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

NCT ID: NCT00253435

Last Updated: 2023-04-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-09-30
• Study Completion Date: 2013-12-31

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.

Conditions

Neuroblastoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

All the patients enrolled in the study

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.

Group Type: EXPERIMENTAL

Filgrastim

Intervention Type: 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.

Carboplatin

Intervention Type: 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".

Etoposide

Intervention Type: 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.

Melphalan

Intervention Type: 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.

Peripheral blood stem cell infusion

Intervention Type: 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.

131I-MIBG

Intervention Type: 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.

Radiation therapy

Intervention Type: 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.

Interventions

Filgrastim

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.

Intervention Type: BIOLOGICAL

Carboplatin

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".

Intervention Type: DRUG

Etoposide

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.

Intervention Type: DRUG

Melphalan

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.

Intervention Type: DRUG

Peripheral blood stem cell infusion

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.

Intervention Type: PROCEDURE

131I-MIBG

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.

Intervention Type: RADIATION

Radiation therapy

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.

Intervention Type: RADIATION

Other Intervention Names

G-CSF; cis-diammine; Paraplatin; Paraplatin-AQ; VP-16; Etopophos; L-phenylalanine mustard; L-PAM; Alkeran; Sarcolysin; Iobenguane I 131

Eligibility Criteria

Inclusion Criteria

• 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

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 29 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Children's Hospital Los Angeles

OTHER

Sponsor Role: lead

Responsible Party

Nant Operations Center

NANT Operations Center

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Gregory Yanik, MD

Role: STUDY_CHAIR

University of Michigan Rogel Cancer Center

Katherine K. Matthay, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

John M. Maris, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Philadelphia

Locations

Childrens Hospital Los Angeles

Los Angeles, California, United States

Lucile Packard Children's Hospital at Stanford University Medical Center

Palo Alto, California, United States

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, United States

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

Atlanta, Georgia, 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

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

Ann Arbor, Michigan, United States

Morgan Stanley Children's Hospital of New York-Presbyterian

New York, New York, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Cook Children's Medical Center - Fort Worth

Fort Worth, Texas, 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

University of Wisconsin Paul P. Carbone Comprehensive Cancer Center

Madison, Wisconsin, United States

Hospital for Sick Children

Toronto, Ontario, Canada

Countries

United States; Canada

Other Identifiers

P01CA081403

Identifier Type: NIH

Identifier Source: secondary_id

View Link

N2001-02

Identifier Type: OTHER

Identifier Source: secondary_id

CDR0000450148

Identifier Type: -

Identifier Source: org_study_id