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

Sponsor

University of Leicester (Other)

Overall Status

Unknown status

CT.gov ID

NCT00030719

Collaborator

(none)

175

Enrollment

Locations

5.5

Patients Per Site

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Neuroblastoma	Biological: filgrastim Biological: monoclonal antibody Ch14.18 Drug: busulfan Drug: carboplatin Drug: cyclophosphamide Drug: etoposide Drug: isotretinoin Drug: melphalan Drug: vincristine sulfate Procedure: bone marrow ablation with stem cell support Procedure: conventional surgery Procedure: peripheral blood stem cell transplantation Radiation: radiation therapy	Phase 3

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

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

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

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 Design

Study Type:

Interventional

Anticipated Enrollment :

175 participants

Allocation:

Randomized

Primary Purpose:

Treatment

Official Title:

High Risk Neuroblastoma Study 1 Of Siop-Europe

Study Start Date :

Dec 1, 2001

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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 []

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 20 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Anna Children's Hospital	Vienna		Austria	A-1090
2	Universitair Ziekenhuis Gent	Ghent		Belgium	B-9000
3	Aarhus Universitetshospital - Aarhus Sygehus	Aarhus		Denmark	DK-8000
4	Institut Gustave Roussy	Villejuif		France	F-94805
5	Our Lady's Hospital for Sick Children Crumlin	Dublin		Ireland	12
6	Schneider Children's Medical Center of Israel	Petah-Tikva		Israel	49202
7	Fondazione Istituto Nazionale dei Tumori	Milan		Italy	20133
8	Rikshospitalet University Hospital	Oslo		Norway	0027
9	Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, SA	Lisbon		Portugal	1099-023 Codex
10	Hospital Universitario La Fe	Valencia		Spain	46009
11	Karolinska University Hospital - Solna	Stockholm		Sweden	S-171 76
12	Centre Hospitalier Universitaire Vaudois	Lausanne		Switzerland	CH-1011
13	Birmingham Children's Hospital	Birmingham	England	United Kingdom	B4 6NH
14	Institute of Child Health at University of Bristol	Bristol	England	United Kingdom	BS2 8AE
15	Addenbrooke's Hospital	Cambridge	England	United Kingdom	CB2 2QQ
16	Leeds Cancer Centre at St. James's University Hospital	Leeds	England	United Kingdom	LS9 7TF
17	Leicester Royal Infirmary	Leicester	England	United Kingdom	LE1 5WW
18	Royal Liverpool Children's Hospital, Alder Hey	Liverpool	England	United Kingdom	L12 2AP
19	Middlesex Hospital	London	England	United Kingdom	W1T 3AA
20	Great Ormond Street Hospital for Children	London	England	United Kingdom	WC1N 3JH
21	Royal Manchester Children's Hospital	Manchester	England	United Kingdom	M27 4HA
22	Sir James Spence Institute of Child Health at Royal Victoria Infirmary	Newcastle-Upon-Tyne	England	United Kingdom	NE1 4LP
23	Queen's Medical Centre	Nottingham	England	United Kingdom	NG7 2UH
24	Oxford Radcliffe Hospital	Oxford	England	United Kingdom	0X3 9DU
25	Children's Hospital - Sheffield	Sheffield	England	United Kingdom	S10 2TH
26	Southampton General Hospital	Southampton	England	United Kingdom	SO16 6YD
27	Royal Marsden - Surrey	Sutton	England	United Kingdom	SM2 5PT
28	Royal Belfast Hospital for Sick Children	Belfast	Northern Ireland	United Kingdom	BT12 6BE
29	Royal Aberdeen Children's Hospital	Aberdeen	Scotland	United Kingdom	AB25 2ZG
30	Royal Hospital for Sick Children	Edinburgh	Scotland	United Kingdom	EH9 1LF
31	Royal Hospital for Sick Children	Glasgow	Scotland	United Kingdom	G3 8SJ
32	Childrens Hospital for Wales	Cardiff	Wales	United Kingdom	CF14 4XW