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

Neuroblastoma Clinical Trial

Official title:

High Risk Neuroblastoma Study 1 Of Siop-Europe

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00030719
• Other study ID #: CDR0000069191
• Secondary ID: SIOP-EUROPE-HR-N
• Status: Recruiting
• Phase: Phase 3
• First received: February 14, 2002
• Last updated: June 23, 2014
• Start date: December 2001

Study information

• Verified date: August 2010
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Unspecified
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 175
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 20 Years

Eligibility

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

Study Design

Allocation: Randomized, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Neuroblastoma

Intervention

Biological:
• filgrastim

• monoclonal antibody Ch14.18

Drug:
• busulfan

• carboplatin

• cyclophosphamide

• etoposide

• isotretinoin

• melphalan

• vincristine sulfate

Procedure:
• bone marrow ablation with stem cell support

• conventional surgery

• peripheral blood stem cell transplantation

Radiation:
• radiation therapy

Locations

Country	Name	City	State
Austria	St. Anna Children's Hospital	Vienna
Belgium	Universitair Ziekenhuis Gent	Ghent
Denmark	Aarhus Universitetshospital - Aarhus Sygehus	Aarhus
France	Institut Gustave Roussy	Villejuif
Ireland	Our Lady's Hospital for Sick Children Crumlin	Dublin
Israel	Schneider Children's Medical Center of Israel	Petah-Tikva
Italy	Fondazione Istituto Nazionale dei Tumori	Milan
Norway	Rikshospitalet University Hospital	Oslo
Portugal	Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, SA	Lisbon
Spain	Hospital Universitario La Fe	Valencia
Sweden	Karolinska University Hospital - Solna	Stockholm
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne
United Kingdom	Royal Aberdeen Children's Hospital	Aberdeen	Scotland
United Kingdom	Royal Belfast Hospital for Sick Children	Belfast	Northern Ireland
United Kingdom	Birmingham Children's Hospital	Birmingham	England
United Kingdom	Institute of Child Health at University of Bristol	Bristol	England
United Kingdom	Addenbrooke's Hospital	Cambridge	England
United Kingdom	Childrens Hospital for Wales	Cardiff	Wales
United Kingdom	Royal Hospital for Sick Children	Edinburgh	Scotland
United Kingdom	Royal Hospital for Sick Children	Glasgow	Scotland
United Kingdom	Leeds Cancer Centre at St. James's University Hospital	Leeds	England
United Kingdom	Leicester Royal Infirmary	Leicester	England
United Kingdom	Royal Liverpool Children's Hospital, Alder Hey	Liverpool	England
United Kingdom	Great Ormond Street Hospital for Children	London	England
United Kingdom	Middlesex Hospital	London	England
United Kingdom	Royal Manchester Children's Hospital	Manchester	England
United Kingdom	Sir James Spence Institute of Child Health at Royal Victoria Infirmary	Newcastle-Upon-Tyne	England
United Kingdom	Queen's Medical Centre	Nottingham	England
United Kingdom	Oxford Radcliffe Hospital	Oxford	England
United Kingdom	Children's Hospital - Sheffield	Sheffield	England
United Kingdom	Southampton General Hospital	Southampton	England
United Kingdom	Royal Marsden - Surrey	Sutton	England

Sponsors (1)

Lead Sponsor	Collaborator
University of Leicester

Countries where clinical trial is conducted

Austria,  Belgium,  Denmark,  France,  Ireland,  Israel,  Italy,  Norway,  Portugal,  Spain,  Sweden,  Switzerland,  United Kingdom, 

References & Publications (1)

Ladenstein R, Valteau-Couanet D, Brock P, Yaniv I, Castel V, Laureys G, Malis J, Papadakis V, Lacerda A, Ruud E, Kogner P, Garami M, Balwierz W, Schroeder H, Beck-Popovic M, Schreier G, Machin D, Pötschger U, Pearson A. Randomized Trial of prophylactic gr — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free survival at 3 years			No
Primary	Mean number of febrile events during induction			No
Secondary	Response rate assessed by the International Neuroblastoma Response Criteria after 4 and 8 induction chemotherapy courses			No
Secondary	Event-free survival at 5 years			No
Secondary	Overall survival			No
Secondary	Toxicity			Yes
Secondary	Biological factors (i.e., MycNM amplification, 1p deletion, ploidy, 17 q+, CD44, and Trk-A)			No
Secondary	Serum concentrations of lactic dehydrogenase, ferritin, neurone specific enolase			No
Secondary	Urinary catecholamines at diagnosis			No