Trial Information

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

OBJECTIVES:

Primary

- 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.

- 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.

- 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

- 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.

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

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

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

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

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

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

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

- 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.

- 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.

- 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.

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

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 and IHC.

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