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

Phase 1

Active, not recruiting

Conditions: Regional Neuroblastoma
Ganglioneuroblastoma
Localized Unresectable Neuroblastoma
Stage 4 Neuroblastoma
Localized Resectable Neuroblastoma
Stage 4S Neuroblastoma

Interventions: Radiation: 3-Dimensional Conformal Radiation Therapy
Procedure: Autologous Hematopoietic Stem Cell Transplantation
Drug: Busulfan
Drug: Cisplatin
Drug: Cyclophosphamide
Drug: Doxorubicin Hydrochloride
Drug: Etoposide Phosphate
Radiation: External Beam Radiation Therapy
Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation
Radiation: Intensity-Modulated Radiation Therapy
Radiation: Iobenguane I-131
Drug: Isotretinoin
Other: Laboratory Biomarker Analysis
Drug: Melphalan
Other: Pharmacological Study
Other: Questionnaire Administration
Procedure: Therapeutic Conventional Surgery
Drug: Topotecan Hydrochloride
Drug: Vincristine Sulfate

Registration Number: NCT01175356

Lead Sponsor: Children's Oncology Group

Brief Summary: This pilot clinical trial studies 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. Radioisotope therapy, such as iobenguane I 131, releases radiation that kills tumor cells. Drugs used in chemotherapy, such as carboplatin, etoposide phosphate, 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. Giving radioisotope therapy, chemotherapy, and peripheral stem cell transplant may kill more tumor cells.

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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 99

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (131I-MIBG, chemotherapy)	3-Dimensional Conformal Radiation Therapy	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Autologous Hematopoietic Stem Cell Transplantation	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Busulfan	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Cisplatin	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Cyclophosphamide	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Doxorubicin Hydrochloride	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Etoposide Phosphate	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	External Beam Radiation Therapy	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	In Vitro-Treated Peripheral Blood Stem Cell Transplantation	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Intensity-Modulated Radiation Therapy	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Iobenguane I-131	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Isotretinoin	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Laboratory Biomarker Analysis	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Melphalan	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Pharmacological Study	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Questionnaire Administration	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Therapeutic Conventional Surgery	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Topotecan Hydrochloride	See Detailed Description.
Treatment (131I-MIBG, chemotherapy)	Vincristine Sulfate	See Detailed Description.

Primary Outcome Measures

Name	Time	Method
Percentage of MIBG Avid Patients Treated With MIBG Labeled With Iodine-131 and Bu/Mel Chemotherapy	Up to day -6 of conditioning	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%.
Percentage of MIBG Avid Patients Treated With Meta-iodobenxylguanide (MIBG) Labeled With Iodine-131	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%.

Secondary Outcome Measures

Name	Time	Method
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	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.

Trial Locations

Locations (25): Children's Healthcare of Atlanta - Arthur M Blank Hospital
🇺🇸
Atlanta, Georgia, United States
University of Wisconsin Carbone Cancer Center - University Hospital
🇺🇸
Madison, Wisconsin, United States
Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
Phoenix Childrens Hospital
🇺🇸
Phoenix, Arizona, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
UCSF Medical Center-Parnassus
🇺🇸
San Francisco, California, United States
UCSF Medical Center-Mission Bay
🇺🇸
San Francisco, California, United States
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸
Dallas, Texas, United States
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Primary Children's Hospital
🇺🇸
Salt Lake City, Utah, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸
Spokane, Washington, United States
Children's Hospital of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States