Irinotecan and Temozolomide in Treating Young Patients With Recurrent Neuroblastoma

OBJECTIVES:

Primary

• Determine the response rate in pediatric patients with relapsed neuroblastoma (NB) treated with irinotecan hydrochloride and temozolomide.
• Determine the toxicities associated with irinotecan and temozolomide in patients treated with this regimen.

Secondary

• Evaluate the impact of p53 loss of function on response rate and event-free survival from start of relapse therapy.
• Collect data for ongoing analyses of UGT1A1 polymorphisms in these patients.
• Collect and bank serum and nucleic acid specimen to facilitate future biomarker studies.
• Evaluate the feasibility of collecting blood samples on a group wide basis for assessment of changes in circulating markers of angiogenesis.
• Assess, preliminarily, the effects of irinotecan hydrochloride and temozolomide on circulating markers of angiogenesis.

OUTLINE: This is a multicenter study.

Patients are stratified according to disease status (measurable disease [measured by conventional CT scan and/or MRI] vs evaluable disease [tumor detected by conventional morphologic analysis of bone marrow aspirate/biopsy AND/OR abnormal uptake at ≥ 1 site on MIBG scan]).

Patients receive irinotecan hydrochloride IV over 1 hour on days 1-5 and 8-12 and oral temozolomide on days 1-5. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 10 years.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed neuroblastoma AND/OR demonstration of tumor cells in the bone marrow with increased urinary catecholamines at initial diagnosis

• Patients with elevated catecholamines only are not eligible
• Meets 1 of the following criteria:

• Recurrent disease following aggressive, multidrug, frontline chemotherapy, defined as chemotherapy given with ≥ 2 agents, including an alkylating agent and a platinum-containing compound
• Resistant/refractory disease during aggressive, multidrug, frontline chemotherapy
• Must meet 1 of the following criteria for documentation of disease:

• Unidimensionally measurable tumor ≥ 20 mm by MRI (Magnetic Resonance Imaging), CT scan (Computed Tomography), or x-ray OR ≥ 10 mm by spiral CT scan within 4 weeks prior to study entry

• Patients with residual stable tumor upon completion of frontline therapy must undergo biopsy to document presence of a viable neuroblastoma
• If the measurable target lesion was previously radiated, a biopsy must be performed ≥ 4 weeks after radiation was completed AND the biopsy must demonstrate viable neuroblastoma
• MIBG scan (metaiodobenzylguanidine scan, a radiopharmaceutical) with positive uptake at ≥ 1 site within 4 weeks prior to study entry

• Patients with residual stable MIBG-positive lesions upon completion of frontline therapy must undergo biopsy to document presence of viable neuroblastoma
• If the patient has only 1 MIBG-positive lesion, and that lesion was previously radiated, a biopsy must be performed ≥ 4 weeks after radiation was completed AND the biopsy must demonstrate viable neuroblastoma
• Bone marrow with tumor cells on routine morphology (not by neuron-specific enolase staining only) of bilateral aspirate and/or biopsy on 1 bone marrow sample within 2 weeks prior to study entry
• No extensive marrow disease
• No myelodysplastic syndrome

PATIENT CHARACTERISTICS:

• Karnofsky performance status (PS) 50-100% (for patients > 16 years of age) OR Lansky PS 50-100% (for patients ≤ 16 years of age)
• Life expectancy ≥ 8 weeks
• Absolute neutrophil count ≥ 750/mm^3
• Platelet count ≥ 75,000/mm^3 (transfusion independent)
• Hemoglobin ≥ 8.5 mg/dL (transfusion allowed)
• Creatinine adjusted according to age as follows:

• No greater than 0.4 mg/dL (≤ 5 months)
• No greater than 0.5 mg/dL (6 months -11 months)
• No greater than 0.6 mg/dL (1 year-23 months)
• No greater than 0.8 mg/dL (2 years-5 years)
• No greater than 1.0 mg/dL (6 years-9 years)
• No greater than 1.2 mg/dL (10 years-12 years)
• No greater than 1.4 mg/dL (13 years and over [female])
• No greater than 1.5 mg/dL (13 years to 15 years [male])
• No greater than 1.7 mg/dL (16 years and over [male]) OR
• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min
• Bilirubin ≤ 1.5 times upper limit of normal (ULN) for age
• ALT < 2.5 times ULN for age
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Seizure disorder allowed provided seizures are well controlled on non-EIAC medication
• No active diarrhea or uncontrolled infection
• No other malignancy, including secondary malignancy

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Prior front-line therapy (e.g., surgery, chemotherapy, immunotherapy, radiotherapy, or retinoids) allowed
• Recovered from prior therapy
• More than 4 weeks since prior radiation therapy to the site of any lesion that will be identified as a target lesion to measure tumor response
• At least 2 weeks since prior myelosuppressive therapy (4 weeks for nitrosourea)
• At least 1 week since prior therapy with an antineoplastic biologic agent or retinoid
• At least 1 week since prior growth factors
• At least 1 week since prior and no other concurrent anticancer agents
• At least 1 week since prior and no concurrent enzyme-inducing anticonvulsants (EIAC), including phenytoin, phenobarbital, valproic acid, or carbamazepine

• Concurrent gabapentin or levetiracetam allowed
• Concurrent palliative radiation therapy to sites not used to measure tumor response allowed
• No prior allogeneic stem cell transplantation (SCT)

• Prior autologous SCT allowed
• No prior second-line chemotherapy for relapsed or refractory disease
• No concurrent immunomodulating agents

• Concurrent steroids for transfusion/infusion reactions or for treatment of edema associated with CNS lesions allowed