Protracted Etoposide During Induction Therapy for High Risk Neuroblastoma
Condition: Neuroblastoma
MeSH terms: Neuroblastoma
Intervention: Protracted Oral Etoposide; Doxorubicin; IV Bolus Etoposide; Cisplatin; Cyclophosphamide; Mesna; Hematopoietic Factor; Primary tumor resection
Intervention description: Cisplatin with Oral Protracted Etoposide for cycles 1, 2 and 4
Day 1 - 5
Hour 0: Etoposide 50 mg/m2 po daily
Hours 1 to 7: Cisplatin 40 mg/m2
Day 6 - 14
Etoposide 50 mg/m2 po once daily; Given together with cyclophosphamide for cycle 3 and 5 of induction chemotherapy Day 1 and 2
Hours 0 to 6: Cyclophosphamide 2000 mg/m2 (67 mg/kg if < 12 kg) with Mesna 400 mg/m2 (13 mg/kg if < 12 kg) in D5½NS 600 mL/m2 IV over 6 hours to run at 100 mL/m2/hr
Hours 6 to 6.25: Doxorubicin 37.5 mg/m2 (1.25 mg/kg if < 12 kg) IV over 15 minutes; Cisplatin with Bolus IV Etoposide
Day 1
Hours 0 to 6: Cisplatin 40 mg/m2
Days 2, 3, 4:
Hours 0 to 1: Etoposide 200 mg/m2 Hours 1 to 7: Cisplatin 40 mg/m2
Day 5:
Hours 0 to 6: Cisplatin 40 mg/m2; Cycle 1, 2, and 4; Cycle 3 and 5 with doxorubicin; Standard weight-based dosing with cyclophosphamide; Standard weight-based dosing after cycle 3 and 5 and if needed for neutropenic recovery after cycles 1,2 and 4; Resection of primary tumor after cycle 3, 4, or 5 as clinically appropriate
Intervention MeSH terms: Cyclophosphamide; Doxorubicin; Etoposide; Etoposide phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Healthy volunteers: No
Keywords: Neuroblastoma; Etoposide; Cisplatin; Adriamycin; Cyclophosphamide; Cytoxan

Summary:

      High-risk neuroblastoma is an aggressive childhood cancer that shows up as a lump or mass in
      the belly or around the spinal cord in the chest, neck, or pelvis. Often the tumor has spread
      around the body to the bones or to the soft center of the bone, called the bone marrow.
      High-risk neuroblastoma often responds to treatment at first, but it frequently comes back
      and may be even more difficult to treat.

      Chemotherapy (drug treatments for cancer) is usually given at high doses in short bursts (3
      to 5 days) followed by a few weeks of rest and recovery. This burst and recovery is called a
      "cycle" and usually takes about 21 days. Some scientists and physicians have tried to give
      chemotherapy at lower doses for more days, called "metronomic" chemotherapy. This method of
      giving chemotherapy has been used to treat neuroblastoma that has failed more standard types
      of treatment (relapsed neuroblastoma) and has shown some promise for those patients. One of
      the reasons it may work is by killing the blood vessels that feed the tumor as well as
      killing tumor cells themselves (the way that burst chemotherapy works). We think that giving
      a burst of chemotherapy together with metronomic therapy may kill the tumor while decreasing
      the side effects that we have seen in the past.

      Treatment for high risk neuroblastoma usually occurs in 3 stages: induction, consolidation,
      and maintenance. During the induction phase, patients will receive chemotherapy and possibly
      more surgery to get rid of most of the tumor cells. Most of the chemotherapy drugs during
      induction will be given in the standard burst method. One of the chemotherapy drugs,
      etoposide, will be given in lower, metronomic doses. The doctors will study how the tumors
      respond and the side effects patients have. After induction most childrens' tumors will have
      disappeared, also called remission. These children will receive the second stage of treatment
      called consolidation. During this stage, subjects will receive radiation treatments to the
      tumor and then higher doses of chemotherapy. Because of the side effects of the high doses of
      chemotherapy, we will collect and store some special blood cells (called hematopoietic stem
      cells) early in treatment and keep them frozen. After the high doses of chemotherapy, these
      cells will be thawed and given to the subject. . This is called hematopoietic stem cell
      transplant (HSCT). The final stage of treatment, called maintenance, consists of a drug taken
      by mouth for 6 months.

      Surgery to remove large, or bulky, tumors is a standard part of treatment for high risk
      neuroblastoma. A few children can have their main tumor removed before chemotherapy, but most
      require the tumor to shrink first. Surgery has usually been scheduled for after 3 to 5 cycles
      of therapy, but no one really knows how quickly the tumors are ready to come out. Because
      chemotherapy has significant side effects that can change the risks of surgery, we will study
      how early surgeries to remove tumors can happen.

      This study is being done to evaluate the outcomes of disease response and survival in
      children with high risk neuroblastoma treated on this regimen.
    

Eligibility criteria:

        Inclusion Criteria:

        Pts can be enrolled but receive standard etoposide bolus dosing based on clinical
        conditions at diagnosis (need for emergency intervention because of renal, neurologic, or
        airway compromise). Pts who meet all other eligibility criteria may also choose to
        participate in the clinical trial w/o receiving the upfront window protracted dosing of
        etoposide; these children will receive standard etoposide bolus dosing.

        Less than 18 yo at diagnosis

        DIAGNOSIS Neuroblastoma or ganglioneuroblastoma verified by histology and/or demonstration
        of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites.

        Pts with newly diagnosed neuroblastoma and age 365 or more days with the following: * INSS
        Stage 2a/2b with MYCN amplification , AND unfavorable pathology * INSS Stage 3 with MYCN
        amplification AND/OR unfavorable pathology

        Pts with newly diagnosed neuroblastoma with INSS Stage 4 are eligible with the following: *
        Age more than 18 months (greater than 547 days) regardless of biologic features * Age 12 to
        18 months (365-547 days) with any unfavorable biologic feature (MYCN amplification,
        unfavorable pathology and/or DNA index equal to 1) or any biologic feature that is
        indeterminant/unsatisfactory/unknown.

        Pts with newly diagnosed neuroblastoma and age less than 365 days with INSS Stage 3, 4, 4S
        neuroblastoma with MYCN amplification (more than 10).

        Pts 365 days or more initially diagnosed with INSS stage 1, 2, 4S who develop distant
        metastatic disease (meet criteria for INSS stage 4).

        Pts may have had no prior systemic therapy except:

          -  Localized emergency radiation to sites of life threatening or function-threatening
             disease

          -  No more than one cycle of chemotherapy according to the intergroup low or intermediate
             risk neuroblastoma studies prior to determination of MYCN amplification and histology.

        TIME FROM DIAGNOSIS Pts must be entered on this study - Within 3 weeks of diagnosis - After
        recovery from only 1 cycle of chemo on low/intermediate risk NB therapy, - Within 3 weeks
        of progression with widely metastatic tumor for INSS stage 1, 2, 4S if they received no
        prior chemotherapy.

        HEMATOPOIETIC FUNCTION

          -  ANC 750/µL or more

          -  Plt 75,000/µL or more

          -  or bone marrow involvement with tumor.

        LIVER FUNCTION Pts must have adequate liver function defined as

          -  Direct Bilirubin 1.5 mg/dL or less

          -  AST and ALT 5 x ULN or less

        Pts of childbearing potential must practice an effective method of birth control while on
        study.

        Exclusion Criteria:

        Patients who do not meet inclusion criteria.

        Patients who are pregnant or lactating are not eligible.

        EXCLUSION CRITERIA UPFRONT WINDOW Patients can be enrolled onto Stratum 1 but receive
        standard etoposide bolus dosing based on clinical conditions at diagnosis. Patients who
        meet all other eligibility criteria may also choose to participate in the clinical trial
        without receiving the upfront window protracted dosing of etoposide; these children will
        receive standard etoposide bolus dosing.

        Patients whose tumor requires emergency intervention because of spinal cord compression,
        CNS compromise, or airway compromise.

        Patients requiring dialysis.

        If the patient and/or the patient's legally authorized guardian chose to participate in the
        clinical trial but chose to not participate in the phase II upfront window.