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

• ClinicalTrials.gov Identifier: NCT01175356
• Recruitment Status: Active, not recruiting
• First Posted: August 4, 2010
• Results First Posted: September 28, 2017
• Last Update Posted: April 4, 2023
• Sponsor: Children's Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Children's Oncology Group

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Ganglioneuroblastoma; Localized Resectable Neuroblastoma; Localized Unresectable Neuroblastoma; Regional Neuroblastoma; Stage 4 Neuroblastoma; Stage 4S Neuroblastoma	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	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 99 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Actual Study Start Date: October 4, 2010
• Actual Primary Completion Date: September 28, 2016
• Estimated Study Completion Date: September 28, 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (131I-MIBG, chemotherapy); See Detailed Description.

Radiation: 3-Dimensional Conformal Radiation Therapy; Undergo radiotherapy; Other Names: 3-dimensional radiation therapy; 3D Conformal; 3D CONFORMAL RADIATION THERAPY; 3D CRT; 3D radiotherapy; 3D-CRT; Conformal Therapy; Radiation Conformal Therapy; Radiation, 3D Conformal; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Undergo autologous in vitro-treated peripheral blood stem cell transplantation; Other Names: AHSCT; Autologous; Autologous Hematopoietic Cell Transplantation; Autologous Stem Cell Transplant; Autologous Stem Cell Transplantation; Stem Cell Transplantation, Autologous; Drug: Busulfan; Given IV; Other Names: 1, 4-Bis[methanesulfonoxy]butane; BUS; Bussulfam; Busulfanum; Busulfex; Busulphan; CB 2041; CB-2041; Glyzophrol; GT 41; GT-41; Joacamine; Methanesulfonic Acid Tetramethylene Ester; Methanesulfonic acid, tetramethylene ester; Mielucin; Misulban; Misulfan; Mitosan; Myeleukon; Myeloleukon; Myelosan; Mylecytan; Myleran; Sulfabutin; Tetramethylene Bis(methanesulfonate); Tetramethylene bis[methanesulfonate]; WR-19508; Drug: Cisplatin; Given IV; Other Names: Abiplatin; Blastolem; Briplatin; CDDP; Cis-diammine-dichloroplatinum; Cis-diamminedichloridoplatinum; Cis-diamminedichloro Platinum (II); Cis-diamminedichloroplatinum; Cis-dichloroammine Platinum (II); Cis-platinous Diamine Dichloride; Cis-platinum; Cis-platinum II; Cis-platinum II Diamine Dichloride; Cismaplat; Cisplatina; Cisplatinum; Cisplatyl; Citoplatino; Citosin; Cysplatyna; DDP; Lederplatin; Metaplatin; Neoplatin; Peyrone's Chloride; Peyrone's Salt; Placis; Plastistil; Platamine; Platiblastin; Platiblastin-S; Platinex; Platinol; Platinol- AQ; Platinol-AQ; Platinol-AQ VHA Plus; Platinoxan; Platinum; Platinum Diamminodichloride; Platiran; Platistin; Platosin; Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CTX; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Cytoxan; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Drug: Doxorubicin Hydrochloride; Given IV; Other Names: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI); ADM; Adriacin; Adriamycin; Adriamycin Hydrochloride; Adriamycin PFS; Adriamycin RDF; ADRIAMYCIN, HYDROCHLORIDE; Adriamycine; Adriblastina; Adriblastine; Adrimedac; Chloridrato de Doxorrubicina; DOX; DOXO-CELL; Doxolem; Doxorubicin HCl; Doxorubicin.HCl; Doxorubin; Farmiblastina; FI 106; FI-106; hydroxydaunorubicin; Rubex; Drug: Etoposide Phosphate; Given IV; Other Name: Etopophos; Radiation: External Beam Radiation Therapy; Undergo radiotherapy; Other Names: Definitive Radiation Therapy; EBRT; External Beam Radiation; External Beam Radiotherapy; External Beam RT; external radiation; External Radiation Therapy; external-beam radiation; Radiation, External Beam; Teleradiotherapy; Teletherapy; Teletherapy Radiation; 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 peripheral blood progenitor cell transplantation; Radiation: Intensity-Modulated Radiation Therapy; Undergo radiotherapy; Other Names: IMRT; Intensity Modulated RT; Intensity-Modulated Radiotherapy; Radiation, Intensity-Modulated Radiotherapy; Radiation: Iobenguane I-131; Given IV; Other Names: (131)I-MIBG; 131I-MIBG; I 131 Meta-iodobenzylguanidine; I-131 Metaiodobenzylguanidine; Iobenguane (131I); Iobenguane I 131; Iodine I 131 Metaiodobenzylguanidine; MIBG I-131; Drug: Isotretinoin; Given PO; Other Names: 13-cis retinoic acid; 13-cis-Retinoate; 13-cis-Retinoic Acid; 13-cis-Vitamin A Acid; 13-cRA; Absorica; Accure; Accutane; Amnesteem; cis-Retinoic Acid; Cistane; Claravis; Isotretinoinum; Isotrex; Isotrexin; Myorisan; Neovitamin A; Neovitamin A Acid; Oratane; Retinoicacid-13-cis; Ro 4-3780; Ro-4-3780; Roaccutan; Roaccutane; Roacutan; Sotret; ZENATANE; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Melphalan; Given IV; Other Names: Alanine Nitrogen Mustard; CB-3025; L-PAM; L-Phenylalanine Mustard; L-Sarcolysin; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine Nitrogen Mustard; Sarcoclorin; Sarkolysin; WR-19813; Other: Pharmacological Study; Correlative studies; Other: Questionnaire Administration; Ancillary studies; Procedure: Therapeutic Conventional Surgery; Undergo surgery; Drug: Topotecan Hydrochloride; Given IV; Other Names: Hycamptamine; Hycamtin; SKF S-104864-A; Topotecan HCl; topotecan hydrochloride (oral); Drug: Vincristine Sulfate; Given IV; Other Names: Kyocristine; Leurocristine Sulfate; Leurocristine, sulfate; Oncovin; Vincasar; Vincosid; Vincrex; Vincristine, sulfate

Outcome Measures

Primary Outcome Measures :

1. 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%.
2. Percentage of MIBG Avid Patients Treated With MIBG Labeled With Iodine-131 and Bu/Mel Chemotherapy [ Time Frame: 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%.

Secondary Outcome Measures :

1. 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.

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 30 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Alabama

Children's Hospital of Alabama

Birmingham, Alabama, United States, 35233

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, United States, 35233

United States, Arizona

Phoenix Childrens Hospital

Phoenix, Arizona, United States, 85016

United States, California

Children's Hospital Los Angeles

Los Angeles, California, United States, 90027

UCSF Medical Center-Parnassus

San Francisco, California, United States, 94143

UCSF Medical Center-Mission Bay

San Francisco, California, United States, 94158

United States, Colorado

Children's Hospital Colorado

Aurora, Colorado, United States, 80045

United States, Connecticut

Connecticut Children's Medical Center

Hartford, Connecticut, United States, 06106

United States, District of Columbia

Children's National Medical Center

Washington, District of Columbia, United States, 20010

United States, Georgia

Children's Healthcare of Atlanta - Egleston

Atlanta, Georgia, United States, 30322

United States, Illinois

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, United States, 60637

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Michigan

C S Mott Children's Hospital

Ann Arbor, Michigan, United States, 48109

United States, North Carolina

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, United States, 27599

Duke University Medical Center

Durham, North Carolina, United States, 27710

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

United States, Texas

UT Southwestern/Simmons Cancer Center-Dallas

Dallas, Texas, United States, 75390

Cook Children's Medical Center

Fort Worth, Texas, United States, 76104

United States, Utah

Primary Children's Hospital

Salt Lake City, Utah, United States, 84113

United States, Washington

Seattle Children's Hospital

Seattle, Washington, United States, 98105

Providence Sacred Heart Medical Center and Children's Hospital

Spokane, Washington, United States, 99204

United States, Wisconsin

University of Wisconsin Carbone Cancer Center

Madison, Wisconsin, United States, 53792

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Children's Oncology Group

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Brian D Weiss; Children's Oncology Group

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Weiss BD, Yanik G, Naranjo A, Zhang FF, Fitzgerald W, Shulkin BL, Parisi MT, Russell H, Grupp S, Pater L, Mattei P, Mosse Y, Lai HA, Jarzembowski JA, Shimada H, Villablanca JG, Giller R, Bagatell R, Park JR, Matthay KK. A safety and feasibility trial of 131 I-MIBG in newly diagnosed high-risk neuroblastoma: A Children's Oncology Group study. Pediatr Blood Cancer. 2021 Oct;68(10):e29117. doi: 10.1002/pbc.29117. Epub 2021 May 24.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT01175356
• Other Study ID Numbers: ANBL09P1; NCI-2011-01745 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); ANBL09P1; CDR0000682629; ANBL09P1 ( Other Identifier: Children's Oncology Group ); ANBL09P1 ( Other Identifier: CTEP ); U10CA180886 ( U.S. NIH Grant/Contract ); U10CA098543 ( U.S. NIH Grant/Contract )
• First Posted: August 4, 2010
• Results First Posted: September 28, 2017
• Last Update Posted: April 4, 2023
• Last Verified: March 2023

Additional relevant MeSH terms:

Neuroblastoma; Ganglioneuroblastoma; 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; Vitamin A; Cyclophosphamide; Melphalan; Busulfan; Mechlorethamine; Nitrogen Mustard Compounds; Cisplatin; Doxorubicin; Liposomal doxorubicin; Etoposide; Vincristine; Topotecan; Tretinoin; Etoposide phosphate; 3-Iodobenzylguanidine; Isotretinoin; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs