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

Ganglioneuroblastoma Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01175356
• Other study ID #: ANBL09P1
• Secondary ID: NCI-2011-01745AN
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: October 4, 2010
• Est. completion date: September 28, 2024

Study information

• Verified date: December 2023
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 99
• Est. completion date: September 28, 2024
• Est. primary completion date: September 28, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 30 Years

Eligibility

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

Related Conditions & MeSH terms

• Ganglioneuroblastoma
• Localized Resectable Neuroblastoma
• Localized Unresectable Neuroblastoma
• Neuroblastoma
• Regional Neuroblastoma
• Stage 4 Neuroblastoma
• Stage 4S Neuroblastoma

Intervention

Radiation:
• 3-Dimensional Conformal Radiation Therapy
Undergo radiotherapy

Procedure:
• Autologous Hematopoietic Stem Cell Transplantation
Undergo autologous in vitro-treated peripheral blood stem cell transplantation

Drug:
• Busulfan
Given IV
• Cisplatin
Given IV
• Cyclophosphamide
Given IV
• Doxorubicin Hydrochloride
Given IV
• Etoposide Phosphate
Given IV

Radiation:
• External Beam Radiation Therapy
Undergo radiotherapy

Procedure:
• In Vitro-Treated Peripheral Blood Stem Cell Transplantation
Undergo autologous in vitro-treated peripheral blood stem cell transplantation

Radiation:
• Intensity-Modulated Radiation Therapy
Undergo radiotherapy
• Iobenguane I-131
Given IV

Drug:
• Isotretinoin
Given PO

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Melphalan
Given IV

Other:
• Pharmacological Study
Correlative studies
• Questionnaire Administration
Ancillary studies

Procedure:
• Therapeutic Conventional Surgery
Undergo surgery

Drug:
• Topotecan Hydrochloride
Given IV
• Vincristine Sulfate
Given IV

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of MIBG Avid Patients Treated With Meta-iodobenxylguanide (MIBG) Labeled With Iodine-131	Number of MIBG avid patients who receive 131I-MIBG divided by the number of patients evaluable for the feasibility of MIBG endpoint x 100%.	Up to 6 weeks after course 5 of induction
Primary	Percentage of MIBG Avid Patients Treated With MIBG Labeled With Iodine-131 and Bu/Mel Chemotherapy	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%.	Up to day -6 of conditioning
Secondary	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	Number of patients who had an unacceptable toxicity or experienced SOS. Unacceptable toxicity was defined as CTC Grade 4-5 Pulmonary/Respiratory.	Up to 6 weeks after course 5 of induction