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

This study has been completed.
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Nant Operations Center, Children's Hospital Los Angeles
ClinicalTrials.gov Identifier:
NCT00253435
First received: November 11, 2005
Last updated: August 23, 2016
Last verified: August 2016

November 11, 2005
August 23, 2016
September 2005
December 2012   (final data collection date for primary outcome measure)
Response (Complete Response, Very Good Partial Response, and Partial Response) at 60-days Post Stem Cell Infusion [ Time Frame: Response assessed 60 days post stem cell infusion ] [ Designated as safety issue: No ]
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).
Not Provided
Complete list of historical versions of study NCT00253435 on ClinicalTrials.gov Archive Site
  • Event-free Survival (EFS) at 3 Years [ Time Frame: 3 years since start of treatment ] [ Designated as safety issue: No ]
    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 [ Time Frame: From treatment start until 60 days post stem cell infusion ] [ Designated as safety issue: Yes ]

    • 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.
  • Dose Limiting Veno-occlusive Disease (VOD) / Sinusoidal Obstruction Syndrome SOS [ Time Frame: Between start of MIBG treatment and 60 days post stem cell infusion ] [ Designated as safety issue: Yes ]

    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
Not Provided
Not Provided
Not Provided
 
N2001-02: I-MIBG With Intensive Chemotherapy and Autologous Stem Cell Rescue for High-Risk Neuroblastoma
I-Metaiodobenzylguanidine (MIBG) With Intensive Chemotherapy and Autologous Stem Cell Rescue for High-Risk Neuroblastoma

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.

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.

Interventional
Phase 2
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Neuroblastoma
  • Biological: 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.
    Other Name: G-CSF
  • Drug: 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".
    Other Name: cis-diammine; Paraplatin; Paraplatin-AQ
  • 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.
    Other Name: VP-16; Etopophos
  • 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.
    Other Name: L-phenylalanine mustard; L-PAM; Alkeran; Sarcolysin
  • Procedure: 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.
  • Radiation: 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.
    Other Name: Iobenguane I 131
  • 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.
Experimental: 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.

Interventions:
  • Biological: Filgrastim
  • Drug: Carboplatin
  • Drug: Etoposide
  • Drug: Melphalan
  • Procedure: Peripheral blood stem cell infusion
  • Radiation: 131I-MIBG
  • Radiation: Radiation therapy
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
50
December 2013
December 2012   (final data collection date for primary outcome measure)

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
Both
1 Year to 29 Years   (Child, Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States,   Canada
 
NCT00253435
CDR0000450148, P01CA081403, N2001-02
Yes
Not Provided
Not Provided
Nant Operations Center, Children's Hospital Los Angeles
Children's Hospital Los Angeles
National Cancer Institute (NCI)
Study Chair: Gregory Yanik, MD University of Michigan Cancer Center
Principal Investigator: Katherine K. Matthay, MD University of California, San Francisco
Principal Investigator: John M. Maris, MD Children's Hospital of Philadelphia
Children's Hospital Los Angeles
August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP