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Clinical Trials (PDQ®)

  • Last Modified: 8/18/2008

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Clinical Trials (PDQ®)

Phase III Study of Sequential Chemotherapy Regimens, Local Radiotherapy, and Marrow Chemoablation/Autologous Bone Marrow Rescue in Children and Adolescents Over 1 Year Old with Stage 4 or Stage 2B/3 N-myc-Amplified Neuroblastoma, with Investigational Window Study of CTX/TOPO in Stage 4 Patients

Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosed365 days to 20 yearsNCIPOG-9340-42
POG-9340, POG-9341, POG-9342

Objectives

I.  Evaluate the response rate and toxicity experienced by adolescents and 
children at least 365 days of age with previously untreated INSS Stage 4 
neuroblastoma treated with 2 courses of cyclophosphamide/topotecan (CTX/TOPO) 
in an investigational window setting prior to Phase III therapy (POG-9340).

II.  Measure response rate, toxicity, event-free and overall survival, and 
patterns of failure among children and adolescents with INSS Stage 4 or N-myc 
amplified INSS Stage 2B/3 neuroblastoma treated sequentially with high-dose 
cisplatin/etoposide (CDDP/VP-16), CTX/doxorubicin/vincristine (CAV), 
ifosfamide/VP-16, carboplatin/VP-16, CDDP/VP-16, and CAV, local radiotherapy, 
and marrow chemoablation/autologous bone marrow rescue (ABMT) (POG-9341 and 
POG-9342).

III.  Measure these same endpoints in children and adolescents for whom ABMT 
is refused and who instead receive 5 additional courses of multiregimen 
chemotherapy followed by local radiotherapy (POG-9341).

IV.  Evaluate further the toxicity of ABMT using marrow-ablative 
CTX/VP-16/carboplatin following local radiotherapy (POG-9342).

V.  Measure event-free survival, overall survival, and patterns of failure 
among patients who achieve a complete, partial, or mixed response following 
induction chemotherapy and prior to ABMT.

VI.  Evaluate further the biologic parameters of neuroblastoma as required for 
POG-9047, and measure and correlate initial and subsequent P-glycoprotein 
levels in marrow or tumor tissue with clinical presentation at diagnosis, 
clinical course, response to therapy, and survival.

Entry Criteria

Disease Characteristics:


Newly diagnosed, histologically proven neuroblastoma
  Eligible stages according to International Staging System:
     Stage 4 with any N-myc number
     Stage 2B/3 with N-myc amplification (> 1 copy per haploid genome)

  Histologic verification waived for Stage 4 patients with either:
     Extensive disease with bone marrow positive for tumor and elevated
     urinary catecholamines OR

     Positive marrow aspirate and negative urinary catecholamines but with
     positive electron microscopic findings or neuron-specific enolase in the
     marrow and presence of a primary thoracic or abdominal lesion containing
     calcifications

  Stage 2B/3 patients must be entered from protocol POG-9244 after
  determination of N-myc status and after 1 course of OPEC
  (vincristine/cyclophosphamide/cisplatin/etoposide) on that protocol
     Direct entry to protocol POG-9341 allowed after POG-9244 closes

Measurable disease required

Concurrent registration on protocol POG-9047 required

Concurrent registration on protocol POG-9280 (intergroup Neuroblastoma
Epidemiology Study) strongly encouraged for Stage D patients


Prior/Concurrent Therapy:


No prior therapy


Patient Characteristics:


Age:
  At least 365 days to under 21 years

Performance status:
  Not specified

Hematopoietic:
  Not specified

Hepatic:
  Not specified

Renal:
  Not specified


Expected Enrollment

137 patients will be entered over 1.2 years to protocol POG-9341.  If more 
than 5 transplant-related fatalities occur among the first 30 patients or if 
more than 10 occur prior to completion of accrual, the study may close early.

Outline

DIAGNOSTIC SURGERY is highly recommended, even in patients with positive bone 
marrow.

PROTOCOL POG-9340:  Stage 4 patients initially receive 2 courses of 
combination chemotherapy on Regimen A in an INVESTIGATIONAL WINDOW (in case of 
life-threatening disease or refusal of treatment on the Investigational 
Window, patients may begin Induction directly).

PROTOCOL POG-9341:  Stage 4 patients begin INDUCTION following Investigational 
Window, while Stage 2B/3 patients will have received 1 course of OPEC 
chemotherapy on protocol POG-9244 prior to starting Induction.  Patients in 
clinical CR, PR, or MR who have a negative marrow following Induction undergo 
POST-INDUCTION SURGERY followed by INTERIM THERAPY and, if still eligible, 
ABMT on protocol POG-9342; responders not eligible for or refusing ABMT do not 
undergo surgery at this time and begin POST-INDUCTION 
CHEMOTHERAPY/RADIOTHERAPY, while patients with no response go off study.

PROTOCOL POG-9342:  MARROW ABLATION/AUTOLOGOUS RESCUE.

The following acronyms are used:
  ABM      Autologous bone marrow
  ABMT     Autologous bone marrow transplantation
  CAV      CTX/DOX/VCR
  CBDCA    Carboplatin, NSC-241240
  CDDP     Cisplatin, NSC-119875
  CTX      Cyclophosphamide, NSC-26271
  DOX      Doxorubicin, NSC-123127
  G-CSF    Granulocyte Colony Stimulating Factor (Amgen), NSC-614629
  GM-CSF   Granulocyte-Macrophage Colony Stimulating Factor (Immunex),
           NSC-613795
  HD CDDP  High-dose CDDP
  IFF      Ifosfamide, NSC-109724
  Mesna    Mercaptoethane sulfonate, NSC-113891
  TOPO     Topotecan, NSC-609699
  VCR      Vincristine, NSC-67574
  VP-16    Etoposide, NSC-141540

DIAGNOSTIC SURGERY.  Biopsy with tumor excision as indicated.

PROTOCOL POG-9340.  INVESTIGATIONAL WINDOW.

Regimen A:  2-Drug Combination Chemotherapy.  CTX/TOPO.

PROTOCOL POG-9341.

INDUCTION:  5 Sequential 2- and 3-Drug Combination Chemotherapy Regimens:  
CDDP/VP-16; followed by CAV; followed by IFF/VP-16; followed by CBDCA/VP-16; 
followed by CDDP/VP-16.

POST-INDUCTION SURGERY (Patients clinically eligible for ABMT):  Documentation 
of disease status, tumor resection as indicated.

INTERIM THERAPY (Patients eligible for ABMT):  3-Drug Combination Chemotherapy 
followed by Radiotherapy.  CAV; followed by tumor-bed irradiation with Co60 or 
accelerator beams of at least 4 MV.  Marrow harvested between CAV and 
radiotherapy.

POST-INDUCTION CHEMOTHERAPY/RADIOTHERAPY (Patients ineligible for or refusing 
ABMT):  5 Sequential 2- and 3-Drug Combination Chemotherapy Regimens followed, 
in selected patients, by Radiotherapy.  IFF/VP-16; followed by CAV; followed 
by CDDP/VP-16; followed by CAV; followed by CBDCA/VP-16; followed, in patients 
refusing ABMT, by local irradiation as in INTERIM THERAPY.

PROTOCOL POG-9342.

MARROW ABLATION/AUTOLOGOUS RESCUE:  3-Drug Combination Ablative Chemotherapy 
followed by Autologous Bone Marrow Rescue followed by Hematopoietic 
Stimulation.  VP-16/CBDCA/CTX; followed by ABM; followed by GM-CSF.

Published Results

Zage PE, Kletzel M, Murray K, et al.: Outcomes of the POG 9340/9341/9342 trials for children with high-risk neuroblastoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 51 (6): 747-53, 2008.[PUBMED Abstract]

Kretschmar CS, Kletzel M, Murray K, et al.: Response to paclitaxel, topotecan, and topotecan-cyclophosphamide in children with untreated disseminated neuroblastoma treated in an upfront phase II investigational window: a pediatric oncology group study. J Clin Oncol 22 (20): 4119-26, 2004.[PUBMED Abstract]

Related Publications

Cantos MF, Gerstle JT, Irwin MS, et al.: Surgical challenges associated with intensive treatment protocols for high-risk neuroblastoma. J Pediatr Surg 41 (5): 960-5, 2006.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Pediatric Oncology Group

Cynthia Kretschmar, MD, Protocol chair
Ph: 617-636-5535
Email: ckretschmar@tufts-nemc.org

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.

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