N2001-02: I-MIBG With Intensive Chemotherapy and Autologous Stem Cell Rescue for High-Risk Neuroblastoma
Condition: Neuroblastoma
MeSH terms: Neuroblastoma
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Filgrastim; Carboplatin; Etoposide; Melphalan; Peripheral blood stem cell infusion; 131I-MIBG; Radiation therapy
Intervention type(s): Biological; Drug; Drug; Drug; Procedure; Radiation; Radiation
Intervention description(s): 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.; 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".; 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.; 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.; 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.; 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.; 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.
Other intervention name(s): G-CSF; cis-diammine; Paraplatin; Paraplatin-AQ; VP-16; Etopophos; L-phenylalanine mustard; L-PAM; Alkeran; Sarcolysin; Iobenguane I 131
Intervention MeSH terms: Carboplatin; Etoposide; Melphalan
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: recurrent neuroblastoma