Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information
Registry Information

Alternate Title

Double Infusion of Iodine I 131 Metaiodobenzylguanidine Followed by Autologous Stem Cell Transplantation in Treating Patients With Refractory Neuroblastoma

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Treatment Closed 1 to 30 NCI NANT-2000-01 NCT00083135

Objectives

Primary

1. Determine the maximum tolerated red marrow radiation dose delivered and associated toxic effects of escalating activity of iodine I 131 metaiodobenzylguanidine (¹³¹I-MIBG) followed by autologous hematopoietic stem cell transplantation in patients with refractory neuroblastoma.
2. Determine the number of days after stem cell transplantation to achieve absolute neutrophil count ≥ 500/mm³ for 3 days and platelet count ≥ 20,000/mm³ for 3 days (without transfusions) in patients treated with this regimen.

Secondary

1. Determine the response rate in patients treated with this regimen, based on lesions measurable by CT or MRI at study entry, patients with ¹³¹I-MIBG scan-positive lesions only, and patients with minimal residual tumor in bone marrow who have complete response by immunocytology and morphology.
2. Determine the tumor absorbed radiation dose in patients with measurable soft tissue lesions treated with this regimen.
3. Correlate, if possible, TP53 mutations with response in patients with accessible bone marrow tumor treated with ¹³¹I-MIBG.

Entry Criteria

Disease Characteristics:

• Diagnosis of neuroblastoma
  • Confirmed by at least 1 of the following methods:
    • Histology
    • Clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites
  • High-risk disease
    • Poor response to induction therapy OR relapse defined by any of the following:
      • No response, stable disease, or mixed response after a minimum of 3 prior courses of chemotherapy
      • More than 100 tumor cells per 10⁵ nucleated cells on bone marrow immunocytology after at least 3 prior courses of chemotherapy
      • Progressive disease at any time during or after therapy
      • Patients with massive bone marrow invasion (more than 50% replacement of bone marrow by tumor cells) are allowed



• Must have positive iodine I 131 metaiodobenzylguanidine (¹³¹I-MIBG) within the past 6 weeks or subsequent to any other prior antitumor therapy delivered within the past 6 weeks



• Must meet the following criteria for minimum number of autologous stem cells:
  • Unpurged peripheral blood stem cells (PBSC)
    • Minimum of 1,500,000/mm³ CD34-positive cells/kg
    • Collected products must have < 1 tumor cell/100,000 normal cells by immunocytology
  • PBSC purged with immunomagnetic beads
    • Minimum of 1,000,000/mm³ viable CD34-positive cells/kg
    • Collected products must have < 1 tumor cell/100,000 normal cells by immunocytology
  • CD34-positive selected PBSC products are not allowed
  • Patients who had PBSC collected previously with no immunocytological testing available may use those products provided bone marrow is tumor free by bilateral bone marrow aspirate AND biopsy for morphology is performed within 4 weeks before PBSC collection
  • Patients with no tumor involvement in bone marrow at diagnosis and PBSC collection before any disease progression do not require documentation of negative bone marrow morphology

Prior/Concurrent Therapy:

Biologic therapy

• At least 2 weeks since prior biologic or other non-myelosuppressive therapy

Chemotherapy

• See Disease Characteristics
• At least 2 weeks since prior chemotherapy
• More than 3 months since prior myeloablative therapy

Endocrine therapy

• Not specified

Radiotherapy

• See Disease Characteristics
• At least 6 months since prior craniospinal, total abdominal, or whole lung radiotherapy
• At least 2 weeks since prior radiotherapy to any site
• No prior total body irradiation
• No prior radiotherapy to > 25% of bone marrow
• No prior ¹³¹I-MIBG

Surgery

• Not specified

Other

• Recovered from all prior therapy
• Concurrent antifungal therapy allowed provided culture and biopsy are negative in suspected radiographic lesions
• Prior re-induction therapy for recurrent tumor allowed
• No concurrent antiretroviral therapy for HIV-positive patients
• No concurrent hemodialysis

Patient Characteristics:

Age

• 1 to 30

Performance status

• ECOG 0-2

Life expectancy

• Less than 1 year

Hematopoietic

• Absolute neutrophil count ≥ 500/mm³
• Platelet count ≥ 50,000/mm³ (without transfusion)
• Hemoglobin ≥ 8 g/dL (transfusion allowed)

Hepatic

• AST and ALT ≤ 5 times normal
• Bilirubin < 2 times normal

Renal

• Creatinine ≤ 1.5 mg/dL
• Glomerular filtration rate OR 12-hour creatinine clearance ≥ 60 mL/min/1.73m²

Cardiovascular

• Ejection fraction ≥ 55% by echocardiogram or MUGA

  OR

• Fractional shortening ≥ 30% OR above lower limit of normal by echocardiogram

Pulmonary

• Normal lung function
• No dyspnea at rest
• No exercise intolerance
• No oxygen requirement

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Able to cooperate physically and psychologically with radiation isolation
• No disease of any major organ system that would preclude study participation
• No active infection requiring antivirals, antibiotics, or antifungals
• No weight that would require exceeding a maximum total allowable dose of ¹³¹I-MIBG

Expected Enrollment

A total of 9-18 patients will be accrued for this study within 2 years.

Outline

This is a dose-escalation, multicenter study.

• Iodine I 131 metaiodobenzylguanidine (¹³¹I-MIBG) therapy: Patients receive¹³¹I-MIBG IV over 2 hours on days 0 and 14.

  Cohorts of 3-6 patients receive escalating doses of ¹³¹I-MIBG until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.




• Stem cell transplantation therapy: Patients undergo autologous peripheral blood stem cell transplantation on day 28. Patients receive filgrastim (G-CSF) IV over 1 hour OR subcutaneously daily beginning on day 28 and continuing until blood counts recover.

Patients are followed every 3 months for 1 year and then annually thereafter.

Trial Contact Information

Trial Lead Organizations

New Approaches to Neuroblastoma Therapy Consortium

Katherine Matthay, MD, Protocol chair		Ph: 415-476-0603; 800-888-8664
Gregory Yanik, MD, Protocol co-chair		Ph: 734-936-8785; 800-865-1125 Email: gyanik@umich.edu
John Maris, MD, Protocol co-chair		Ph: 215-590-2821 Email: maris@chop.edu

Registry Information
Official Title		I-MIBG Escalating Dose Rapid Sequence Double Infusion Followed By Autologous Stem Cell Infusion For Refractory Neuroblastoma
Trial Start Date		2004-03-24
Registered in ClinicalTrials.gov		NCT00083135
Date Submitted to PDQ		2004-03-23
Information Last Verified		2006-04-19
NCI Grant/Contract Number		CA81403

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