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Eligibility
for people ages up to 30 years
Location
at Oakland, California and other locations
Dates
study started

Description

Summary

This randomized phase III trial compares two different high-dose myeloablative chemotherapy regimens followed by autologous stem cell transplant as consolidation treatment of younger patients with high-risk neuroblastoma. All patients receive the same 6 cycles of initial multi-agent chemotherapy induction regimen. Peripheral blood stem cells are collected after the 2nd cycle of chemotherapy. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Patients underwent resection of their primary tumor mass after 5 cycles of chemotherapy. Those patients without progressive disease at completion of induction therapy who has sufficient stem cells collected and had adequate organ function were eligible to proceed to consolidation therapy. Those patients who met consolidation eligibility were randomized to either a single myeloablative regimen or 2 myeloablative regimens delivered in tandem followed by re-infusion of autologous stem cells. Patients received radiation therapy after recovery from the assigned myeloablative therapy. It is not yet known which regimen of high-dose chemotherapy is more effective for patients with high-risk neuroblastoma undergoing a peripheral blood stem cell transplant.

Official Title

Phase III Randomized Trial of Single vs. Tandem Myeloablative Consolidation Therapy for High-Risk Neuroblastoma

Details

PRIMARY OBJECTIVES:

I. 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.

II. 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.

III. 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 OBJECTIVES:

I. To evaluate the pharmacogenetic relationship of cyclophosphamide metabolizing enzymes (i.e., cytochrome p 450 2B6 [CYP2B6], CYP2C9, and glutathione S-transferase alpha 1 [GSTA1] genotypes) with toxicity and response following dose-intensive cyclophosphamide and topotecan induction chemotherapy.

II. To determine if resection completeness is predictive of local control rate or EFS rate in patients with high-risk neuroblastoma.

III. To prospectively describe the complications related to efforts at local control (i.e., surgery and radiotherapy) in patients with high-risk neuroblastoma.

IV. To describe the neurologic outcome of patients with paraspinal primary neuroblastoma tumors.

V. To determine the variability of isotretinoin pharmacokinetics (PKs) and relationship to pharmacogenomic parameters.

VI. To determine if isotretinoin PK levels are predictive of the EFS rate or associated with systemic toxicity following isotretinoin.

VII. To determine if pharmacogenomic variations are predictive of the EFS rate or associated with systemic toxicity following isotretinoin.

VIII. To evaluate total topotecan PKs and correlate with patient specific data for use in an ongoing topotecan population PK analysis.

IX. 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.

X. 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.

XI. To characterize minimal residual disease burden using reverse transcriptase-polymerase chain reaction (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.

XII. To evaluate the EFS and overall survival of patients nonrandomly assigned to treatment with single myeloablative transplant (Arm A).

OUTLINE:

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.

At end induction, those patients with adequate organ function and peripheral blood stem cell collection are eligible to undergo randomized assignment to Consolidation therapy. Randomization is stratified by initial stage of disease, MYCN status, 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 (single myeloablative regimen with autologous stem cell support, arm A or tandem (2) myeloablative regimens each followed by autologous stem cell support, arm B). 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 greater than 547 days of age with stage III, MYCN nonamplified tumor AND unfavorable histopathology or indeterminant histology will be nonrandomly assigned to Arm A.

Consolidation chemotherapy was recommended to begin 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 autologous peripheral blood stem cell transplant (PBSCT) 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. Following clinical recovery from initial myeloablative therapy, patients also receive melphalan, etoposide, and carboplatin as in Arm A but at reduced dosages. Patients undergo autologous PBSCT on day 0.

RADIOTHERAPY: Patients undergo external beam radiation therapy (EBRT) to primary site of disease as well as to MIBG-avid sites seen at pre-transplantation (i.e., end- induction) evaluation no sooner than day 28 and recommended by 42 days post-transplant. An additional boost of radiotherapy is administered to residual tumor at primary site.

MAINTENANCE THERAPY: Patients are encouraged to enroll onto Children's Oncology Group (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 of cyclophosphamide metabolites and the existence of polymorphisms in genes involved in cyclophosphamide metabolism, event-free survival, and toxicity rates; pharmacogenomics for uridine diphosphate (UDP) glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1), UGT2B7, CYP2C8 and CYP3A7 alleles; topotecan systemic clearance; survivin-specific cytotoxic T-lymphocytes (CTLs) detected using peptide/major histocompatibility complex (MHC) tetramers in human leukocyte antigen (HLA)-A2+ patients; interferon (IFN)-gamma production in enzyme-linked immunospot (ELISPOT) assays to APCs loaded with tumor ribonucleic acid (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 and immunohistochemistry (IHC).

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

Keywords

Localized Resectable Neuroblastoma Localized Unresectable Neuroblastoma Recurrent Neuroblastoma Regional Neuroblastoma Stage 4 Neuroblastoma Stage 4S Neuroblastoma Doxorubicin Liposomal doxorubicin Etoposide Etoposide phosphate Cyclophosphamide Carboplatin Melphalan Vincristine Topotecan Thiotepa Cisplatin Mechlorethamine Tretinoin Nitrogen Mustard Compounds Podophyllotoxin Lenograstim Isotretinoin Succinylcholine

Eligibility

For people ages up to 30 years

Inclusion Criteria:

  • 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 deoxyribonucleic acid [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
  • 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
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 10 times ULN for age
  • Not pregnant or nursing
  • Negative pregnancy test
  • Shortening fraction>= 27% by echocardiogram (ECHO) OR left ventricular ejection fraction (LVEF)>= 50% by radionuclide angiogram
  • No known contraindication (e.g., size, weight or physical condition) to peripheral blood stem cell collection
  • 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

Locations

  • Kaiser Permanente-Oakland
    Oakland, California, 94611, United States
  • Children's Hospital Central California
    Madera, California, 93636-8762, United States
  • Lucile Packard Children's Hospital Stanford University
    Palo Alto, California, 94304, United States
  • University of California Davis Comprehensive Cancer Center
    Sacramento, California, 95817, United States
  • Children's Hospital Los Angeles
    Los Angeles, California, 90027, United States
  • City of Hope Comprehensive Cancer Center
    Duarte, California, 91010, United States
  • City of Hope Medical Center
    Duarte, California, 91010, United States
  • Southern California Permanente Medical Group
    Downey, California, 90242, United States
  • Miller Children's and Women's Hospital Long Beach
    Long Beach, California, 90806, United States
  • Childrens Hospital of Orange County
    Orange, California, 92868, United States
  • Loma Linda University Medical Center
    Loma Linda, California, 92354, United States
  • Nevada Cancer Research Foundation CCOP
    Las Vegas, Nevada, 89106, United States

Details

Status
in progress, not accepting new patients
Start Date
Sponsor
Children's Oncology Group
ID
NCT00567567
Phase
Phase 3
Study Type
Interventional
Last Updated
January 1, 2017