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

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Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIIBiomarker/Laboratory analysis, TreatmentActive1 to 20 at diagnosisOtherCDR0000069191
SIOP-EUROPE-HR-NBL-1, ESIOP, EU-20148, NCT00030719

Trial Description

Summary

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.

Further Study Information

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.

Eligibility Criteria

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

Trial Contact Information

Trial Lead Organizations/Sponsors

University Hospitals of Leicester NHS Trust

    Ruth Ladenstein, Study Chair

    Trial Sites

    Austria

    Vienna

    St. Anna Children's Hospital

    Ruth Ladenstein, MD
    Ph: 43-1-404-700

    Belgium

    Ghent

    Universitair Ziekenhuis Gent

    Genevieve Laureys, MD, PhD
    Ph: 32-9-240-21-11
    Email: Genevieve.Laureys@UGent.be

    Denmark

    Aarhus

    Aarhus Universitetshospital - Aarhus Sygehus

    Henrik Schroder, MD
    Ph: 45-89-49-44-44

    France

    Villejuif

    Institut Gustave Roussy

    D. Valteau-Couanet
    Ph: 33-1-4211-4339

    Ireland

    Dublin

    Our Lady's Hospital for Sick Children Crumlin

    Fin Breatnach, MD, FRCPE
    Ph: 353-1-409-6659
    Email: fin.breatnach@olhsc.ie

    Israel

    Petah-Tikva

    Schneider Children's Medical Center of Israel

    Isaac Yaniv, MD
    Ph: 972-3-925-3669
    Email: iyaniv@clalit.org.il

    Italy

    Milan

    Fondazione Istituto Nazionale dei Tumori

    Roberto Luksch, MD
    Ph: 39-02-2390-2592
    Email: luksch@institutotumori.mi.it

    Norway

    Oslo

    Rikshospitalet University Hospital

    Ingebjorg Storm-Mathisen, MD
    Ph: 47-23-07-45-60

    Portugal

    Lisbon

    Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, SA

    Ana Forjaz De Lacerda, MD, FAAP
    Ph: 351-21-726-0429
    Email: hdiap@ipolisboa.min-saude.pt

    Spain

    Valencia

    Hospital Universitario La Fe

    Victoria Castel
    Ph: 34-96-386-2700

    Sweden

    Stockholm

    Karolinska University Hospital - Solna

    Per Kogner, MD, PhD
    Ph: 46-85-177-3534
    Email: per.kogner@ki.se

    Switzerland

    Lausanne

    Centre Hospitalier Universitaire Vaudois

    Maja B. Popovic, MD
    Ph: 41-21-314-3567
    Email: maja.beck-popovic@chuv.ch

    United Kingdom

    Belfast

    Royal Belfast Hospital for Sick Children

    Anthony McCarthy, MD
    Ph: 44-289-063-3631
    Email: anthonymcarthy@royalhospital.n.i.nhs.uk

    England
    Birmingham

    Birmingham Children's Hospital

    Martin W. English, MD
    Ph: 44-121-333-8412
    Email: martin.english@bch.nhs.uk

    Bristol

    Institute of Child Health at University of Bristol

    Pamela Kearns, MD
    Ph: 44-117-342-8260

    Cambridge

    Addenbrooke's Hospital

    Amos Burke, MD
    Ph: 44-1223-348-151

    Leeds

    Leeds Cancer Centre at St. James's University Hospital

    Adam Glaser, MD
    Ph: 44-113-206-4984
    Email: adam.glaser@leedsth.nhs.uk

    Leicester

    Leicester Royal Infirmary

    Johann Visser, MD
    Ph: 44-116-258-5309
    Email: johannes.visser@uhl-tr.nhs.uk

    Liverpool

    Royal Liverpool Children's Hospital, Alder Hey

    Heather P. McDowell, MD
    Ph: 44-151-293-3679

    London

    Great Ormond Street Hospital for Children

    Penelope Brock, MD, PhD
    Ph: 44-20-7829-7924
    Email: Brockp@gosh.nhs.uk

    Middlesex Hospital

    Ananth Shankar, MD
    Ph: 44-20-7380-9300 ext. 9950

    Manchester

    Royal Manchester Children's Hospital

    Bernadette Brennan, MD
    Ph: 44-161-922-2227
    Email: bernadette.brennan@cmmc.nhs.uk

    Newcastle-Upon-Tyne

    Sir James Spence Institute of Child Health at Royal Victoria Infirmary

    Juliet Hale, MD
    Ph: 44-191-282-4101
    Email: j.p.hale@ncl.ac.uk

    Nottingham

    Queen's Medical Centre

    Martin Hewitt, MD, BSc, FRCP, FRCPCH
    Ph: 44-115-924-9924 ext. 43394
    Email: martin.hewitt@nuh.nhs.uk

    Oxford

    Oxford Radcliffe Hospital

    Kate Wheeler, MD
    Ph: 44-186-522-1066

    Sheffield

    Children's Hospital - Sheffield

    Mary P. Gerrard, MBChB, FRCP, FRCPCH
    Ph: 44-114-271-7366
    Email: mary.gerrard@sch.nhs.uk

    Southampton

    Southampton General Hospital

    Janice A. Kohler, MD, FRCP
    Ph: 44-23-8079-6942

    Sutton

    Royal Marsden - Surrey

    Mary Taj, MD
    Ph: 44-20-8642-6011 ext. 1307

    Scotland
    Aberdeen

    Royal Aberdeen Children's Hospital

    Veronica Neefjes
    Ph: 44-1224-550-217

    Edinburgh

    Royal Hospital for Sick Children

    W. Hamish Wallace, MD
    Ph: 44-131-536-0426

    Glasgow

    Royal Hospital for Sick Children

    Milind D. Ronghe, MD
    Ph: 44-141-201-9309

    Wales
    Cardiff

    Childrens Hospital for Wales

    Heidi Traunecker, MD, PhD
    Ph: 44-29-2074-2285
    Email: heidi.traunecker@cardiffandvale.wales.nhs.uk

    Link to the current ClinicalTrials.gov record.
    NLM Identifier NCT00030719
    ClinicalTrials.gov processed this data on April 09, 2015

    Note: Information about this trial is from the ClinicalTrials.gov database. The versions designated for health professionals and patients contain the same text. Minor changes may be made to the ClinicalTrials.gov record to standardize the names of study sponsors, sites, and contacts. Cancer.gov only lists sites that are recruiting patients for active trials, whereas ClinicalTrials.gov lists all sites for all trials. Questions and comments regarding the presented information should be directed to ClinicalTrials.gov.