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

Phase 2

Completed

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

• Registration Number: NCT00253435
• Lead Sponsor: Children's Hospital Los Angeles

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.

Detailed Description

OBJECTIVES:

Primary

* Determine the response rate in patients with relapsed or refractory neuroblastoma treated with iodine I 131 metaiodobenzylguanidine (\^131I-MIBG) and combination chemotherapy comprising carboplatin, etoposide, and melphalan followed by autologous bone marrow or peripheral blood stem cell transplantation and radiotherapy.

Secondary

* Determine the hematopoietic and nonhematopoietic toxicity of this regimen in these patients.

* Determine the tumor self-absorbed radiation dose (TSARD) in patients with measurable soft tissue lesions treated with this regimen.

* Correlate the TSARD with tumor response in patients with measurable residual soft tissue disease treated with this regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to risk (poor-risk group \[mixed or no response to induction therapy or progression during or after induction therapy\] vs good-risk group \[partial response after 4 courses of induction therapy\]) and kidney function at study entry (glomerular filtration rate \[GFR\] ≥ 100 mL/min vs GFR 60-99 mL/min)

* Stem cell harvest: Patients undergo a peripheral blood stem cell harvest or bone marrow harvest provided they have an adequate number of cells available. At least 2 weeks later, patients proceed to iodine I 131 metaiodobenzylguanidine (\^131I-MIBG) and combination chemotherapy.

* 131I-MIBG and combination chemotherapy: Patients receive \^131I-MIBG IV over 2 hours on day -21, carboplatin IV continuously on days -7 to -4, etoposide IV continuously on days -7 to -4, and melphalan IV over 1 hour on days -7 to -5.

* Stem cell infusion and filgrastim (G-CSF): Three days after completion of chemotherapy, patients undergo transplantation of either stem cells or bone marrow on day 0. Patients also receive G-CSF subcutaneously or IV over 1 hour once daily beginning on day 0 and continuing until blood counts return to normal.

* Radiotherapy: Once blood counts return to normal, patients undergo radiotherapy to primary and metastatic sites that have not received previous irradiation over 12 days beginning after day 42.

After completion of study treatment, patients are followed for 2 years and then periodically thereafter.

PROJECTED ACCRUAL: Approximately 50 patients (40 low-risk patients and 8-10 high-risk patients) will be accrued for this study.

Study Timeline

• Study Start: 2005-09
• Study First Submitted: 2005-11-11
• Study First Submitted QC: 2005-11-11
• Study First Posted: 2005-11-15
• Primary Completion: 2012-12
• Study Completion: 2013-12
• Results First Submitted: 2014-08-25
• Results First Submitted QC: 2016-08-23
• Results First Posted: 2016-08-24
• Status Verified: 2023-04
• Last Update Submitted: 2023-04-06
• Last Update Posted: 2023-04-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
All the patients enrolled in the study	Etoposide	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.
All the patients enrolled in the study	Filgrastim	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.
All the patients enrolled in the study	131I-MIBG	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.
All the patients enrolled in the study	Peripheral blood stem cell infusion	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.
All the patients enrolled in the study	Radiation therapy	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.
All the patients enrolled in the study	Carboplatin	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.
All the patients enrolled in the study	Melphalan	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.

Primary Outcome Measures

Name	Time	Method
Response (Complete Response, Very Good Partial Response, and Partial Response) at 60-days Post Stem Cell Infusion	Response assessed 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).

Secondary Outcome Measures

Name	Time	Method
Dose Limiting Veno-occlusive Disease (VOD) / Sinusoidal Obstruction Syndrome SOS	Between start of MIBG treatment and 60 days post stem cell infusion	Dose limiting veno-occlusive disease (VOD) defined as: * the presence of hepatomegaly with right upper quadrant tenderness and an elevation of total bilirubin \> grade 1, PLUS; * the presence of grade 3 abnormalities of any ONE of the following: total bilirubin, hypoalbuminemia, weight gain, or hypoxia without other attribution
Event-free Survival (EFS) at 3 Years	3 years since start of treatment	EFS will be measured from start of treatment until progression, death or start of another treatment - whichever comes first. We report the estimated probability of EFS at 3 years.
Engraftment DLT	From treatment start until 60 days post stem cell infusion	• Engraftment toxicity: delayed engraftment and/or failure to engraft defined as: * neutrophils (ANC) \< 500/μL by day 28 post transplant, or; * platelets \< 20,000 /μL by day 56 post transplant, or; * if additional stem cells are required to be infused for any medical reason prior to initial engraftment of neutrophils or platelets.

Trial Locations

Locations (15)

AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus; 🇺🇸 Atlanta, Georgia, United States

Childrens Hospital Los Angeles; 🇺🇸 Los Angeles, California, United States

University of Chicago Comer Children's Hospital; 🇺🇸 Chicago, Illinois, United States

Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital; 🇺🇸 Houston, Texas, United States

Children's Hospital and Regional Medical Center - Seattle; 🇺🇸 Seattle, Washington, United States

Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada

C.S. Mott Children's Hospital at University of Michigan Medical Center; 🇺🇸 Ann Arbor, Michigan, United States

UCSF Helen Diller Family Comprehensive Cancer Center; 🇺🇸 San Francisco, California, United States

Lucile Packard Children's Hospital at Stanford University Medical Center; 🇺🇸 Palo Alto, California, United States

Cook Children's Medical Center - Fort Worth; 🇺🇸 Fort Worth, Texas, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States

Morgan Stanley Children's Hospital of New York-Presbyterian; 🇺🇸 New York, New York, United States

University of Wisconsin Paul P. Carbone Comprehensive Cancer Center; 🇺🇸 Madison, Wisconsin, United States