A randomised trial of bevacizumab added to temozolomide with our without irinotecan for children with neuroblastoma that has relapsed, or is resistant to current treatment

Phase 1

• Conditions: euroblastoma; MedDRA version: 20.0 Level: LLT Classification code 10029261 Term: Neuroblastoma NOS System Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2012-000072-42-NL
• Lead Sponsor: The University of Birmingham

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2014-03-19
• Last Update Posted: 16 December 2019

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: Not specified
• Target Recruitment: 224

Inclusion Criteria

Disease specific

• Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS) definition
• 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)
• 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

General

• Age =1 to =21 years
• Informed consent from patient, parent or guardian

Performance and organ function

• Performance Status:
o Lansky = 50%, Karnofsky = 50% or ECOG =3
(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)
• Life expectancy of =12 weeks
• Bone marrow function (within 72 hours of randomisation):
o No bone marrow disease:
? Platelets = 75 x 10e9/L (unsupported for 72 hours)
? ANC = 0.75 x 10e9/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 10e9/L (no G-CSF for 72 hours)
? Haemaglobin = 8 g/dL (transfusions allowed)
• Renal function (within 7 days of randomisation):
o 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
• Liver function (within 72 hours of randomisation): AST and ALT =3 ULN and total bilirubin =1.5 ULN. In case of liver metastases, AST and ALT =5 ULN and total bilirubin =2.5 ULN
• Cardiac function measured by echocardiogram within 4 weeks of randomization or within 12 weeks if the patient has not received anthracyclines or cardiotoxics in between, shortening fraction =29% on echocardiogram
• Adequate lung function: no dyspnea at rest and pulse oximetry > 94% in room air
• 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 male patients must agree to use condoms during the study for at least 6 months after the last study treatment administration.
• 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

Are the trial subjects under 18? yes
Number of subjects

Exclusion Criteria

• Previous treatment with temozolomide
• 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
• Known hypersensitivity to:
o Any study drug or component of the formulation
o Patients 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 deficit, uncontrolled seizures or objective peripheral neuropathy ( >grade 2). (Unresolved neurological deficits from spinal cord compression are acceptable)
• Uncontrolled infection
• 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):
o Two weeks from prior chemotherapy. One week from prior oral metronomic chemotherapy (i.e. oral etoposide or oral cyclophosphamide)
o 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.
o Eight weeks from prior high dose chemotherapy with autologous haempoietic stem cell rescue
o 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
o 14 days or 5 half-lives (whichever occurs later) from last administration of an IMP in an IMP-trial
o 14 days or 5 half-lives (whichever occurs later) from last administration of any other biological/targeted anticancer agent
• 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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified