Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Active	1 to 20 at diagnosis	Other	SIOP-EUROPE-HR-NBL-1 ESIOP, EU-20148, NCT00030719

Objectives

1. 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.
2. Compare the 3-year EFS in these patients treated with isotretinoin with or without monoclonal antibody Ch14.18 after myeloablative therapy.
3. Determine the response at metastatic sites after induction chemotherapy in these patients.
4. Determine the effect of metastatic disease response after induction chemotherapy on EFS, PFS, and OS in these patients.
5. Compare the toxicity and episodes of febrile neutropenia in patients treated with induction chemotherapy with or without filgrastim (G-CSF).
6. Determine the effect of elective hematopoietic support with G-CSF during induction chemotherapy on peripheral blood stem cell collection in these patients.
7. Compare the acute and long-term toxic effects of the 2 myeloablative therapy regimens in these patients.
8. Determine the effect of radiotherapy on pre-surgical tumor volume at the primary site on local control, EFS, PFS, and OS in these patients.
9. Determine the tolerability of isotretinoin with or without monoclonal antibody Ch14.18 after myeloablative therapy in these patients.

Entry 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

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

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

Expected Enrollment

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

Outcomes

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

Response rate assessed by the International Neuroblastoma Response Criteria after 4 and 8 induction chemotherapy courses
Event-free survival at 5 years
Overall survival
Toxicity
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

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

Trial Contact Information

Trial Lead Organizations

University Hospitals of Leicester NHS Trust

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

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 Popovic, MD	Ph:  41-21-314-3567
			Email: maja.beck-popovic@chuv.ch
United Kingdom
England
	Birmingham
	Birmingham Children's Hospital
		Martin 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 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 Gerrard, MBChB, FRCP, FRCPCH	Ph:  44-114-271-7366
			Email: mary.gerrard@sch.nhs.uk
	Southampton
	Southampton General Hospital
		Janice Kohler, MD, FRCP	Ph:  44-23-8079-6942
	Sutton
	Royal Marsden - Surrey
		Mary Taj, MD	Ph:  44-20-8642-6011 ext. 1307
Northern Ireland
	Belfast
	Royal Belfast Hospital for Sick Children
		Anthony McCarthy, MD	Ph:  44-289-063-3631
			Email: anthonymcarthy@royalhospital.n.i.nhs.uk
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 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

Registry Information
Official Title		High Risk Neuroblastoma Study 1 Of Siop-Europe
Trial Start Date		2001-12-15
Registered in ClinicalTrials.gov		NCT00030719
Date Submitted to PDQ		2001-12-14
Information Last Verified		2008-01-02

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