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

Condition(s) targeted: Neuroblastoma

Intervention: busulfan (Drug); carboplatin (Drug); cyclophosphamide (Drug); etoposide (Drug); filgrastim (Drug); isotretinoin (Drug); melphalan (Drug); monoclonal antibody Ch14.18 (Drug); vincristine sulfate (Drug); bone marrow ablation with stem cell support (Procedure); conventional surgery (Procedure); peripheral blood stem cell transplantation (Procedure); radiation therapy (Procedure)

Phase: Phase 3

Status: Recruiting

Sponsored by: University Hospitals, Leicester

Official(s) and/or principal investigator(s):
Ruth Ladenstein, MD, Study Chair, Affiliation: St. Anna Children's Hospital

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.

Official title: High Risk Neuroblastoma Study 1 Of Siop-Europe

Study design: Treatment, Randomized, Active Control

Primary outcome:

Event-free survival at 3 years

Mean number of febrile events during induction

Secondary outcome:

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

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.

Minimum age: 1 Year. Maximum age: 20 Years. Gender(s): Both.

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

St. Anna Children's Hospital, Vienna A-1090, Austria; Recruiting
Ruth Ladenstein, MD, Phone: 43-1-404-700

Universitair Ziekenhuis Gent, Ghent B-9000, Belgium; Recruiting
Genevieve Laureys, MD, PhD, Phone: 32-9-240-21-11, Email: Genevieve.Laureys@UGent.be

Aarhus Universitetshospital - Aarhus Sygehus, Aarhus DK-8000, Denmark; Recruiting
Henrik Schroder, MD, Phone: 45-89-49-44-44

Institut Gustave Roussy, Villejuif F-94805, France; Recruiting
D. Valteau-Couanet, Phone: 33-1-4211-4339

Our Lady's Hospital for Sick Children Crumlin, Dublin 12, Ireland; Recruiting
Fin Breatnach, MD, FRCPE, Phone: 353-1-409-6659, Email: fin.breatnach@olhsc.ie

Schneider Children's Medical Center of Israel, Petah-Tikva 49202, Israel; Recruiting
Isaac Yaniv, MD, Phone: 972-3-925-3669, Email: iyaniv@clalit.org.il

Fondazione Istituto Nazionale dei Tumori, Milan 20133, Italy; Recruiting
Roberto Luksch, MD, Phone: 39-02-2390-2592, Email: luksch@institutotumori.mi.it

Rikshospitalet University Hospital, Oslo 0027, Norway; Recruiting
Ingebjorg Storm-Mathisen, MD, Phone: 47-23-07-45-60

Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, SA, Lisbon 1099-023 Codex, Portugal; Recruiting
Ana Forjaz De Lacerda, MD, FAAP, Phone: 351-21-726-0429, Email: hdiap@ipolisboa.min-saude.pt

Hospital Universitario La Fe, Valencia 46009, Spain; Recruiting
Victoria Castel, Phone: 34-96-386-2700

Karolinska University Hospital - Solna, Stockholm S-171 76, Sweden; Recruiting
Per Kogner, MD, PhD, Phone: 46-85-177-3534, Email: per.kogner@ki.se

Centre Hospitalier Universitaire Vaudois, Lausanne CH-1011, Switzerland; Recruiting
Maja B. Popovic, MD, Phone: 41-21-314-3567, Email: maja.beck-popovic@chuv.ch

Addenbrooke's Hospital, Cambridge, England CB2 2QQ, United Kingdom; Recruiting
Amos Burke, MD, Phone: 44-1223-348-151

Birmingham Children's Hospital, Birmingham, England B4 6NH, United Kingdom; Recruiting
Martin W. English, MD, Phone: 44-121-333-8412, Email: martin.english@bch.nhs.uk

Children's Hospital - Sheffield, Sheffield, England S10 2TH, United Kingdom; Recruiting
Mary P. Gerrard, BSc, MBChB, FRCP, FRCPCH, Phone: 44-114-271-7366, Email: mary.gerrard@sch.nhs.uk

Great Ormond Street Hospital for Children, London, England WC1N 3JH, United Kingdom; Recruiting
Penelope Brock, MD, PhD, Phone: 44-20-829-8832, Email: Brockp@gosh.nhs.uk

Institute of Child Health at University of Bristol, Bristol, England BS2 8AE, United Kingdom; Recruiting
Pamela Kearns, MD, Phone: 44-117-342-8260

Leeds Cancer Centre at St. James's University Hospital, Leeds, England LS9 7TF, United Kingdom; Recruiting
Adam Glaser, MD, Phone: 44-113-206-4984, Email: adam.glaser@leedsth.nhs.uk

Leicester Royal Infirmary, Leicester, England LE1 5WW, United Kingdom; Recruiting
Johann Visser, MD, Phone: 44-116-258-5309, Email: johannes.visser@uhl-tr.nhs.uk

Middlesex Hospital, London, England W1T 3AA, United Kingdom; Recruiting
Ananth Shankar, MD, Phone: 44-20-7380-9300 ext. 9950

Oxford Radcliffe Hospital, Oxford, England 0X3 9DU, United Kingdom; Recruiting
Kate Wheeler, MD, Phone: 44-186-522-1066

Queen's Medical Centre, Nottingham, England NG7 2UH, United Kingdom; Recruiting
Martin Hewitt, MD, BSc, FRCP, FRCPCH, Phone: 44-115-924-9924 ext. 43394, Email: martin.hewitt@nuh.nhs.uk

Royal Liverpool Children's Hospital, Alder Hey, Liverpool, England L12 2AP, United Kingdom; Recruiting
Heather P. McDowell, MD, Phone: 44-151-293-3679

Royal Manchester Children's Hospital, Manchester, England M27 4HA, United Kingdom; Recruiting
Bernadette Brennan, MD, Phone: 44-161-922-2227, Email: bernadette.brennan@cmmc.nhs.uk

Royal Marsden - Surrey, Sutton, England SM2 5PT, United Kingdom; Recruiting
Mary Taj, MD, Phone: 44-20-8642-6011 ext. 1307

Sir James Spence Institute of Child Health, Newcastle-Upon-Tyne, England NE1 4LP, United Kingdom; Recruiting
Juliet Hale, MD, Phone: 44-191-282-4101, Email: j.p.hale@ncl.ac.uk

Southampton General Hospital, Southampton, England SO16 6YD, United Kingdom; Recruiting
Janice A. Kohler, MD, FRCP, Phone: 44-23-8079-6942

Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland BT12 6BE, United Kingdom; Recruiting
Anthony McCarthy, MD, Phone: 44-289-063-3631, Email: anthonymcarthy@royalhospital.n.i.nhs.uk

Royal Aberdeen Children's Hospital, Aberdeen, Scotland AB25 2ZG, United Kingdom; Recruiting
Veronica Neefjes, Phone: 44-1224-550-217

Royal Hospital for Sick Children, Glasgow, Scotland G3 8SJ, United Kingdom; Recruiting
Milind D. Ronghe, MD, Phone: 44-141-201-9309

Royal Hospital for Sick Children, Edinburgh, Scotland EH9 1LF, United Kingdom; Recruiting
W. Hamish Wallace, MD, Phone: 44-131-536-0426

Childrens Hospital for Wales, Cardiff, Wales CF14 4XW, United Kingdom; Recruiting
Heidi Traunecker, MD, PhD, Phone: 44-29-2074-2285, Email: heidi.traunecker@cardiffandvale.wales.nhs.uk

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: December 2001
Last updated: August 23, 2008