Combination Chemotherapy Plus Peripheral Stem Cell Transplantation With or Without Rituximab in Treating Patients With Relapsed Non-Hodgkin's Lymphoma

Randomized Study of Rituximab (Mabthera) in Patients With Relapsed Follicular Lymphoma Prior to High-Dose Therapy as In Vivo Purging and to Maintain Remission Following High-Dose Therapy

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. It is not yet known if combination chemotherapy plus peripheral stem cell transplantation is more effective with or without rituximab for non-Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is studying giving combination chemotherapy and peripheral stem cell transplantation together with rituximab to see how well it works compared to combination chemotherapy and peripheral stem cell transplantation alone in treating patients with relapsed non-Hodgkin's lymphoma.

Study Overview

• Status: Completed
• Conditions: Lymphoma
• Intervention / Treatment: Drug: cyclophosphamide; Drug: cytarabine; Drug: etoposide; Procedure: peripheral blood stem cell transplantation; Biological: filgrastim; Biological: rituximab; Drug: melphalan; Drug: carmustine; Procedure: bone marrow ablation with stem cell support

Detailed Description

OBJECTIVES:

• Determine the effects of in vivo rituximab purging and maintenance on progression-free survival in patients with relapsed or resistant follicular non-Hodgkin's lymphoma undergoing high-dose chemotherapy.
• Determine the effects of this regimen on response rate and overall survival in this patient population.
• Determine the effects of in vivo purging with rituximab on molecular remission rates in the hematopoietic product and the patients.
• Determine the safety of rituximab in the transplant setting.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to type of remission (complete vs good partial) and which remission (second vs third). Patients are randomized to one of four treatment arms.

All patients receive induction chemotherapy comprising cyclophosphamide IV over 3-4 hours on day 0 or a standard induction chemotherapy regimen. Filgrastim (G-CSF) is administered subcutaneously daily beginning on day 1.

Patients are then randomized to receive either in vivo rituximab purging or no purging following restaging after completion of induction. For those patients receiving purging (arms I and II), rituximab is administered IV once weekly for 4 weeks.

Peripheral blood stem cells (PBSC) are collected between days 8 and 12 post induction chemotherapy. Within 4 weeks of PBSC collection, patients receive carmustine IV over 2 hours on day -6, etoposide IV over 2 hours on days -5 to -2, cytarabine IV over 5 minutes twice daily on days -5 to -2, and melphalan IV over 10-15 minutes on day -1. (Alternatively, high dose cyclophosphamide and total body irradiation beginning 2-4 weeks after cyclophosphamide or standard induction chemotherapy priming is also allowed.) PBSC are reinfused on day 0.

Patients are further randomized to receive either rituximab maintenance or observation only. For those patients receiving maintenance (arms I and III), rituximab is administered IV once every 2 months for 4 doses beginning 30 days after PBSC reinfusion.

Patients are followed at 30 days, 3, 6, 9, and 12 months after PBSC transplant, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 460 patients (115 per treatment arm) will be accrued for this study within 5 years.

• Study Type: Interventional
• Enrollment (Anticipated): 460
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2050
      • Sydney Cancer Centre at Royal Prince Alfred Hospital
    • Westmead, New South Wales, Australia, 2145
      • Westmead Institute for Cancer Research at Westmead Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital Cancer Centre
    • Woodville, South Australia, Australia, 5011
      • Queen Elizabeth Hospital
  • Victoria
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital
  • Western Australia
    • Fremantle, Western Australia, Australia, 6160
      • Fremantle Hospital
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital
• Austria
  • Vienna, Austria, A-1090
    • Allgemeines Krankenhaus - Universitatskliniken
• Belgium
  • Antwerpen, Belgium, B-2020
    • Ziekenhuis Netwerk Antwerpen Middelheim
  • Brussels, Belgium, 1000
    • Institut Jules Bordet
  • Brussels, Belgium, 1090
    • Academisch Ziekenhuis der Vrije Universiteit Brussel
  • Ghent, Belgium, B-9000
    • Universitair Ziekenhuis Gent
  • Leuven, Belgium, B-3000
    • U.Z. Gasthuisberg
  • Liege, Belgium, B-4000
    • CHU Liege - Domaine Universitaire du Sart Tilman
  • Mont-Godinne Yvoir, Belgium, 5530
    • Clinique Universitaire De Mont-Godinne
  • Roeselaere, Belgium, 8800
    • H. Hartziekenhuis - Roeselaere.
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre - Calgary
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Hospital Regional Cancer Centre - General Campus
• Czech Republic
  • Prague, Czech Republic, 10034
    • University Hospital Kralovske Vinohr
• Denmark
  • Aalborg, Denmark, DK-9000
    • Aalborg Hospital
  • Copenhagen, Denmark, 2100
    • Rigshospitalet - Copenhagen University Hospital
  • Odense, Denmark, DK-5000
    • Odense University Hospital
• France
  • Angers, France, 49033
    • Centre Hospitalier Regional et Universitaire d'Angers
  • Caen, France, 14076
    • Centre Regional Francois Baclesse
  • Caen, France, 14052
    • Polyclinique du Parc
  • Grenoble, France, 38043
    • CHU de Grenoble - Hopital de la Tronche
  • Lyon, France, 69373
    • Centre Leon Berard
  • Melun, France, 77000
    • Polyclinique Saint Jean
  • Montpellier, France, 34298
    • Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
  • Nantes, France, 44093
    • CHR Hotel Dieu
  • Paris, France, 75651
    • CHU Pitié-Salpêtrière
  • Paris, France, 75475
    • Hopital Saint-Louis
  • Pierre Benite, France, 69495
    • Centre Hospitalier Lyon Sud
  • Rennes, France, 35033
    • Centre Hospitalier Universitaire de Rennes
  • Rouen, France, 76038
    • Centre Henri Becquerel
  • Tours, France, 37044
    • Centre Hospitalier Universitaire Bretonneau de Tours
  • Villejuif, France, F-94805
    • Institut Gustave Roussy
• Germany
  • Augsburg, Germany, DOH-86156
    • Klinikum Augsburg
  • Bremen, Germany, D-28239
    • DIAKO Ev. Diakonie Krankenhaus gGmbH
  • Goettingen, Germany, D-37075
    • Universitaetsklinikum Goettingen
  • Hamburg, Germany, D-20099
    • Asklepios Klinik St. Georg
  • Homburg, Germany, D-66424
    • Universitaetsklinikum des Saarlandes
  • Homburg, Germany, 66421
    • Medical University Hospital Homburg
  • Nuernberg, Germany, D-90419
    • Klinikum Nuernberg - Klinikum Nord
  • Oldenburg, Germany, D-26133
    • Klinikum Oldenburg
  • Tuebingen, Germany, D-72076
    • Southwest German Cancer Center at Eberhard-Karls-University
• Israel
  • Tel Hashomer, Israel, 52621
    • Chaim Sheba Medical Center
• New Zealand
  • Auckland, New Zealand, 1
    • Auckland City Hospital
  • Christchurch, New Zealand
    • Canterbury Health Laboratories
  • Hamilton, New Zealand, 2020
    • Waikato Hospital
• Poland
  • Warsaw, Poland, 02-781
    • Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
  • Wroclaw, Poland, 53 439
    • K. Dluski Hospital-Medical Academy
• Portugal
  • Lisboa, Portugal, 1099-023 Codex
    • Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, S.A.
• Spain
  • Alicante, Spain, 3010
    • Hospital General - Alicante
  • Barakaldo Bilbao, Spain, E-48903
    • Hospital de Cruces
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08025
    • Hospital de la Santa Cruz i Sant Pau
  • Barcelona, Spain, 08916
    • Hospital Universitari Germans Trias i Pujol
  • Barcelona, Spain, 08022
    • Centro Medico Teknon
  • Caceres, Spain, 10000
    • Hospital San Pedro de Alcántara
  • Cadiz, Spain, 11000
    • Hospital Universitario Puerta del Mar
  • Castellon, Spain, 12004
    • Hospital General de Castellon
  • El Palmar, Spain, 30120
    • Hospital Virgen de la Arrixaca
  • Galdakao Vizcaya, Spain, 48000
    • Hospital de Galdakao
  • Granada, Spain, 18014
    • Hospital Virgen de las Nieves
  • Jaen, Spain, E-23006
    • Hospital Cuidad de Jaen
  • La Coruna, Spain, 15000
    • Hospital Juan Canalejo
  • Las Palmas de Gran Canaria, Spain, 350311
    • Hospital De Gran Canaria Dr. Negrin
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28034
    • Hospital Ramón y Cajal
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
  • Madrid, Spain, 28040
    • Hospital Universitario San Carlos
  • Madrid, Spain, 28006
    • Hospital De La Princesa
  • Madrid, Spain, 28905
    • Hospital Universitario de Getafe
  • Murcia, Spain, 30008
    • Hospital General Universitario Morales Meseguer
  • Oviedo, Spain, 33006
    • Hospital Universitario Central de Asturias
  • Palma De Mallorca, Spain, 07014
    • Hospital Son Dureta
  • Salamanca, Spain, 37007
    • University Hospital - Salamanca
  • Salamanca, Spain, 37007
    • Hospital Virgen de la Vega
  • Santander, Spain, 39008
    • Hospital Universitario Marques de Valdecilla
  • Sevilla, Spain, E- 41013
    • Hospital Universidad Virgen Del Rocio
  • Terrassa, Spain, 08221
    • Hospital Mutua de Terrassa
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia
  • Valencia, Spain, 46017
    • Unidad De Oncol/Hemat. Hospital
  • Vigo Pontevedra, Spain, 36204
    • Complexo Hospitalario Xeral de Vigo
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
  • Zaragoza, Spain, 50006
    • Hospital Clinico Universitario Lozano Blesa
• Sweden
  • Stockholm, Sweden, SE-141 86
    • Karolinska University Hospital - Huddinge
• Switzerland
  • Bruderholz, Switzerland, CH-4101
    • Kantonsspital Bruderholz
  • Zurich, Switzerland, CH-8091
    • Universitaetsspital Zuerich
• Turkey
  • Ankara, Turkey, 06100
    • Ibn-i Sina Hospital
• United Kingdom
  • England
    • Aylesbury-Buckinghamshire, England, United Kingdom, HP21 8AL
      • Stoke Mandeville Hospital
    • Bath, England, United Kingdom, BA1 3NG
      • Royal United Hospital
    • Birmingham, England, United Kingdom, B9 5SS
      • Birmingham Heartlands Hospital
    • Bournemouth, England, United Kingdom, BH7 7DW
      • Royal Bournemouth Hospital
    • Bristol, England, United Kingdom, BS2 8ED
      • Bristol Haematology and Oncology Centre
    • Exeter, England, United Kingdom, EX2 5DW
      • Royal Devon and Exeter Hospital
    • Huddersfield, West Yorks, England, United Kingdom, HD3 3EA
      • Huddersfield Royal Infirmary
    • Hull, England, United Kingdom, HU3 2KZ
      • Hull Royal Infirmary
    • Kettering, Northants, England, United Kingdom, NNI6 8UZ
      • Kettering General Hosptial
    • Leeds, England, United Kingdom, LS2 9N9
      • Clinical Trials and Research Unit of the University of Leeds
    • Leicester, England, United Kingdom, LE1 5WW
      • Leicester Royal Infirmary
    • Liverpool, England, United Kingdom, L7 8XP
      • Royal Liverpool and Broadgreen Hospitals NHS Trust
    • Liverpool, England, United Kingdom, L9 7AL
      • Liverpool University Hospital
    • London, England, United Kingdom, EC1A 7BE
      • Saint Bartholomew's Hospital
    • London, England, United Kingdom, SW17 ORE
      • St. Georges, University of London
    • London, England, United Kingdom, SE1 7EH
      • St. Thomas' Hospital
    • London, England, United Kingdom, WC1E 6HX
      • Middlesex Hospital
    • London, England, United Kingdom, WC1E 6AU
      • University College Hospital - London
    • London, England, United Kingdom, SW17 ORE
      • Clinique Sainte Elisabeth
    • Norfolk, England, United Kingdom, NR31 6LA
      • James Paget Hospital
    • Nottingham, England, United Kingdom, NG5 1PB
      • Nottingham City Hospital NHS Trust
    • Oxford, England, United Kingdom, 0X3 9DU
      • Oxford Radcliffe Hospital
    • Pontefract West Yorkshire, England, United Kingdom, WF8 1PL
      • Pontefract General Infirmary
    • Rotherham, England, United Kingdom, S60 2UD
      • Rotherham District General Hospital - NHS Trust
    • Sheffield, England, United Kingdom, S1O 2SJ
      • Cancer Research Centre at Weston Park Hospital
    • Southampton, England, United Kingdom, SO16 6YD
      • Southampton University Hospital NHS Trust
    • Stafford, England, United Kingdom, ST16 3SA
      • Staffordshire General Hospital
    • Sutton, England, United Kingdom, SM2 5PT
      • Royal Marsden NHS Foundation Trust - Surrey
    • Swindon, England, United Kingdom, SN3 6BB
      • Great Western Hospital
    • Swindon, England, United Kingdom, SN3 6BB
      • Princess Margaret Hospital
    • Uxbridge, England, United Kingdom, UB8 3NN
      • Hillingdon Hospital
    • West Bromwich, England, United Kingdom, B71 4HJ
      • Sandwell General Hospital
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom, BT9 7AB
      • Centre for Cancer Research and Cell Biology at Belfast City Hospital
  • Scotland
    • Aberdeen, Scotland, United Kingdom, AB25 2ZN
      • Aberdeen Royal Infirmary
    • Glasgow, Scotland, United Kingdom, G4 0SF
      • Royal Infirmary - Castle
    • Wakefield, Scotland, United Kingdom, WF1 4DG
      • Pinderfields Hospital NHS Trust
  • Wales
    • Bangor, Wales, United Kingdom, LL57 2PW
      • Ysbyty Gwynedd
    • Dyfed, Wales, United Kingdom, SA14 8QF
      • Prince Philip Hospital
    • Swansea, Wales, United Kingdom, SA2 8QA
      • Singleton Hospital of the Swansea NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Relapsed or resistant follicular non-Hodgkin's lymphoma (NHL)

  • No evidence of transformation to high grade or diffuse large B-cell NHL
• CD20 positive with no evidence of transformation

• Achievement of complete remission (CR) or very good partial remission (VGPR) following reinduction chemotherapy with any standard regimen

  • Includes patients who fail to respond to first-line chemotherapy but who achieve CR or VGPR after proceeding directly to second-line chemotherapy
• Platelet count greater than 100,000/mm^3 after induction chemotherapy and before randomization
• No CNS involvement

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• WHO 0-1

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Bilirubin normal
• ALT no greater than 2 times upper limit of normal (ULN)
• Alkaline phosphatase no greater than 2 times ULN
• Hepatitis B negative
• Hepatitis C negative

Renal:

• Creatinine no greater than 2 times ULN
• BUN no greater than 2 times ULN

Cardiovascular:

• No inadequate cardiac function

Pulmonary:

• No inadequate pulmonary function

Other:

• Not pregnant or nursing
• HIV negative
• No other uncontrolled serious medical conditions
• No other malignancy within the past 5 years except nonmelanoma skin tumors or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• More than 12 months since prior CD20 therapy, including rituximab
• No prior peripheral blood stem cell transplantation

Chemotherapy:

• See Disease Characteristics
• No more than 3 prior chemotherapy regimens for NHL

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy to greater than 30% of bone marrow

Surgery:

• Not specified

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time to disease progression

Secondary Outcome Measures

Outcome Measure
Safety
Response rate and survival
Molecular remission rates

Collaborators and Investigators

• Sponsor: EBMT Solid Tumors Working Party
• Collaborators: Lymphoma Trials Office
• Investigators: Study Chair: Ruth Pettengell, MD, St George's, University of London; Study Chair: David C. Linch, Middlesex Hospital

Publications and helpful links

General Publications

• Pettengell R, Schmitz N, Gisselbrecht C, Smith G, Patton WN, Metzner B, Caballero D, Tilly H, Walewski JA, Bence-Bruckler I, To B, Geisler CH, Schots R, Kimby E, Taverna CJ, Kozak T, Dreger P, Uddin R, Ruiz de Elvira C, Goldstone AH. Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol. 2013 May 1;31(13):1624-30. doi: 10.1200/JCO.2012.47.1862. Epub 2013 Apr 1.

Study record dates

Study Major Dates

• Study Start: October 1, 1999
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: May 2, 2000
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): September 17, 2013
• Last Update Submitted That Met QC Criteria: September 16, 2013
• Last Verified: March 1, 2007

More Information

Terms related to this study

• Keywords: recurrent grade 3 follicular lymphoma; recurrent grade 1 follicular lymphoma; recurrent grade 2 follicular lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Cyclophosphamide; Etoposide; Rituximab; Melphalan; Cytarabine; Carmustine
• Other Study ID Numbers: CDR0000067665; EBMT-EBMTLYM1; BNLI-EBMT-EBMTLYM1; EU-99050