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-DE
• Lead Sponsor: The University of Birmingham

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2014-09-25
• Last Update Posted: 28 February 2019

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Not specified
• Target Recruitment: 160

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 10^9/L (unsupported for 72 hours)
? ANC = 0.75 x10^9/L (no G-CSF support for 72 hours)
? Haemoglobin = 7.5 g/dL (transfusions allowed)
o Bone marrow disease:
? Platelets = 50 x10^9/L (unsupported for 72 hours)
? ANC = 0.5 x 10^9/L (no G-CSF for 72 hours)
? Haemoglobin = 7.5 g/dL (transfusions allowed)
• Renal function (within 7 days of randomisation):
o Absence of clinically significant proteinuria (early morning urine dipstick < 2+). When the dipstick urinalysis shows a proteinuria =2+, a protein:creatinine (Pr/Cr) ratio must be < 0.5 or a 24 hour protein excretion must be < 0.5g
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 or ALT = 2.5 ULN and Total bilirubin =1.5 ULN. In case of liver metastases, AST or ALT = 5 ULN and Total bilirubin = 2.5 ULN
• Cardiac function, measured using echocardiogram within 4 weeks of randomisation or 12 weeks if patient has not received anthracyclines or cardiotoxics. Shortening fraction = 29% on echocardiogram
• Coagulation, patients not on anticoagulation must have an INR =1.5 and APTT =1.5 ULN for age. Anti-coagulation is permitted as long as the INR or APTT is within therapeutic limits (according to the medical standard of the institution) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of study enrolment
• Blood pressure below 95th centile for age and sex. Use of antihypertensive medication is permitted
• Males or females of reproductive potential may not participate unless they agree to use an adequate method of birth control, i.e. with a failure rate of less than 1% per year, (e.g. implants, injectables, combined oral contraceptives, IUDs, sexua

Exclusion Criteria

• Previous treatment with bevacizumab, temozolomide, irinotecan or any combination of these drugs
• Known hypersensitivity to:
o Any study drug or component of the formulation
o Chinese hamster ovary products or other recombinant human or humanised antibodies
o Dacarbazine
• Prior severe arterial thrombo-embolic events (e.g. cardiac ischemia, cerebral vascular accident, peripheral arterial thrombosis)
• Any ongoing arterial thrombo-embolic events
• Patient less than (at point of planned date of randomisation):
o 48 hours post bone marrow aspirate/trephine
o 48 hours post central line insertion
o Four weeks post major surgery
o One week post core biopsy
o Two weeks from prior chemotherapy
o Six weeks from prior craniospinal radiotherapy or MIBG therapy and two weeks from radiotherapy to the tumour bed
o Eight weeks from prior myeloablative therapy with haematopoietic stem cell rescue (autologous stem cell transplant)
o Three months from prior allogeneic stem cell transplant
o 14 days or 5 half-lives (whichever occurs later) from last administration of an IMP in an IMP-trial
o Six months from presentation of lung haemorrhage/haemoptysis
• Bleeding metastases (Patients with CNS metastases can be enrolled as long as the metastases are not bleeding)
• Invasion of major blood vessels
• Use of enzyme inducing anticonvulsants within 72 hours of randomisation
• 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
• Current chronic intestinal inflammatory disease/bowel obstruction
• Intolerance to galactose and fructose, lactase deficiency, and/or defect of absorption of galactose and fructose
• Pregnant or lactating patient
• Any uncontrolled medical condition that poses an additional risk to the patient (i.e. haemoptysis, non-healing, bone fracture, wound/ulcer)
• Low probability of treatment compliance
• Planned immunisation with live vaccine

Study & Design

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