Combination Chemotherapy With or Without Filgrastim Before Surgery, High-Dose Chemotherapy, and Radiation Therapy Followed by Isotretinoin With or Without Monoclonal Antibody in Treating Patients With Neuroblastoma

June 23, 2014 updated by: University of Leicester

High Risk Neuroblastoma Study 1 Of Siop-Europe

RATIONALE: Colony-stimulating factors such as filgrastim may increase the number of immune cells found in bone marrow or peripheral blood and may help a person's immune system recover from the side effects of chemotherapy. Combining chemotherapy with peripheral stem cell transplant may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining isotretinoin and monoclonal antibodies may kill any remaining tumor cells following surgery. It is not yet known which treatment regimen is more effective in treating neuroblastoma.

PURPOSE: This randomized phase III trial is studying how well combination chemotherapy with or without filgrastim before surgery, high-dose chemotherapy, and radiation therapy followed by isotretinoin with or without monoclonal antibody work in treating patients with neuroblastoma.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

  • Compare the efficacy of myeloablative therapy with busulfan and melphalan vs carboplatin, etoposide, and melphalan, in terms of 3- and 5-year event-free survival (EFS), progression-free survival (PFS), and overall survival (OS), in patients with high-risk neuroblastoma.
  • Compare the 3-year EFS in these patients treated with isotretinoin with or without monoclonal antibody Ch14.18 after myeloablative therapy.
  • Determine the response at metastatic sites after induction chemotherapy in these patients.
  • Determine the effect of metastatic disease response after induction chemotherapy on EFS, PFS, and OS in these patients.
  • Compare the toxicity and episodes of febrile neutropenia in patients treated with induction chemotherapy with or without filgrastim (G-CSF).
  • Determine the effect of elective hematopoietic support with G-CSF during induction chemotherapy on peripheral blood stem cell collection in these patients.
  • Compare the acute and long-term toxic effects of the 2 myeloablative therapy regimens in these patients.
  • Determine the effect of radiotherapy on pre-surgical tumor volume at the primary site on local control, EFS, PFS, and OS in these patients.
  • Determine the tolerability of isotretinoin with or without monoclonal antibody Ch14.18 after myeloablative therapy in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to disease stage (2 or 3 with MycN amplification vs 4). Patients are randomized to 1 of 8 treatment arms:

Arm I:

  • Patients receive induction chemotherapy comprising vincristine IV, carboplatin IV over 1 hour, and etoposide IV over 4 hours on days 1 and 41; vincristine IV and cisplatin IV over 24 hours on days 11, 31, 51, and 71; and vincristine IV on days 21 and 61 and cyclophosphamide IV and etoposide over 4 hours on days 21, 22, 61, and 62. Patients receive filgrastim (G-CSF) subcutaneously on days 3-8, 12-18, 23-28, 32-38, 43-48, 52-58, 63-68, and 72 until peripheral blood stem cell (PBSC) collection.
  • Patients undergo PBSC collection beginning on day 80. Patients then undergo surgery on day 95.
  • Patients receive myeloablative therapy comprising oral busulfan 4 times daily on days -6 to -3 and melphalan IV over 15 minutes on day -2. Patients undergo PBSC infusion on day 0.
  • Patients undergo radiotherapy in 14 fractions over 21 days.
  • Beginning within 30 days after radiotherapy, patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for 6 courses.

Arm II:

  • Patients receive induction chemotherapy as in arm I, but with no G-CSF. Patients then undergo PBSC collection and surgery as in arm I. Patients receive myeloablative therapy and undergo PBSC infusion as in arm I. Patients undergo radiotherapy as in arm I.
  • Patients receive oral isotretinoin twice daily on days 1-14 and monoclonal antibody Ch14.18 IV over 8 hours on days 1-5. Treatment repeats every 28 days for 6 courses for isotretinoin and every 28 days for 5 courses for monoclonal antibody Ch14.18.

Arm III:

  • Patients receive induction chemotherapy and G-CSF as in arm I. Patients then undergo PBSC collection and surgery as in arm I. Patients receive myeloablative therapy and undergo PBSC infusion as in arm I. Patients undergo radiotherapy as in arm I. Patients receive isotretinoin as in arm I.

Arm IV:

  • Patients receive induction chemotherapy as in arm II. Patients then undergo PBSC collection and surgery as in arm I. Patients receive myeloablative therapy and undergo PBSC infusion as in arm I. Patients undergo radiotherapy as in arm I. Patients receive isotretinoin and monoclonal antibody Ch14.18 as in arm II.

Arm V:

  • Patients receive induction chemotherapy and G-CSF as in arm I.
  • Patients receive myeloablative therapy comprising carboplatin IV continuously and etoposide IV continuously on days -7 to -4 and melphalan IV over 15 minutes on days -7 to -5. Patients undergo PBSC infusion on day 0.
  • Patients undergo radiotherapy as in arm I. Patients receive isotretinoin as in arm I.

Arm VI:

  • Patients receive induction chemotherapy as in arm II. Patients receive myeloablative therapy and undergo PBSC infusion as in arm V. Patients undergo radiotherapy as in arm I. Patients receive isotretinoin and monoclonal antibody Ch14.18 as in arm II.

Arm VII:

  • Patients receive induction chemotherapy and G-CSF as in arm I. Patients receive myeloablative therapy and undergo PBSC infusion as in arm V. Patients undergo radiotherapy as in arm I. Patients receive isotretinoin as in arm I.

Arm VIII:

  • Patients receive induction chemotherapy as in arm II. Patients receive myeloablative therapy and undergo PBSC infusion as in arm V. Patients undergo radiotherapy as in arm I. Patients receive isotretinoin and monoclonal antibody Ch14.18 as in arm II.

Patients on all treatment arms are followed every 6 months for 3 years and then annually for 2 years.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: Approximately 175 patients per year will be accrued for this study.

Study Type

Interventional

Enrollment (Anticipated)

175

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Austria
      • Vienna, Austria, A-1090
        • Recruiting
        • St. Anna Children's Hospital
  • Belgium
      • Ghent, Belgium, B-9000
        • Recruiting
        • Universitair Ziekenhuis Gent
        • Contact:
  • Denmark
      • Aarhus, Denmark, DK-8000
        • Recruiting
        • Aarhus Universitetshospital - Aarhus Sygehus
        • Contact:
          • Henrik Schroder, MD
          • Phone Number: 45-89-49-44-44
  • France
      • Villejuif, France, F-94805
        • Recruiting
        • Institut Gustave Roussy
        • Contact:
          • D. Valteau-Couanet
          • Phone Number: 33-1-4211-4339
  • Ireland
      • Dublin, Ireland, 12
        • Recruiting
        • Our Lady's Hospital for Sick Children Crumlin
  • Israel
      • Petah-Tikva, Israel, 49202
        • Recruiting
        • Schneider Children's Medical Center of Israel
        • Contact:
  • Italy
      • Milan, Italy, 20133
        • Recruiting
        • Fondazione Istituto Nazionale dei Tumori
        • Contact:
  • Norway
      • Oslo, Norway, 0027
        • Recruiting
        • Rikshospitalet University Hospital
        • Contact:
          • Ingebjorg Storm-Mathisen, MD
          • Phone Number: 47-23-07-45-60
  • Portugal
      • Lisbon, Portugal, 1099-023 Codex
        • Recruiting
        • Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, SA
        • Contact:
  • Spain
      • Valencia, Spain, 46009
        • Recruiting
        • Hospital Universitario la Fe
        • Contact:
          • Victoria Castel
          • Phone Number: 34-96-386-2700
  • Sweden
      • Stockholm, Sweden, S-171 76
        • Recruiting
        • Karolinska University Hospital - Solna
        • Contact:
  • Switzerland
      • Lausanne, Switzerland, CH-1011
        • Recruiting
        • Centre Hospitalier Universitaire Vaudois
        • Contact:
  • United Kingdom
    • England
      • Birmingham, England, United Kingdom, B4 6NH
        • Recruiting
        • Birmingham Children's Hospital
      • Bristol, England, United Kingdom, BS2 8AE
        • Recruiting
        • Institute of Child Health at University of Bristol
      • Cambridge, England, United Kingdom, CB2 2QQ
        • Recruiting
        • Addenbrooke's Hospital
      • Leeds, England, United Kingdom, LS9 7TF
        • Recruiting
        • Leeds Cancer Centre at St. James's University Hospital
      • Leicester, England, United Kingdom, LE1 5WW
        • Recruiting
        • Leicester Royal Infirmary
      • Liverpool, England, United Kingdom, L12 2AP
        • Recruiting
        • Royal Liverpool Children's Hospital, Alder Hey
      • London, England, United Kingdom, WC1N 3JH
        • Recruiting
        • Great Ormond Street Hospital for Children
        • Contact:
      • London, England, United Kingdom, W1T 3AA
        • Recruiting
        • Middlesex Hospital
      • Manchester, England, United Kingdom, M27 4HA
        • Recruiting
        • Royal Manchester Children's Hospital
      • Newcastle-Upon-Tyne, England, United Kingdom, NE1 4LP
        • Recruiting
        • Sir James Spence Institute of Child Health at Royal Victoria Infirmary
      • Nottingham, England, United Kingdom, NG7 2UH
        • Recruiting
        • Queen's Medical Centre
      • Oxford, England, United Kingdom, 0X3 9DU
        • Recruiting
        • Oxford Radcliffe Hospital
      • Sheffield, England, United Kingdom, S10 2TH
        • Recruiting
        • Children's Hospital - Sheffield
      • Southampton, England, United Kingdom, SO16 6YD
        • Recruiting
        • Southampton General Hospital
      • Sutton, England, United Kingdom, SM2 5PT
        • Recruiting
        • Royal Marsden - Surrey
    • Northern Ireland
      • Belfast, Northern Ireland, United Kingdom, BT12 6BE
        • Recruiting
        • Royal Belfast Hospital for Sick Children
    • Scotland
      • Aberdeen, Scotland, United Kingdom, AB25 2ZG
        • Recruiting
        • Royal Aberdeen Children's Hospital
      • Edinburgh, Scotland, United Kingdom, EH9 1LF
        • Recruiting
        • Royal Hospital for Sick Children
      • Glasgow, Scotland, United Kingdom, G3 8SJ
        • Recruiting
        • Royal Hospital for Sick Children
    • Wales
      • Cardiff, Wales, United Kingdom, CF14 4XW
        • Recruiting
        • Childrens Hospital for Wales

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 20 years (ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

  • Diagnosis of neuroblastoma according to International Neuroblastoma Staging System

    • Stage 2 or 3 with MycN amplification
    • Stage 4
  • Tumor material available for determination of biological prognostic factors

PATIENT CHARACTERISTICS:

Age:

  • 1 to 20 at diagnosis

Performance status:

  • Not specified

Life expectancy:

  • Not specified

Hematopoietic:

  • Not specified

Hepatic:

  • Bilirubin less than 3 times normal
  • ALT less than 3 times normal

Renal:

  • Creatinine less than 1.5 mg/mL
  • Creatinine clearance and/or glomerular filtration rate at least 60 mL/min

Cardiovascular:

  • Shortening fraction at least 28% OR
  • Ejection fraction at least 55%
  • No clinical congestive heart failure

Pulmonary:

  • Chest x-ray normal
  • Oxygen saturation normal

Other:

  • HIV negative
  • No Brock grade 2 or greater
  • No uncontrolled infections requiring IV antivirals, antibiotics, or antifungals
  • Not pregnant or nursing
  • Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

  • Not specified

Chemotherapy:

  • No more than 1 prior chemotherapy regimen for localized unresectable disease
  • No concurrent anthracyclines
  • No other concurrent chemotherapy

Endocrine:

  • Not specified

Radiotherapy:

  • Not specified

Surgery:

  • Not specified

Other:

  • No other concurrent investigational therapy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Event-free survival at 3 years
Mean number of febrile events during induction

Secondary Outcome Measures

Outcome Measure
Toxicity
Overall survival
Response rate assessed by the International Neuroblastoma Response Criteria after 4 and 8 induction chemotherapy courses
Event-free survival at 5 years
Biological factors (i.e., MycNM amplification, 1p deletion, ploidy, 17 q+, CD44, and Trk-A)
Serum concentrations of lactic dehydrogenase, ferritin, neurone specific enolase
Urinary catecholamines at diagnosis

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Leicester

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2001

Study Registration Dates

First Submitted

February 14, 2002

First Submitted That Met QC Criteria

January 26, 2003

First Posted (ESTIMATE)

January 27, 2003

Study Record Updates

Last Update Posted (ESTIMATE)

June 24, 2014

Last Update Submitted That Met QC Criteria

June 23, 2014

Last Verified

August 1, 2010

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000069191
  • SIOP-EUROPE-HR-NBL-1
  • ESIOP
  • EU-20148

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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