Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Comparing Two Different Myeloablation Therapies in Treating Young Patients Who Are Undergoing a Stem Cell Transplant for High-Risk Neuroblastoma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Biomarker/Laboratory analysis, Treatment	Temporarily closed	30 and under	NCI	COG-ANBL0532 ANBL0532, NCT00567567

Objectives

Primary

1. To improve the 3-year event-free survival (EFS) rate of high-risk neuroblastoma patients through treatment with a tandem consolidation of thiotepa/cyclophosphamide followed by carboplatin/etoposide/melphalan (CEM) as compared to single CEM consolidation.
2. To improve the rate of end-induction complete response and very good partial response, compared to historical controls, by use of a topotecan-containing induction regimen.
3. To improve the 3-year local control rate, compared to historical controls, by increasing the local dose of radiation to the residual primary tumor for patients with less than a gross total resection.

Secondary

1. To evaluate the pharmacogenetic relationship of cyclophosphamide metabolizing enzymes (i.e., CYP2B6, CYP2C9, and GSTA1 genotypes) with toxicity and response following dose-intensive cyclophosphamide and topotecan induction chemotherapy.
2. To determine if resection completeness is predictive of local control rate or EFS rate in patients with high-risk neuroblastoma.
3. To prospectively describe the complications related to efforts at local control (i.e., surgery and radiotherapy) in patients with high-risk neuroblastoma.
4. To describe the neurologic outcome of patients with paraspinal primary neuroblastoma tumors.
5. To determine the variability of isotretinoin pharmacokinetics (PKs) and relationship to pharmacogenomic parameters.
6. To determine if isotretinoin PK levels are predictive of the EFS rate or associated with systemic toxicity following isotretinoin.
7. To determine if pharmacogenomic variations are predictive of the EFS rate or associated with systemic toxicity following isotretinoin.
8. To evaluate total topotecan PKs and correlate with patient specific data for use in an ongoing topotecan population PK analysis.
9. To evaluate the presence and function of T cells capable of recognizing neuroblastoma by assessing the following: if T cells recognizing the neuroblastoma antigen, survivin, circulate at diagnosis; if these T cells can be expanded using autologous antigen presenting cells (APCs); if these T cells will kill neuroblastoma cells as detected in functional assays; and if the presence and activity of anti-neuroblastoma immunity is decreased by stem cell transplantation.
10. To characterize the recovery of T-cell numbers after myeloablative consolidation and hematopoietic stem cell transplantation (HSCT) and to assess the impact of tandem myeloablative consolidation on T-cell recovery.
11. To characterize minimal residual disease burden using RT-PCR evaluation of a panel of neuroblastoma specific transcripts in patient bone marrow and peripheral blood following induction chemotherapy and after single versus tandem myeloablative chemotherapy and to evaluate impact on EFS.
12. To evaluate the EFS and overall survival of patients nonrandomly assigned to treatment with single myeloablative transplant (Arm A).

Entry Criteria

Disease Characteristics:

• Diagnosis of neuroblastoma or ganglioneuroblastoma by histology or as evidenced by the presence of clumps of tumor cells in bone marrow and elevated catecholamine metabolites in urine meeting any of the following criteria:
  • Patients with newly diagnosed neuroblastoma with International Neuroblastoma Staging System (INSS) stage 4 disease are eligible with the following:
    • MYCN amplification (i.e., greater than four-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features
    • Age > 18 months (i.e., > 547 days) regardless of biologic features
    • Age 12-18 months (i.e., 365-547 days) with none of the following three favorable biologic features (i.e., non-amplified MYCN, favorable pathology, and DNA index > 1)
  • Patients with newly diagnosed neuroblastoma with INSS stage 3 are eligible with the following:
    • MYCN amplification (i.e., greater than four-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features
    • Age > 18 months (i.e., > 547 days) with unfavorable pathology, regardless of MYCN status
  • Patients with newly diagnosed INSS stage 2a or 2b with MYCN amplification (i.e., greater than four-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features
  • Patients with newly diagnosed INSS stage 4s with MYCN amplification (i.e., greater than four-fold increase in MYCN signals as compared to reference signals), regardless of additional biologic features
  • Patients ≥ 365 days initially diagnosed with INSS stage 1, 2, or 4S and who progressed to a stage 4 without interval chemotherapy
    • Must have been enrolled on COG-ANBL00B1

Prior/Concurrent Therapy:

• No prior systemic therapy except for localized emergency radiation to sites of life-threatening or function-threatening disease
• No more than one course of chemotherapy per low- or intermediate-risk neuroblastoma therapy prior to determination of MYCN amplification and histology

Patient Characteristics:

• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70mL/min OR serum creatinine based on age/gender as follows:
  • 1 month to < 6 months: 0.4 mg/dL
  • 6 months to < 1 year: 0.5 mg/dL
  • 1 to < 2 years: 0.6 mg/dL
  • 2 to < 6 years: 0.8 mg/dL
  • 6 to < 10 years: 1 mg/dL
  • 10 to < 13 years: 1.2 mg/dL
  • 10 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female)
  • ≥ 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age
• AST or ALT < 10 times ULN for age
• Not pregnant or nursing
• Negative pregnancy test
• Shortening fraction ≥ 27% by ECHO OR LVEF ≥ 50% by radionuclide angiogram
• No known contraindication (e.g., size, weight or physical condition) to peripheral blood stem cell collection

Expected Enrollment

Outcomes

Event-free survival rate
Response after induction therapy
Incidence rate of local recurrence

Duration of ≥ grade 3 neutropenia during course one
Duration of ≥ grade 3 thrombocytopenia during course one
Response rate after two courses of induction therapy

Outline

This is a multicenter study.

• Induction chemotherapy:
  • Courses 1 and 2: Patients receive cyclophosphamide IV over 30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 and filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients undergo peripheral blood stem cell (PBSC) mobilization and harvest after course 2.
  • Courses 3 and 5: Patients receive cisplatin IV over 1 hour on days 1-4, etoposide IV over 1 hour on days 1-3, and G-CSF SC or IV beginning on day 5 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients undergo surgical resection of soft tissue disease after course 5 (or after course 6 if medically necessary).
  • Courses 4 and 6: Patients receive cyclophosphamide IV over 6 hours on days 1-2, doxorubicin hydrochloride IV over 24 hours on days 1-3, vincristine IV on days 1-3, and G-CSF SC or IV beginning on day 5 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses.

Patients are then stratified by initial stage of disease and MYCN status, biologic characteristics, and response to induction chemotherapy (complete response/very good partial response vs partial response vs mixed response/no response). Patients are randomized to 1 of 2 arms. Patients 12–18 months old (i.e., 365-547 days) with stage IV, MYCN nonamplified tumor with unfavorable histopathology or diploid DNA content or with indeterminant histology or ploidy AND patients who are > 547 days of age with stage III, MYCN nonamplified tumor AND unfavorable histopathology or indeterminant histology will be nonrandomly assigned to Arm A. Patients begin consolidation chemotherapy no later than 8 weeks after the start of induction course 6.

• Consolidation therapy:
  • Arm A (single myeloablative consolidation): Patients receive melphalan IV over 15-30 minutes on days -7 to -5, etoposide IV over 24 hours and carboplatin IV over 24 hours on days -7 to -4, and G-CSF SC or IV beginning on day 0 and continuing until blood counts recover. Patients undergo PBSC reinfusion on day 0.
  • Arm B (tandem myeloablative consolidation): Patients receive thiotepa IV over 2 hours on days -7 to -5, cyclophosphamide IV over 1 hour on days -5 to -2, and G-CSF SC or IV beginning on day 0 and continuing until blood counts recover. Patients undergo PBSC reinfusion on day 0. Following clinical recovery from initial myeloablative therapy, patients also receive melphalan, etoposide, and carboplatin as in Arm A. Patients undergo PBSC reinfusion on day 0.
• Radiotherapy: Patients undergo radiotherapy to primary site of disease as well as to MIBG-avid sites seen at pre-transplantation (i.e., end-induction) evaluation between 28-42 days post-transplant. Additional radiotherapy is administered to residual tumor at primary site.
• Maintenance therapy: Patients are encouraged to enroll onto COG-ANBL0032 following assessment of tumor response after completion of the consolidation phase and radiotherapy. Beginning on day 60 post-transplantation patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for up to 6 months in the absence of disease progression or unacceptable toxicity.

Patients undergo blood and tissue sample collection periodically for the following analyses: correlation between peak serum concentration level and the existence of polymorphisms, event-free survival, and toxicity rates; pharmacogenomics for UGT1A1, UGT2B7, CYP2C8 and CYP3A7 alleles; topotecan systemic clearance; survivin-specific cytotoxic T-lymphocytes (CTLs) detected using peptide/MHC tetramers in HLA-A2+ patients; IFN-gamma production in ELISPOT assays to antigen-presenting cells (APCs) loaded with tumor RNA, survivin RNA, or control RNA; response of APC-stimulated CTL response to neuroblastoma cells; rate of T cell recovery; and proportion of patients with neuroblastoma detected in bone marrow and peripheral blood using RT-PCR.

After completion of study treatment, patients are followed periodically for 5 years and then annually thereafter.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Julie Park, MD, Protocol chair		Ph: 206-987-2106

Registry Information
Official Title		Phase III Randomized Trial of Single vs. Tandem Myeloablative Consolidation Therapy for High-Risk Neuroblastoma
Trial Start Date		2007-11-05
Trial Completion Date		2011-03-26 (estimated)
Registered in ClinicalTrials.gov		NCT00567567
Date Submitted to PDQ		2007-11-06
Information Last Verified		2009-11-25
NCI Grant/Contract Number		CA98543

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