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

• Conditions: euroblastoma; MedDRA version: 16.1Level: LLTClassification code 10029261Term: Neuroblastoma NOSSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

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

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2014-04-03
• Last Update Posted: 4 August 2015

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 120

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 eligibility assessment):
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 > 7.5 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 > 7.5 g/dL (transfusions allowed)
• Renal function (within 72 hours of eligibility assessment):
o Absence of clinically significant proteinuria (early morning urine dipstick =2+). When the dipstick urinalysis shows a proteinuria > 2+, a protein:creatinine (Pr/Cr) ration 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) must be = 60 ml/min/1.73 m2
• Liver function (within 72 hours of eligibility assessment): AST and ALT =2.5 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, shortening fraction =29% on echocardiogram
• Coagulation, patients not on anticoagulation must have an INR =1.5 and APTT =1.5 ULN for age. Anticoagulation 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 effective contraceptive method, for the duration of study therapy and for up to 6 months after the last dose of trial drugs. A negative urine pregnancy test must be obtained within 72 hours prior to dosing in females who are post-menarche

Are the trial subjects under 18? yes
Number of subjects for this age range: 116
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 4
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

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
• 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 eligibility assessment):
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 or MIBG therapy and two weeks from radiotherapy to the tumour bed
o Eight weeks from prior myeloablative therapy with haempoietic stem cell rescue (autologous stem cell transplant)
o Three months from prior allogeneic stem cell transplant
o Two weeks from last administration of an IMP in an IMP-trial
• 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 eligibility assessment
• 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
• 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

Study & Design

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

Primary Outcome Measures

Name	Time	Method
Main Objective: - To test whether bevacizumab added to a backbone chemotherapy regimen (temozolomide or irinotecan-temozolomide) demonstrates activity in children with relapsed or refractory neuroblastoma<br><br>- To test whether the addition of irinotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma;Secondary Objective: 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. ;Primary end point(s): Best response (Complete Response [CR], or Partial Response [PR]) at any time during the 6 cycles of trial treatment.;Timepoint(s) of evaluation of this end point: Response will be assessed after 2, 4 and 6 cycles of trial treatment.