Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

RATIONALE: Radioisotope therapy, such as iobenguane I 131, releases radiation that kills tumor cells. Drugs used in chemotherapy, such as carboplatin, etoposide, busulfan, and melphalan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. A peripheral stem cell transplant may be able to replace blood-forming cells that are destroyed by iobenguane I 131 and chemotherapy.

PURPOSE: This clinical trial is studying induction therapy followed by iobenguane I 131 and chemotherapy in treating patients with newly diagnosed high-risk neuroblastoma undergoing stem cell transplant, radiation therapy, and maintenance therapy with isotretinoin.

Further Study Information

OBJECTIVES:

Primary

• To assess the feasibility of treating high-risk neuroblastoma patients, age 365 days to 30 years, with an induction block of meta-iodobenzylguanidine labeled with iodine-131 (^131I-MIBG)/irinotecan/vincristine delivered after multi-agent chemotherapy, and post-Induction busulfan/melphalan consolidation therapy.

Secondary

• To assess the tolerability of these regimens in these patients.

• To assess the response rate of patients treated with these regimens.

• To describe the relationship of tumor norepinephrine transporter (hNET) expression with ^131I-MIBG uptake at diagnosis and immediately after ^131I-MIBG therapy, and tumor response.

• To assess the relative reliability of ^123 I-MIBG and 18FDG-PET imaging in assessment of tumor activity at diagnosis, after 2 courses of induction chemotherapy, before surgical resection and ^131I-MIBG.

• To compare detectable tumor burden before and immediate after therapy on the ^123I-MIBG diagnostic scan.

• To test for the relationship of occurrence of sinusoidal obstruction syndrome (SOS) to dosages of myeloablative consolidation therapy with busulfan/melphalan and whole-body radiation dose or delay of radiation clearance due to^131I-MIBG.

• To analyze busulfan first-dose pharmacokinetics as measured by area under the curve (AUC) and to relate exposure to SOS incidence.

• To describe the toxicity of ^131I-MIBG combined with vincristine and irinotecan given on a 5-day schedule.

OUTLINE: This is a pilot, multicenter study.

• Induction chemotherapy: Patients receive 5 courses of induction therapy.

• Courses 1-2: Patients receive cyclophosphamide IV over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5.

Patients undergo peripheral blood stem cell (PBSC) collection after course 2.

• Course 3 and 5: Patients receive cisplatin IV over 1 hour on days 1-4 and etoposide phosphate IV over 1-2 hours on days 1-3.

Patients undergo surgery to remove remaining tumor following course 5.

• Course 4: Patients receive cyclophosphamide IV over 1-6 hours on days 1-2 and vincristine sulfate IV and doxorubicin hydrochloride IV over 24 hours on days 1-3.

Treatment repeats every 21 days for a total of 5 courses in the absence of disease progression or unacceptable toxicity. Patients without progressive disease proceed to iobenguane I 131 (^131I-MIBG) induction therapy beginning 3-6 weeks after course 5.

• Patients receive vincristine IV on day 0, irinotecan IV over 90 minutes on day 0-4, and iobenguane I 131 IV over 90-120 minutes on day 1.

• Surgery: Patients ùundergo surgery after course 4 or before consolidation therapy.

• Consolidation therapy: Within 4-6 weeks after completion of induction therapy, patients receive busulfan IV over 2 hours every 6 hours on days -6 to -3 and melphalan IV on day -1.

Patients also complete a questionnaire regarding costs for travel and accommodations during therapy.

Blood samples maybe collected after the first dose of busulfan for pharmacokinetic assays.

• Autologous stem cell rescue: Patients undergo infusion of PBSC on day 0.

• Radiotherapy: Beginning 28-42 days after peripheral blood stem cell infusion, patients undergo 12 fractions of external-beam radiotherapy (2D, 3D-conformal, or intensity-modulated) to all areas of residual disease, primary tumor site, and involved nodal disease.

• Maintenance therapy: Beginning 66 days after transplantation, patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for 6 courses.

After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for 4 years, and then annually for 5 years.

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of neuroblastoma (ICD-O morphology 9500/3) or ganglioneuroblastoma by histology or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites meeting 1 of the following staging criteria:

• Newly diagnosed International Neuroblastoma Staging System (INSS) stage 4 disease meeting 1 of the following criteria:

• MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals) and age ≥ 365 days regardless of additional biologic features

• Age > 18 months (> 547 days) regardless of biologic features

• Age 12-18 months (365-547 days) with any of the following 3 unfavorable biologic features: MYCN amplification, unfavorable pathology, and/or DNA index = 1, or any biologic feature that is indeterminant, unsatisfactory, or unknown

• Newly diagnosed INSS stage 3 disease meeting 1 of the following criteria:

• MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals) and age ≥ 365 days, regardless of additional biologic features

• Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status

• Newly diagnosed INSS stage 2a/2b with MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals) and age ≥ 365 days, regardless of additional biologic features

• Age ≥ 365 days initially diagnosed with INSS stage 1, 2, or 4S who progressed (within the past 4 weeks) to a stage 4 without interval chemotherapy

• No patients aged 12-18 months with INSS stage 4 and all 3 favorable biologic features (i.e., non-amplified MYCN, favorable pathology, and DNA index > 1)

• Must be enrolled onto ANBL00B1 biologic study

• Must have ≥ 1 "MIBG-avid target lesion" present on MIBG scan in the past 4 weeks

PATIENT CHARACTERISTICS:

• Total bilirubin ≤1.5 times upper limit of normal (ULN)

• AST or ALT ≤ 10 times ULN

• Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on age and/or gender as follows:

• ≤ 0.6 mg/dL (1 to < 2 years of age)

• ≤ 0.8 mg/dL (2 to < 6 years of age)

• ≤ 1.0 mg/dL (6 to < 10 years of age)

• ≤ 1.2 mg/dL (10 to < 13 years of age)

• ≤ 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)

• ≤ 1.7 mg/dL (male) or 1.4 mg/dL (female) ( ≥ 16 years of age)

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Shortening fraction ≥ 27% by ECHO OR ejection fraction ≥ 50% by radionuclide evaluation

• Able to tolerate peripheral blood stem cell (PBSC) collection

• No contraindications to PBSC collection including weight, size, or physical condition that would preclude apheresis

PRIOR CONCURRENT THERAPY:

• No prior systemic therapy

• Localized emergency radiotherapy to sites of life-threatening or function-threatening disease and ≥ 1 measurable lesion is not irradiated

• No more than 1 course of chemotherapy per low- or intermediate-risk neuroblastoma therapy before determination of MYCN amplification and histology

• No local radiotherapy that includes any of the following:

• 1,200 cGy to more than 33% of both kidneys

• Patient must have ≥ 1 kidney that has not exceeded the dose/volume of radiation listed

• 1,800 cGy to more than 30% of liver and/or 900 cGy to more than 50% of liver

• No other concurrent cancer chemotherapy or immunomodulating agents (including steroids)

Trial Contact Information

Trial Lead Organizations/Sponsors

Children's Oncology Group

Brian Weiss

Principal Investigator

U.S.A.
Alabama
	Birmingham
	UAB Comprehensive Cancer Center
		Alyssa T Reddy	Ph: 205-934-0309

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01175356
Information obtained from ClinicalTrials.gov on April 04, 2013

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