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Clinical Trials (PDQ®)

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

Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

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 LadensteinStudy 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 Identifer NCT00030719
ClinicalTrials.gov processed this data on September 16, 2014

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.

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