Neuroblastoma, the most common extra-cranial solid tumor of childhood, has poor long-term survival in the 45% of children with high-risk features at diagnosis, despite intensive therapy. Tumor specific therapy is needed to overcome resistance, since maximal dose intensity alone, even with myeloablative therapy, has only modestly improved survival. Objectives: 131I-metaiodobenzylguanidine (131I-MIBG) is similar in structure to norepinephrine and has been shown to concentrate in neuroblastoma and therefore will be tested for cell-specific radiation treatment of this tumor. Hypothesis: 131I-MIBG will produce responses in resistant tumors since it is specifically targeted to the neuroblastoma cells, and can therefore deliver much higher doses of radiation locally than conventional external beam radiotherapy. We further hypothesize that there is a relationship between delivered activity of 131I -MIBG and tumor response in resistant neuroblastoma. Previous studies have been limited by the hematopoietic toxicity and by the radiation safety limits. The dose can be augmented with a double successive infusion supported by hematopoietic stem cells (HSC).
Specific Aims : (1) To determine the maximum tolerated red marrow radiation dose delivered and associated toxicities of escalating activity of 131I-MIBG infused in two consecutive treatments separated by 2 weeks when supported by HSC infusion 2 weeks after the second infusion; (2) to determine engraftment with this regimen; (3) to determine, within the confines of a Phase 1 study, tumor response; (4) to determine, in patients with evaluable lesions, radiation dose to the tumor. (5) To investigate possible correlation of TP53 mutations with response to 131I-MIBG. Design/Methods: The study will be a standard Phase I (3+3) dose escalation open to children with resistant neuroblastoma. Patients will receive 131I -MIBG on day 0 and 14, with HSC rescue on day 28. The first infusion will be based on body weight, while the second will be adjusted to reach the desired total red marrow radiation dose. Three dose levels will be studied, and a maximum of 18 patients accrued from the NANT Consortium institutions. All patients will be studied with whole body dosimetry, and, if evaluable, tumor dosimetry using conjugate planar imaging. Biologic correlations include PCR for minimal bone marrow disease and tumor TP53 mutations. The maximum tolerated red marrow dose will be defined and engraftment, dosimetry, and response correlation described. Significance: The higher tumor-specific radiation doses possible with this protocol may provide a treatment to improve response and survival in children with resistant neuroblastoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA097758-02
Application #
6763972
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Wong, Rosemary S
Project Start
2003-06-20
Project End
2006-05-31
Budget Start
2004-07-06
Budget End
2006-05-31
Support Year
2
Fiscal Year
2004
Total Cost
$261,006
Indirect Cost
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Matthay, Katherine K; George, Rani E; Yu, Alice L (2012) Promising therapeutic targets in neuroblastoma. Clin Cancer Res 18:2740-53
Quach, Alekist; Ji, Lingyun; Mishra, Vikash et al. (2011) Thyroid and hepatic function after high-dose 131 I-metaiodobenzylguanidine (131 I-MIBG) therapy for neuroblastoma. Pediatr Blood Cancer 56:191-201
Taggart, Denah R; Han, Myo M; Quach, Alekist et al. (2009) Comparison of iodine-123 metaiodobenzylguanidine (MIBG) scan and [18F]fluorodeoxyglucose positron emission tomography to evaluate response after iodine-131 MIBG therapy for relapsed neuroblastoma. J Clin Oncol 27:5343-9
Matthay, Katherine K; Quach, Alekist; Huberty, John et al. (2009) Iodine-131--metaiodobenzylguanidine double infusion with autologous stem-cell rescue for neuroblastoma: a new approaches to neuroblastoma therapy phase I study. J Clin Oncol 27:1020-5
Koral, Kenneth F; Huberty, John P; Frame, Bill et al. (2008) Hepatic absorbed radiation dosimetry during I-131 metaiodobenzylguanidine (MIBG) therapy for refractory neuroblastoma. Eur J Nucl Med Mol Imaging 35:2105-12
DuBois, Steven G; Matthay, Katherine K (2008) Radiolabeled metaiodobenzylguanidine for the treatment of neuroblastoma. Nucl Med Biol 35 Suppl 1:S35-48
Howard, James P; Maris, John M; Kersun, Leslie S et al. (2005) Tumor response and toxicity with multiple infusions of high dose 131I-MIBG for refractory neuroblastoma. Pediatr Blood Cancer 44:232-9