A Phase 1 study of Temozolomide, Irinotecan, and O6BG (O6-Benzylguanine) for Children with Recurrent or Resistant Neuroblastoma

Inclusion Criteria33

• Age - Patients must be 1- 16 years of age at the time of study entry.
• Diagnosis - Patients must have had a diagnosis of neuroblastoma either by histological verification of neuroblastoma and/or demonstration of tumour cells in the bone marrow with increased urinary catecholamines. Participants are not required to have measurable disease at the time of study entry.
• Disease status - Patients must have neuroblastoma with at least ONE of the following:
• Recurrent/progressive disease at any time. A new biopsy of current tumour sites is not required to document eligibility.
• Resistant disease (i.e. less than a partial response to frontline therapy with minimum of 4 cycles of chemotherapy). No new biopsy is required for eligibility for study for this patient group.
• Persistent disease after at least a partial response to frontline therapy (i.e. patient has had at least a partial response to frontline therapy but still has residual disease by MIBG, CT/MRI, or bone marrow). Patients in this category are REQUIRED to have a biopsy of at least one residual site demonstrating viable neuroblastoma. Tumour by routine bone marrow morphology is sufficient for this patient group to verify persistent disease although bone marrow alone is insufficient for eligibility into the study. If biopsy and/or bone marrow aspirate cell detection demonstrates only ganglioneuroma, then patient is not eligible.
• Location of disease - Patients must have at least ONE of the following sites of disease:
• Tumour on MRI or CT scans or X-ray. For patients with persistent disease, as in point (3) above, a biopsy of site seen on CT/MRI must have demonstrated viable neuroblastoma. If the lesion was radiated, then biopsy must be done > 4 weeks after radiation completed.
• MIBG scan with positive uptake at a minimum of one site. For patients with persistent disease, as in point (3) above, a biopsy of an MIBG positive site must demonstrate viable neuroblastoma. If the lesion was irradiated, then biopsy must be done > 4 weeks after radiation completed.
• Bone marrow with tumour cells seen on routine morphology (not by immunocytology staining only) of one bone marrow sample of a bilateral aspirate and/or biopsy.
• Life Expectancy
• Must have a life expectancy of at least 8 weeks.
• Performance level - Performance will be assessed using a Lansky score which must be greater than or equal to 50% for children less than or equal to 16 years of age. Patients who are unable to walk because of paralysis but who are up and in a wheelchair will be considered ambulatory for the purposes of assessing the performance scale.
• Prior Therapy - Patients need to have exhausted standard curative options of therapy.
• There is no limit to the number of prior regimens allowed. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
• Myelosuppressive chemotherapy and/or biologics: 2 weeks
• Autologous stem cell transplant, including non-myeloablative therapy with stem cell support: 6 weeks
• Radiotherapy (XRT): No treatment within 2 weeks of study entry. Six week delays are required following large field radiation (TBI, craniospinal, whole abdomen, total lung, >50% marrow space).
• MIBG therapy: 6 weeks
• Organ Function Requirements
• Adequate Bone Marrow Function Defined as:
• Absolute neutrophil count (ANC) > 1,000/microl
• Platelets > 100,000/microl (transfusion independent, i.e. patients must not have received platelet transfusions within 7 days of enrolment)
• Patients may have bone marrow involvement as long as eligibility criteria met.
• Adequate Renal Function Defined As:
• Serum creatinine <= 1. 5X upper limit of normal
• OR
• A normal serum creatinine based on age.
• Adequate Liver Function Defined As:
• AST and ALT <= 3X upper limit normal
• AND
• total bilirubin <= 1.5X upper limit normal for age
• Regulatory Requirements - All patients and/or their parents or legal guardians must sign a written informed consent. All institutional ethics requirements for human studies must be met prior to patient accrual. A patient, parent and youth information sheet and consent form have been prepared for this study.