Induction Therapy Including 131 I-MIBG and Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma Undergoing Stem Cell Transplant, Radiation Therapy, and Maintenance Therapy With Isotretinoin

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Children's Oncology Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT01175356
First received: August 3, 2010
Last updated: April 23, 2014
Last verified: April 2014
  Purpose

This clinical trial is studying induction therapy followed by meta-iodobenzylguanidine (MIBG) labeled with iodine-131 and chemotherapy in treating patients with newly diagnosed high-risk neuroblastoma undergoing stem cell transplant, radiation therapy, and maintenance therapy with isotretinoin. Radioisotope therapy, such as MIBG labeled with iodine-131, releases radiation that kills tumor cells. Drugs used in chemotherapy, such as cisplatin, 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 can replace blood-forming cells that are damaged by MIBG labeled with iodine-131 and chemotherapy.


Condition Intervention
Disseminated Neuroblastoma
Localized Resectable Neuroblastoma
Localized Unresectable Neuroblastoma
Regional Neuroblastoma
Drug: doxorubicin hydrochloride
Other: pharmacological study
Other: questionnaire administration
Procedure: autologous hematopoietic stem cell transplantation
Procedure: in vitro-treated peripheral blood stem cell transplantation
Procedure: therapeutic conventional surgery
Radiation: 3-dimensional conformal radiation therapy
Radiation: external beam radiation therapy
Radiation: intensity-modulated radiation therapy
Drug: cyclophosphamide
Drug: topotecan hydrochloride
Drug: cisplatin
Drug: etoposide phosphate
Drug: vincristine sulfate
Radiation: meta-iodobenzylguanidine (MIBG) labeled with iodine-131
Drug: busulfan
Drug: melphalan
Drug: isotretinoin

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A COG Pilot Study of Intensive Induction Chemotherapy and 131I-MIBG Followed by Myeloablative Busulfan/Melphalan (Bu/Mel) for Newly Diagnosed High-Risk Neuroblastoma

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Proportion of MIBG avid patients treated with meta-iodobenzylguanidine (MIBG) labeled with iodine-131 [ Time Frame: Up to 6 weeks after course 5 of induction ] [ Designated as safety issue: No ]
    This proportion will be calculated as the number of MIBG avid patients who receive MIBG labeled with iodine-131 divided by the number of patients evaluable for the feasibility of MIBG endpoint. The definition of receive MIBG labeled with iodine-131 is receiving MIBG labeled with iodine-131.

  • Proportion of MIBG avid patients treated with MIBG labeled with iodine-131 and Bu/Mel chemotherapy [ Time Frame: Day -6 of conditioning ] [ Designated as safety issue: No ]
    This proportion will be calculated as the number of MIBG avid patients who receive MIBG labeled with iodine-131 and Bu/Mel divided by the number of patients evaluable for the feasibility of MIBG and Bu/Mel consolidation endpoint. The definition of receiving Bu/Mel conditioning is receiving the first dose of planned Busulfan on Day -6 of conditioning.

  • Percentage of average per capita income encompassed by the total of travel + housing + lost wages [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Patient/caregiver surveys will provide the information about travel for each patient. Cost of travel for each person will be determined using standard mileage reimbursement rates. Standard federal per diem rates will be utilized for families who stay in a hotel. Lost wages will be calculated for up to a maximum of 2 adults. In order to determine if the 'out-of-pocket' costs are less than 10% of yearly income, expenditures will be totaled and compared to the average per capita income, assuming 52-weeks with a 40-hour work week.

  • Proportion of eligible high-risk patients accrued to the study [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
  • Event-free survival rate [ Time Frame: Time from enrollment to the first occurrence of relapse, progression, secondary malignancy or death, assessed at 1 year ] [ Designated as safety issue: No ]
    A 95% confidence interval will be calculated for the 1-year EFS rate. Will perform a comparison of the 1-year EFS rate on this study versus a hypothesized model of the standard using the methodology of Woolson.


Secondary Outcome Measures:
  • Incidence of adverse events and SOS, assessed by Common Terminology Criteria (CTC)v.4.0 for toxicity assessment and grading [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 105
Study Start Date: October 2010
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: MIBG labeled with iodine-131/isotretinoin/vincristine
See Detailed Description
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: questionnaire administration
Ancillary studies
Procedure: autologous hematopoietic stem cell transplantation
Undergo autologous in vitro-treated peripheral blood stem cell transplantation
Procedure: in vitro-treated peripheral blood stem cell transplantation
Undergo autologous in vitro-treated peripheral blood stem cell transplantation
Other Names:
  • in vitro-treated PBPC transplantation
  • in vitro-treated PBSC
  • in vitro-treated peripheral blood progenitor cell transplantation
  • PBPC transplantation, in vitro-treated
  • peripheral blood progenitor cell transplantation, in vitro-treated
Procedure: therapeutic conventional surgery
Undergo surgery
Radiation: 3-dimensional conformal radiation therapy
Undergo radiotherapy
Other Names:
  • 3D conformal radiation therapy
  • 3D-CRT
Radiation: external beam radiation therapy
Undergo radiotherapy
Other Name: EBRT
Radiation: intensity-modulated radiation therapy
Undergo radiotherapy
Other Name: IMRT
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: topotecan hydrochloride
Given IV
Other Names:
  • hycamptamine
  • Hycamtin
  • SKF S-104864-A
  • TOPO
Drug: cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
Drug: etoposide phosphate
Given IV
Other Names:
  • ETOP
  • Etopophos
Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS
Radiation: meta-iodobenzylguanidine (MIBG) labeled with iodine-131
Given IV
Other Names:
  • 131 I-MIBG
  • I 131 Metaiodobenzylguanidine
  • Iodine I 131 Metaiodobenzylguanidine
Drug: busulfan
Given IV
Other Names:
  • BSF
  • BU
  • Misulfan
  • Mitosan
  • Myeloleukon
Drug: melphalan
Given IV
Other Names:
  • Alkeran
  • CB-3025
  • L-PAM
  • L-phenylalanine mustard
  • L-Sarcolysin
Drug: isotretinoin
Given PO
Other Names:
  • 13-CRA
  • Amnesteem
  • Cistane
  • Claravis
  • Sotret

  Hide Detailed Description

Detailed Description:

PRIMARY OBJECTIVE:

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

SECONDARY OBJECTIVES:

I. To assess the tolerability of these regimens in these patients, age 365 days - 30 years, with a) an Induction block of meta-iodobenzylguanidine labeled with iodine-131 therapy delivered after multi-agent chemotherapy, and b) the tolerability of receiving post-Induction Bu/Mel Consolidation therapy with autologous stem-cell rescue (ASCR), and local radiation therapy.

TERTIARY OBJECTIVES:

I. To assess the response rate after a regimen of Induction chemotherapy and meta-iodobenzylguanidine (MIBG) labeled with iodine-131 and after a consolidation regimen of Bu/Mel with ASCR and local radiation therapy.

II. To describe the relationship of tumor norepinephrine transporter (hNET) expression with radioiodinated MIBG uptake, at diagnosis as well as with tumor response.

III. To assess the relative reliability of 123 I-MIBG and 18FDG-PET imaging in assessment of tumor activity at diagnosis, and prior to surgical resection.

IV. To compare detectable tumor burden on the pre-surgical resection radioiodinated -MIBG diagnostic scan and the immediate post-MIBG therapy meta-iodobenzylguanidine labeled with iodine-131 scan.

V. To test for the relationship of occurrence of sinusoidal obstruction syndrome (SOS) to Bu/Mel or to whole-body radiation dose or delayed radiation clearance due to MIBG labeled with iodine-131.

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

OUTLINE: This is a pilot, multicenter study.

INDUCTION CHEMOTHERAPY: Patients receive 5 courses of induction therapy.

Course 1: Patients receive cyclophosphamide intravenously (IV) over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 for 3 weeks of weeks 1-3.

Course 2: Patients receive cyclophosphamide intravenously (IV) over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 for 3 weeks/21 days of weeks 4-6. Patients undergo peripheral blood stem cell (PBSC) collection.

Course 3: Patients receive cisplatin IV over 1 hour on days 1-4 and etoposide phosphate IV over 1-2 hours on days 1-3 for 3 weeks/21 days of weeks 7-9.

Course 4: Patients receive cyclophosphamide IV over 1-6 hours on days 1-2 and vincristine sulfate IV over 1 minute and doxorubicin hydrochloride IV over 24 hours on days 1-3 for 3 weeks/21 days of weeks 10-12. Patients undergo surgery to remove remaining tumor following course 4.

Course 5: Patients receive cisplatin IV over 1 hour on days 1-4 and etoposide phosphate IV over 1-2 hours on days 1-3 for 3 weeks/21 days of weeks 13-15.

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 MIBG labeled with iodine-131 induction therapy beginning 3-6 weeks after course 5.

SURGERY: Patients undergo 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 no sooner than 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 isotretinoin orally (PO) twice daily (BID) 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

Ages Eligible for Study:   1 Year to 30 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients have a diagnosis of neuroblastoma (ICD-O morphology 9500/3) or ganglioneuroblastoma verified by histology or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites; patients with the following disease stages at diagnosis are eligible, if they meet the other specified criteria:

    • Patients with newly diagnosed neuroblastoma with INSS Stage 4 are eligible with the following:

      • 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/unknown
    • Patients with newly diagnosed neuroblastoma with INSS Stage 3 are eligible with the following:

      • 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
    • Patients with 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
    • Patients >= 365 days initially diagnosed with: INSS Stage 1, 2, 4S who progressed to a Stage 4 without interval chemotherapy; these patients must have been enrolled on ANBL00B1; it is to be noted that study enrollment must occur within 4 weeks of progression to Stage 4 for INSS Stage 1, 2, 4S
  • Patients must have had no prior systemic therapy except for localized emergency radiation to sites of life- threatening or function-threatening disease and/or no more than 1 cycle of chemotherapy per Low- or Intermediate-Risk neuroblastoma therapy (P9641, A3961, ANBL0531) prior to determination of MYCN amplification and histology
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73m^2 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)
  • Total bilirubin =< 1.5 times upper limit of normal (ULN) for age
  • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 10 times ULN for age
  • Shortening fraction >= 27% by echocardiogram (ECHO) or
  • Ejection fraction >= 50% by radionuclide evaluation
  • No known contraindication to peripheral blood stem cell (PBSC) collection; examples of contraindications might be a weight or size less than the collecting institution finds feasible, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure
  • All patients and/or their parents or legal guardians must sign a written informed consent
  • All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

  • Females of childbearing potential must have a negative pregnancy test; patients of childbearing potential must agree to use an effective birth control method
  • Female patients who are lactating must agree to stop breast-feeding
  • Patients that are 12-18 months of age with INSS Stage 4 and all 3 favorable biologic features (i.e., non-amplified MYCN, favorable pathology, and DNA index > 1) are not eligible
  • Patients are not eligible if they have received local radiation which includes any of the following: 1200 cGy to more than 33% of both kidneys (patient must have at least 1 kidney that has not exceeded the dose/volume of radiation listed) or 1800 cGy to more than 30% of liver and/or 900 cGy to more than 50% of liver; emergency local irradiation is allowed prior to study entry, provided the patient still meets eligibility criteria
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01175356

  Show 19 Study Locations
Sponsors and Collaborators
Children's Oncology Group
Investigators
Principal Investigator: Brian Weiss, MD Children's Oncology Group
  More Information

No publications provided

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT01175356     History of Changes
Other Study ID Numbers: ANBL09P1, NCI-2011-01745, CDR0000682629, COG-ANBL09P1, ANBL09P1, U10CA098543
Study First Received: August 3, 2010
Last Updated: April 23, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
3-Iodobenzylguanidine
Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Busulfan
Cyclophosphamide
Melphalan
Etoposide phosphate
Cisplatin
Doxorubicin
Etoposide
Vincristine
Topotecan
Iodine
Cadexomer iodine
Isotretinoin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 28, 2014