Irinotecan and Temozolomide in Treating Young Patients With Recurrent Neuroblastoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as irinotecan and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving irinotecan together with temozolomide works in treating young patients with recurrent neuroblastoma.

Detailed Description
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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.

Official Title
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A Phase II Study of Irinotecan + Temozolomide in Children With Recurrent Neuroblastoma

Conditions
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Neuroblastoma

Intervention / Treatment
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* Drug: irinotecan hydrochloride
* Drug: temozolomide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Disease measurable by CT or MRI scan (Irinotecan/Temozolomide)<br>Measurable by CT scan (Computed Tomography) or MRI scan (Magnetic Resonance Imaging). Patients receive irinotecan hydrochloride IV (10 mg/m2/dose) over 1 hour on days 1-5 and 8-12 and oral temozolomide (100 mg/m2/dose) on days 1-5. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: NSC #616348;Drug: temozolomide<br>* Given IV<br>* Other names: NSC #362856;|
| Experimental: Disease eval by bone marrow or MIBG (Irinotecan/Temozolomide)<br>Evaluation by bone marrow or MIBG scan (metaiodobenzylguanidine scan, a radiopharmaceutical). Patients receive irinotecan hydrochloride IV (10 mg/m2/dose) over 1 hour on days 1-5 and 8-12 and oral temozolomide (100 mg/m2/dose) on days 1-5. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: NSC #616348;Drug: temozolomide<br>* Given IV<br>* Other names: NSC #362856;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response - Complete Response (CR), Very Good Partial Response (VGPR) and Partial Response (PR) | The patient's best overall response obtained during Reporting Periods 1 and 2 will be scored as best response. Patients enrolled on Stratum 1 with bone marrow disease, a responder has no tumor cells detectable by routine morphology on 2 subsequent bilateral bone marrow aspirates and biopsies done at least 3 weeks apart. For patients enrolled on stratum 1 with MIBG only disease, response will be assessed using the Curie scale. Patients who have complete resolution of all MIBG positive lesions (CR) or resolution of at least one MIBG positive lesion with persistence of other lesions (PR) will be considered responders. For Stratum 2 a responder is defined to be a patient who achieves a best overall response of CR, VGPR or PR from CT/MRI scans from central review using (RECIST) Response Evaluation Criteria in Solid Tumor. A responder is defined to be a patient who achieves a best overall response of CR (Complete Response), VGPR (Very Good Partial Response) or PR (Partial Response). | up to 6 courses of therapy, or about 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent neuroblastoma