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Best response (Complete Response [CR], or Partial Response [PR](Brodeur et al. 1988) at any time during the first 6 cycles of trial treatment
2. For the bevacizumab part 2 only: Progression-free survival (PFS)

Secondary endpoints 4

1. Safety of the regimens: Incidence and severity of Adverse Events (AE)
2. PFS
3. Event-free survival (EFS)
4. Overall survival (OS)

Investigational products

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

Test 11

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

The University Of Birmingham

Sponsor organisation

The University Of Birmingham

Address

Vincent Drive

City

Birmingham

Postcode

B15 2TT

Country

United Kingdom

Scientific contact point

Organisation

The University Of Birmingham

Contact name

Trial Coordinator

Public contact point

Organisation

The University Of Birmingham

Contact name

Trial Coordinator

Third parties 3

Locations

5 EU/EEA countries · 19 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 56 files

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

Application history

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