N2001-02: I-MIBG With Intensive Chemotherapy and Autologous Stem Cell Rescue for High-Risk Neuroblastoma

NCT00253435 | Completed Phase 2 Results DMC

• 3 other identifiers: CDR0000450148P01CA081403N2001-02
• Study Type: interventional
• Target: 50
• Locations: 2 countries
• Sites: 15

Brief Summary

RATIONALE: Radioactive drugs, such as iodine I 131 metaiodobenzylguanidine, may carry radiation directly to tumor cells and not harm normal cells. Drugs used in chemotherapy, such as carboplatin, etoposide, and melphalan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. An autologous peripheral stem cell or bone marrow transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy. Giving iodine I 131 metaiodobenzylguanidine and combination chemotherapy with an autologous peripheral stem cell or bone marrow transplant may allow more chemotherapy to be given so that more tumor cells are killed. Giving radiation therapy after an autologous peripheral stem cell or bone marrow transplant may kill any remaining tumor cells. PURPOSE: This phase II trial is studying how well giving iodine I 131 metaiodobenzylguanidine together with combination chemotherapy and radiation therapy works in treating patients who are undergoing an autologous peripheral stem cell or bone marrow transplant for relapsed or refractory neuroblastoma.

Conditions

Neuroblastoma

Keywords

recurrent neuroblastoma

Outcome Measures

Primary Outcomes (1)

• Response (Complete Response, Very Good Partial Response, and Partial Response) at 60-days Post Stem Cell Infusion

  Tumor response based on evaluation performed on day 60 or at the time of disease progression/recurrence or start of another treatment - whichever comes first. Such evaluations will include 123I-MIBG scan, CT/MRI, urine catecholamine measurement, and bone marrow analysis (for those with marrow disease at study entry).

  Response assessed 60 days post stem cell infusion

Secondary Outcomes (3)

• Event-free Survival (EFS) at 3 Years

  3 years since start of treatment

• Engraftment DLT

  From treatment start until 60 days post stem cell infusion

• Dose Limiting Veno-occlusive Disease (VOD) / Sinusoidal Obstruction Syndrome SOS

  Between start of MIBG treatment and 60 days post stem cell infusion

Study Arms (1)

All the patients enrolled in the study

EXPERIMENTAL

This is a single arm study. The following description applies to all the patients who are enrolled in the study: On Day -21, patients receive 131I-MIBG infusion. On Day -7, Day -6, Day -5, patients receive Carboplatin, Etoposide, Melphalan. On Day -4, patients receive Carboplatin, Etoposide. On Day -3, Day -2, Day -1, patients rest. On Day 0, patients receive peripheral blood stem cell infusion. Dosing of Carboplatin, Etoposide and Melphalan is based upon whole body dosimetry (cGy) estimates. Filgrastim 5 micrograms/kg/day S.C. or IV will be given daily beginning on Day 0. Local radiation therapy is to be given to previously non-irradiated primary and metastatic sites of disease.

Biological: Filgrastim; Drug: Carboplatin; Drug: Etoposide; Drug: Melphalan; Procedure: Peripheral blood stem cell infusion; Radiation: 131I-MIBG; Radiation: Radiation therapy

Interventions

Filgrastim BIOLOGICAL

Filgrastim 5 micrograms/kg/day S.C. or IV will be given daily beginning on Day 0. The first dose should begin four hours after the stem cell infusion is completed. Filgrastim will continue daily until the ANC \>=1500/uL for three consecutive days.

Also known as: G-CSF

All the patients enrolled in the study

Carboplatin DRUG

The carboplatin will be administered as a continuous IV infusion Day - 7 through Day - 4, with dosing based upon pretreatment GFR levels. The carboplatin should be diluted to a concentration of 0.3 mg/ml in D5W 0.45NS and infused concomitantly with etoposide through the same central venous catheter using a "Y" connector; a controlled rate infusion pump is used for each arm of the "Y".

Also known as: cis-diammine; Paraplatin; Paraplatin-AQ

All the patients enrolled in the study

Etoposide DRUG

The etoposide shall be administered day -7 through day -4 via continuous intravenous infusion over 96 hours. For patients with a corrected GFR \>= 100 ml/min/1.72 m\^2, a dose of 300 mg/m\^2/day (10 mg/kg/day if child is \< 12 kg) shall be given. For patients with a corrected GFR 60-99 ml/min/1.72 m\^2, the etoposide will be administered at a dose of 160 mg/m\^2/day (5.3 mg/kg/day). The etoposide will be diluted in D5W 0.45%NS at a concentration of \< 0.4 mg/ml. Etoposide should not be mixed with carboplatin, but administered using a Y-connector.

Also known as: VP-16; Etopophos

All the patients enrolled in the study

Melphalan DRUG

For patients in either the normal GFR strata (\>=100 ml/min/1.73 m\^2), or reduced GFR strata (60-99 ml/min/1.73m\^2), melphalan shall be administered at a dose of 60 mg/m\^2/day (2 mg/kg/day if child is \< 12 kg) on day -7, -6, and -5 of study. The melphalan should be infused at a rate of less than 10 mg/minute, and should complete within 1 hour of reconstitution each day. The melphalan should be diluted in 0.9% NaCl at a concentration \< 2 mg/ml. The total dosage of melphalan to be administered will be 180 mg/m\^2.

Also known as: L-phenylalanine mustard; L-PAM; Alkeran; Sarcolysin

All the patients enrolled in the study

Peripheral blood stem cell infusion PROCEDURE

Stem cells or marrow will be infused on day 0 of study therapy. Where the DMSO concentration in the stem cell product would exceed accepted level for infusion within a 24 hour period, stem cell products may be infused over two days to meet this standard. For purged PBSC: A minimum of 2.0 x 10\^6 viable CD34+ cells/kg must be available. For unpurged PBSC, a minimum of 2.0 x 10\^6 viable CD34+ cells/kg must be available. Having a back-up of 2.0 x 10\^6 viable CD34+ cells/kg purged or unpurged PBSC is recommended but not required. For purged bone marrow, a minimum of 1.5 x10\^8 mononuclear cells/kg must be available.

All the patients enrolled in the study

131I-MIBG RADIATION

Therapeutic 131I MIBG will be synthesized by Draximage Canada.with specific activity between 15 and 25mCi/ml. Radiopurity will be initially determined by Draximage, prior to shipment to participating centers. Free radioiodide content must then be rechecked at the treating center prior to infusion using HPLC or Sep-Pac methodology.

Also known as: Iobenguane I 131

All the patients enrolled in the study

Radiation therapy RADIATION

Local irradiation is to be given to previously non-irradiated primary and metastatic sites of disease. Local irradiation should not start till the patient is medically stable, has an ANC \> 1000/uL, platelets \> 30,000 / uL, and is \> 42 days post transplant. Recommended radiation guidelines consist of 2160 cGy total, given over 12 days using a single 180 cGy fraction/day. Any delay in local radiation that would extend treatment beyond day +84 should be discussed with the study chair. Local radiation will be administered at a participating NANT member site.

All the patients enrolled in the study

Eligibility Criteria

• Age: 1 Year - 29 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

DISEASE CHARACTERISTICS: * Diagnosis of relapsed or refractory neuroblastoma * Histologically confirmed and/or demonstration of tumor cells in bone marrow with elevated urinary catecholamine metabolites * High-risk neuroblastoma must meet one of the following: * Progressive disease prior to or after completion of induction therapy * Mixed response or no response after completion of 4 courses of induction therapy * Partial response after 4 courses of induction therapy allowed provided no prior participation in COG-A3973 or other phase III COG trials * Measurable disease, defined as at least one metaiodobenzylguanidine (MIBG)-avid target lesion determined by diagnostic MIBG scan within 6 weeks of study entry (tumor sites that have received local irradiation within 3 months of study entry are not considered target lesions) PATIENT CHARACTERISTICS: Performance status * Lansky 60-100% OR * Karnofsky 60-100% Life expectancy * At least 2 months Hematopoietic * Hemoglobin ≥ 10 g/dL * Absolute neutrophil count ≥ 750/mm\^3 * Platelet count ≥ 50,000/mm\^3 (if no marrow involvement by morphologic exam/no transfusion allowed) (\> 20,000/mm\^3 if metastatic tumor involvement of marrow by morphologic exam/transfusion allowed) Hepatic * Bilirubin \< 1.3 mg/dL * SGOT and SGPT \< 5 times normal * Hepatitis B surface antigen negative * Hepatitis C negative Renal * Glomerular filtration rate or creatinine clearance ≥ 60 ml/min * Creatinine ≤ 1.5 times normal for age as follows: * 0.8 mg/dL (for patients ≤ 5 years of age) * 1.0 mg/dL (for patients 6 to 10 years of age) * 1.2 mg/dL (for patients 11 to 15 years of age) * 1.5 mg/dL (for patients \> 15 years of age) Cardiovascular * Ejection fraction ≥ 55% by echocardiogram or radionuclide MUGA OR * Fractional shortening ≥ 27% by echocardiogram Pulmonary * Normal lung function defined as no dyspnea at rest and no oxygen requirement OR measured oxygen saturation \> 93% on room air Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No disease of any major organ system that would preclude study compliance * No concurrent hemodialysis * No active infection requiring IV antivirals, antibiotics, or antifungals (patients on antifungal therapy are eligible provided they are culture- and biopsy-negative in suspected residual radiographic lesions) * Patient weight within limits to receive ≤ maximum total allowable dose of \^131I-MIBG PRIOR CONCURRENT THERAPY: Biologic therapy * No prior myeloablative transplantation * Prior submyeloablative transplantation allowed at discretion of principal investigator * More than 3 weeks since prior biologic therapy Chemotherapy * More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for mitomycin C or nitrosoureas) * No prior melphalan therapy with a total dose of \> 100 mg/m\^2 Radiotherapy * See Disease Characteristics * At least 6 weeks since prior radiotherapy (6 months for craniospinal or whole lung radiotherapy) * No prior total body irradiation * No prior iodine I 131 MIBG (\^131I-MIBG) * No prior total abdominal or whole liver radiotherapy * No prior local radiotherapy, including any of the following: * 1200 cGy to more than 33% of both kidneys (patient must have at least one kidney that has not exceeded the dose/volume of radiation listed) * 1800 cGy to more than 30% of liver and/or 900 cGy to more than 50% of liver Other * Recovered from all prior therapy * No medications with a potential interference of \^131I-MIBG uptake 1 week before and 2 weeks after completion of \^131I-MIBG

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• National Cancer Institute (NCI): collaborator
• New Approaches to Neuroblastoma Therapy Consortium: lead

Study Sites (15)

Childrens Hospital Los Angeles

Los Angeles, California, 90027-0700, United States

Location

Lucile Packard Children's Hospital at Stanford University Medical Center

Palo Alto, California, 94304, United States

Location

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, 94143, United States

Location

AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus

Atlanta, Georgia, 30322, United States

Location

University of Chicago Comer Children's Hospital

Chicago, Illinois, 60637, United States

Location

Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

C.S. Mott Children's Hospital at University of Michigan Medical Center

Ann Arbor, Michigan, 48109-0286, United States

Location

Morgan Stanley Children's Hospital of New York-Presbyterian

New York, New York, 10032, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229-3039, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104-4318, United States

Location

Cook Children's Medical Center - Fort Worth

Fort Worth, Texas, 76104, United States

Location

Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital

Houston, Texas, 77030-2399, United States

Location

Children's Hospital and Regional Medical Center - Seattle

Seattle, Washington, 98105, United States

Location

University of Wisconsin Paul P. Carbone Comprehensive Cancer Center

Madison, Wisconsin, 53792-6164, United States

Location

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

MeSH Terms

Conditions

Neuroblastoma

Interventions

Filgrastim; Granulocyte Colony-Stimulating Factor; Carboplatin; Etoposide; etoposide phosphate; Melphalan; 3-Iodobenzylguanidine; Radiotherapy

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Coordination Complexes; Organic Chemicals; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Glucosides; Glycosides; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Guanidines; Amidines; Iodobenzenes; Benzene Derivatives; Hydrocarbons, Iodinated; Therapeutics

Results Point of Contact

• Title: Araz Marachelian, MD, NANT Medical Director
• Organization: Chidlren's Hospital Los Angeles

amarachelian@chla.usc.edu

323-3691-5687

Study Officials

• Gregory Yanik, MD

  University of Michigan Rogel Cancer Center

  STUDY CHAIR

• Katherine K. Matthay, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• John M. Maris, MD

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 11, 2005
• First Posted: November 15, 2005
• Study Start: September 1, 2005
• Primary Completion: December 1, 2012
• Study Completion: December 1, 2013
• Last Updated: April 28, 2026
• Results First Posted: August 24, 2016

Record last verified: 2023-04

Locations

US (14); CA (1)