- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01175356
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
A COG Pilot Study of Intensive Induction Chemotherapy and 131I-MIBG Followed by Myeloablative Busulfan/Melphalan (Bu/Mel) for Newly Diagnosed High-Risk Neuroblastoma
Study Overview
Status
Conditions
Intervention / Treatment
- Other: Laboratory Biomarker Analysis
- Other: Pharmacological Study
- Other: Questionnaire Administration
- Drug: Cisplatin
- Drug: Cyclophosphamide
- Drug: Vincristine Sulfate
- Procedure: Therapeutic Conventional Surgery
- Drug: Doxorubicin Hydrochloride
- Drug: Etoposide Phosphate
- Drug: Topotecan Hydrochloride
- Drug: Melphalan
- Drug: Busulfan
- Drug: Isotretinoin
- Radiation: Iobenguane I-131
- Radiation: External Beam Radiation Therapy
- Radiation: Intensity-Modulated Radiation Therapy
- Radiation: 3-Dimensional Conformal Radiation Therapy
- Procedure: Autologous Hematopoietic Stem Cell Transplantation
- Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation
Detailed Description
PRIMARY OBJECTIVE:
I. To assess the feasibility of treating high-risk neuroblastoma patients, age 365 days - 30 years, with a) an induction block of meta-iodobenzylguanidine labeled with iodine-131 (131I-MIBG [iobenguane I 131]) delivered after multi-agent chemotherapy, and b) post-induction busulfan/melphalan (Bu/Mel) consolidation therapy.
SECONDARY OBJECTIVES:
I. To assess the tolerability of treating high-risk neuroblastoma patients, age 365 days - 30 years, with a) an induction block of 131I-MIBG 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 131I-MIBG 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 fludeoxyglucose F-18 (18FDG)-positron emission tomography (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 131I-MIBG 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 131I-MIBG.
VI. To analyze busulfan pharmacokinetics as measured by area under the curve (AUC) and relate exposure to SOS incidence.
OUTLINE:
INDUCTION CHEMOTHERAPY: Patients receive 5 courses of induction therapy.
Courses 1-2: Patients receive cyclophosphamide intravenously (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 over 1 minute 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 induction therapy beginning 3-6 weeks after course 5. Patients receive iobenguane I 131 IV over 90-120 minutes on day 1.
SURGERY: Patients undergo surgery after course 4 or before consolidation therapy.
CONSOLIDATION THERAPY: Within 10-12 weeks from the date of iobenguane I 131 infusion, patients receive busulfan IV over 2 hours every 6 hours on days -6 to -3 and melphalan IV on day -1.
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 (2 dimensional [D], 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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Alabama
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Birmingham, Alabama, United States, 35233
- University of Alabama at Birmingham Cancer Center
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Birmingham, Alabama, United States, 35233
- Children's Hospital of Alabama
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Arizona
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Phoenix, Arizona, United States, 85016
- Phoenix Childrens Hospital
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California
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Los Angeles, California, United States, 90027
- Children's Hospital Los Angeles
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San Francisco, California, United States, 94158
- UCSF Medical Center-Mission Bay
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San Francisco, California, United States, 94143
- UCSF Medical Center-Parnassus
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Colorado
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Aurora, Colorado, United States, 80045
- Children's Hospital Colorado
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Connecticut
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Hartford, Connecticut, United States, 06106
- Connecticut Children's Medical Center
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District of Columbia
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Washington, District of Columbia, United States, 20010
- Children's National Medical Center
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Georgia
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Atlanta, Georgia, United States, 30322
- Children's Healthcare of Atlanta - Egleston
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Illinois
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Chicago, Illinois, United States, 60637
- University of Chicago Comprehensive Cancer Center
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Massachusetts
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Boston, Massachusetts, United States, 02215
- Dana-Farber Cancer Institute
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Michigan
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Ann Arbor, Michigan, United States, 48109
- C S Mott Children's Hospital
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North Carolina
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Chapel Hill, North Carolina, United States, 27599
- UNC Lineberger Comprehensive Cancer Center
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Durham, North Carolina, United States, 27710
- Duke University Medical Center
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Ohio
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Cincinnati, Ohio, United States, 45229
- Cincinnati Children's Hospital Medical Center
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19104
- Children's Hospital of Philadelphia
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South Carolina
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Charleston, South Carolina, United States, 29425
- Medical University of South Carolina
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Texas
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Dallas, Texas, United States, 75390
- UT Southwestern/Simmons Cancer Center-Dallas
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Fort Worth, Texas, United States, 76104
- Cook Children's Medical Center
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Utah
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Salt Lake City, Utah, United States, 84113
- Primary Children's Hospital
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Washington
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Seattle, Washington, United States, 98105
- Seattle Children's Hospital
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Spokane, Washington, United States, 99204
- Providence Sacred Heart Medical Center and Children's Hospital
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Wisconsin
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Madison, Wisconsin, United States, 53792
- University of Wisconsin Carbone Cancer Center
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Milwaukee, Wisconsin, United States, 53226
- Children's Hospital of Wisconsin
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
Patients have a diagnosis of neuroblastoma (International Classification of Diseases for Oncology [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 International Neuroblastoma Staging System (INSS) stage 4 are eligible with the following:
- v-MYC myelocytomatosis viral related oncogene, neuroblastoma derived (avian) (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 deoxyribonucleic acid [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/1.73 m^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 x upper limit of normal (ULN) for age
- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x ULN for age
- Shortening fraction >= 27% by echocardiogram 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 centigray (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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (131I-MIBG, chemotherapy)
See Detailed Description.
|
Correlative studies
Correlative studies
Ancillary studies
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Undergo surgery
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given PO
Other Names:
Given IV
Other Names:
Undergo radiotherapy
Other Names:
Undergo radiotherapy
Other Names:
Undergo radiotherapy
Other Names:
Undergo autologous in vitro-treated peripheral blood stem cell transplantation
Other Names:
Undergo autologous in vitro-treated peripheral blood stem cell transplantation
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percentage of MIBG Avid Patients Treated With Meta-iodobenxylguanide (MIBG) Labeled With Iodine-131
Time Frame: Up to 6 weeks after course 5 of induction
|
Number of MIBG avid patients who receive 131I-MIBG divided by the number of patients evaluable for the feasibility of MIBG endpoint x 100%.
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Up to 6 weeks after course 5 of induction
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Percentage of MIBG Avid Patients Treated With MIBG Labeled With Iodine-131 and Bu/Mel Chemotherapy
Time Frame: Up to day -6 of conditioning
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Number of MIBG avid patients who receive 131I-MIBG and Bu/Mel divided by the number of patients evaluable for the feasibility of MIBG and Bu/Mel consolidation endpoint x 100%.
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Up to day -6 of conditioning
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of Unacceptable Toxicity and Sinusoidal Obstruction Syndrome (SOS), Assessed by Common Terminology Criteria (CTV)v.4.0 for Toxicity Assessment and Grading for I-MIBG
Time Frame: Up to 6 weeks after course 5 of induction
|
Number of patients who had an unacceptable toxicity or experienced SOS.
Unacceptable toxicity was defined as CTC Grade 4-5 Pulmonary/Respiratory.
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Up to 6 weeks after course 5 of induction
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Brian D Weiss, Children's Oncology Group
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms, Glandular and Epithelial
- Neoplasms, Neuroepithelial
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Neuroectodermal Tumors, Primitive
- Neuroectodermal Tumors, Primitive, Peripheral
- Neuroblastoma
- Ganglioneuroblastoma
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antirheumatic Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Tubulin Modulators
- Antimitotic Agents
- Mitosis Modulators
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Antineoplastic Agents, Phytogenic
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Dermatologic Agents
- Radiopharmaceuticals
- Micronutrients
- Antibiotics, Antineoplastic
- Vitamins
- Keratolytic Agents
- Topoisomerase I Inhibitors
- Cyclophosphamide
- Etoposide
- Etoposide phosphate
- Cisplatin
- Melphalan
- Doxorubicin
- Liposomal doxorubicin
- Vincristine
- Topotecan
- Busulfan
- Tretinoin
- Isotretinoin
- 3-Iodobenzylguanidine
- Mechlorethamine
- Nitrogen Mustard Compounds
- Vitamin A
Other Study ID Numbers
- ANBL09P1 (Other Identifier: CTEP)
- U10CA180886 (U.S. NIH Grant/Contract)
- U10CA098543 (U.S. NIH Grant/Contract)
- NCI-2011-01745 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- CDR0000682629 (ClinicalTrials.gov)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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