Clinical trial NCT00005589: Combination Chemotherapy Plus Peripheral Stem Cell Transplantation With or Without Rituximab in Treating Patients With Relapsed Non-Hodgkin's Lymphoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lymphoma
Keywords: recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: Lymphoma Trials Office
First posted: 2003-01-27
Enrollment: 460
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to disease progression
Secondary outcomes:
measure: Response rate and survival
measure: Molecular remission rates
measure: Safety
Other outcomes:
Locations:
city: Sydney
country: Australia
facility: Sydney Cancer Centre at Royal Prince Alfred Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Institute for Cancer Research at Westmead Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital Cancer Centre
state: South Australia
city: Woodville
country: Australia
facility: Queen Elizabeth Hospital
state: South Australia
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Fremantle
country: Australia
facility: Fremantle Hospital
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Vienna
country: Austria
facility: Allgemeines Krankenhaus - Universitatskliniken
city: Antwerpen
country: Belgium
facility: Ziekenhuis Netwerk Antwerpen Middelheim
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Brussels
country: Belgium
facility: Academisch Ziekenhuis der Vrije Universiteit Brussel
city: Ghent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Leuven
country: Belgium
facility: U.Z. Gasthuisberg
city: Liege
country: Belgium
facility: CHU Liege - Domaine Universitaire du Sart Tilman
city: Mont-Godinne Yvoir
country: Belgium
facility: Clinique Universitaire De Mont-Godinne
city: Roeselaere
country: Belgium
facility: H. Hartziekenhuis - Roeselaere.
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre - Calgary
state: Alberta
city: Ottawa
country: Canada
facility: Ottawa Hospital Regional Cancer Centre - General Campus
state: Ontario
city: Prague
country: Czech Republic
facility: University Hospital Kralovske Vinohr
city: Aalborg
country: Denmark
facility: Aalborg Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet - Copenhagen University Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Angers
country: France
facility: Centre Hospitalier Regional et Universitaire d'Angers
city: Caen
country: France
facility: Polyclinique Du Parc
city: Caen
country: France
facility: Centre Regional Francois Baclesse
city: Grenoble
country: France
facility: CHU de Grenoble - Hopital de la Tronche
city: Lyon
country: France
facility: Centre Leon Berard
city: Melun
country: France
facility: Polyclinique Saint Jean
city: Montpellier
country: France
facility: Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
city: Nantes
country: France
facility: CHR Hotel Dieu
city: Paris
country: France
facility: Hopital Saint-Louis
city: Paris
country: France
facility: CHU Pitie-Salpetriere
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Rennes
country: France
facility: Centre Hospitalier Universitaire de Rennes
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Tours
country: France
facility: Centre Hospitalier Universitaire Bretonneau de Tours
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Bremen
country: Germany
facility: DIAKO Ev. Diakonie Krankenhaus gGmbH
city: Goettingen
country: Germany
facility: Universitaetsklinikum Goettingen
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg
city: Homburg
country: Germany
facility: Medical University Hospital Homburg
city: Homburg
country: Germany
facility: Universitaetsklinikum des Saarlandes
city: Nuernberg
country: Germany
facility: Klinikum Nuernberg - Klinikum Nord
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Tuebingen
country: Germany
facility: Southwest German Cancer Center at Eberhard-Karls-University
city: Tel Hashomer
country: Israel
facility: Chaim Sheba Medical Center
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Christchurch
country: New Zealand
facility: Canterbury Health Laboratories
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Warsaw
country: Poland
facility: Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
city: Wroclaw
country: Poland
facility: K. Dluski Hospital-Medical Academy
city: Lisboa
country: Portugal
facility: Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, S.A.
city: Alicante
country: Spain
facility: Hospital General - Alicante
city: Barakaldo Bilbao
country: Spain
facility: Hospital de Cruces
city: Barcelona
country: Spain
facility: Centro Medico Teknon
city: Barcelona
country: Spain
facility: Hospital de la Santa Cruz i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
city: Caceres
country: Spain
facility: Hospital San Pedro de Alcantara
city: Cadiz
country: Spain
facility: Hospital Universitario Puerta Del Mar
city: Castellon
country: Spain
facility: Hospital General de Castellon
city: El Palmar
country: Spain
facility: Hospital Virgen de la Arrixaca
city: Galdakao Vizcaya
country: Spain
facility: Hospital de Galdakao
city: Granada
country: Spain
facility: Hospital Virgen de las Nieves
city: Jaen
country: Spain
facility: Hospital Cuidad de Jaen
city: La Coruna
country: Spain
facility: Hospital Juan Canalejo
city: Las Palmas de Gran Canaria
country: Spain
facility: Hospital de Gran Canaria Dr. Negrin
city: Madrid
country: Spain
facility: Hospital de la Princesa
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario de Getafe
city: Murcia
country: Spain
facility: Hospital General Universitario Morales Meseguer
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Palma De Mallorca
country: Spain
facility: Hospital Son Dureta
city: Salamanca
country: Spain
facility: Hospital Virgen de la Vega
city: Salamanca
country: Spain
facility: University Hospital - Salamanca
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Universidad Virgen Del Rocio
city: Terrassa
country: Spain
facility: Hospital Mutua de Terrassa
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valencia
country: Spain
facility: Unidad De Oncol/Hemat. Hospital
city: Vigo Pontevedra
country: Spain
facility: Complexo Hospitalario Xeral de Vigo
city: Zaragoza
country: Spain
facility: Hospital Clinico Universitario Lozano Blesa
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Stockholm
country: Sweden
facility: Karolinska University Hospital - Huddinge
city: Bruderholz
country: Switzerland
facility: Kantonsspital Bruderholz
city: Zurich
country: Switzerland
facility: UniversitaetsSpital Zuerich
city: Ankara
country: Turkey
facility: Ibn-i Sina Hospital
city: Aylesbury-Buckinghamshire
country: United Kingdom
facility: Stoke Mandeville Hospital
state: England
city: Bath
country: United Kingdom
facility: Royal United Hospital
state: England
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
state: England
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
state: England
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
state: England
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
state: England
city: Huddersfield, West Yorks
country: United Kingdom
facility: Huddersfield Royal Infirmary
state: England
city: Hull
country: United Kingdom
facility: Hull Royal Infirmary
state: England
city: Kettering, Northants
country: United Kingdom
facility: Kettering General Hosptial
state: England
city: Leeds
country: United Kingdom
facility: Clinical Trials and Research Unit of the University of Leeds
state: England
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool and Broadgreen Hospitals NHS Trust
state: England
city: Liverpool
country: United Kingdom
facility: Liverpool University Hospital
state: England
city: London
country: United Kingdom
facility: Saint Bartholomew's Hospital
state: England
city: London
country: United Kingdom
facility: St. Thomas' Hospital
state: England
city: London
country: United Kingdom
facility: Clinique Sainte Elisabeth
state: England
city: London
country: United Kingdom
facility: St. Georges, University of London
state: England
city: London
country: United Kingdom
facility: University College Hospital - London
state: England
city: London
country: United Kingdom
facility: Middlesex Hospital
state: England
city: Norfolk
country: United Kingdom
facility: James Paget Hospital
state: England
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital NHS Trust
state: England
city: Oxford
country: United Kingdom
facility: Oxford Radcliffe Hospital
state: England
city: Pontefract West Yorkshire
country: United Kingdom
facility: Pontefract General Infirmary
state: England
city: Rotherham
country: United Kingdom
facility: Rotherham District General Hospital - NHS Trust
state: England
city: Sheffield
country: United Kingdom
facility: Cancer Research Centre at Weston Park Hospital
state: England
city: Southampton
country: United Kingdom
facility: Southampton University Hospital NHS Trust
state: England
city: Stafford
country: United Kingdom
facility: Staffordshire General Hospital
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust - Surrey
state: England
city: Swindon
country: United Kingdom
facility: Great Western Hospital
state: England
city: Swindon
country: United Kingdom
facility: Princess Margaret Hospital
state: England
city: Uxbridge
country: United Kingdom
facility: Hillingdon Hospital
state: England
city: West Bromwich
country: United Kingdom
facility: Sandwell General Hospital
state: England
city: Belfast
country: United Kingdom
facility: Centre for Cancer Research and Cell Biology at Belfast City Hospital
state: Northern Ireland
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
state: Scotland
city: Glasgow
country: United Kingdom
facility: Royal Infirmary - Castle
state: Scotland
city: Wakefield
country: United Kingdom
facility: Pinderfields Hospital NHS Trust
state: Scotland
city: Bangor
country: United Kingdom
facility: Ysbyty Gwynedd
state: Wales
city: Dyfed
country: United Kingdom
facility: Prince Philip Hospital
state: Wales
city: Swansea
country: United Kingdom
facility: Singleton Hospital of the Swansea NHS Trust
state: Wales
Study officials:
affiliation: St George's, University of London
name: Ruth Pettengell, MD
role: STUDY_CHAIR
affiliation: Middlesex Hospital
name: David C. Linch
role: STUDY_CHAIR
References:
citation: 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.