Clinical trial NCT00641095: Phase III, Multicentre, Randomised Study of Fludarabine/Cyclophosphamide Combination With or Without Rituximab in Patients With Untreated Mantle Cell Lymphoma
Official title: Phase III, Multicentre, Randomised Study of Fludarabine/Cyclophosphamide Combination With or Without Rituximab in Patients With Untreated Mantle Cell Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Lymphoma
Keywords: contiguous stage II mantle cell lymphoma
noncontiguous stage II mantle cell lymphoma
stage I mantle cell lymphoma
stage III mantle cell lymphoma
stage IV mantle cell lymphoma
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: Cancer Research UK
First posted: 2008-03-21
Enrollment: 370
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized phase III trial is comparing how well fludarabine and cyclophosphamide work when given together with or without rituximab in treating patients with previously untreated mantle cell lymphoma.

Detailed description: RATIONALE: Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. It is not yet known whether giving combination chemotherapy together with rituximab is more effective than combination chemotherapy alone in treating mantle cell lymphoma.

OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive fludarabine phosphate IV or orally once daily and oral cyclophosphamide once daily on days 1-3. Treatment repeats every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients receive rituximab IV on day 1 and fludarabine phosphate IV or orally once daily and oral cyclophosphamide once daily on days 1-3. Treatment repeats every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo bone marrow and blood sample collection periodically for molecular studies. Samples are analyzed for morphology; sIgM, sIgD, CD19, CD20, CD5, CD10, CD23, bcl-1, bcl-6 via immunophenotyping and immunohistochemistry; and t(11,14) translocation via interphase fluorescence in situ hybridization (FISH) mutational analysis.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

This trial follows on from the Phase II randomised study of fludarabine/cyclophosphamide combination with or without Rituximab in patients with untreated mantle cell lymphoma. ISRCTN number: NCT00053092

Peer Reviewed and Funded or Endorsed by Cancer Research UK

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed mantle cell lymphoma (MCL), meeting the following criteria:

  * Diagnosis confirmed by examination of representative material (lymph nodes or bone marrow) together with a typical immunophenotype CD5+, CD23-, sIgM, cyclin D1 nuclear positivity is desirable but not essential
  * Central review of histology will be performed on diagnostic material
  * Molecular or cytogenetic confirmation of diagnosis is not required
* Previously untreated disease at any stage requiring therapy in the opinion of the treating physician

PATIENT CHARACTERISTICS:

* Life expectancy ≥ 3 months

  * Life expectancy not severely limited by other illness
* Creatinine clearance ≥ 30 mL/min
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during study therapy
* No known serological positivity for HBV, HCV, or HIV
* No concurrent uncontrolled serious medical conditions
* No severe impairment of renal or liver function (alkaline phosphatase, bilirubin or creatinine \> 2.5 times upper limit of normal) not related to lymphoma
* No known hypersensitivity to murine proteins
* No prior malignancy in the past 5 years, except for nonmelanoma skin tumor or curatively resected carcinoma in situ of the uterine cervix
* No history of a psychological illness or condition that, in the opinion of the investigator, may adversely affect compliance with study medication

PRIOR CONCURRENT THERAPY:

* No prior chemotherapy

Primary outcomes:
measure: Overall survival
timeFrame: From date of first administration of treatment until the date of death from any cause, assessed up to a maximum of 60 months
Secondary outcomes:
measure: Progression-free survival
timeFrame: From date of first treatment administration until the date of first documented progression or relapse, whichever came first, assessed up to a maximum of 60 months
measure: Toxicity - Number of patients with >=grade 3 toxicity
timeFrame: Within 30 days after last dose of treatment
measure: Toxicity - Percentage of patients with >=grade 3 toxicity
timeFrame: Within 30 days after last dose of treatment
measure: Tumor response duration
timeFrame: From date of first documentation of PR or CR until the date of first progression up to a maximum of 60 months
Other outcomes:
Locations:
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Ashford
country: United Kingdom
facility: William Harvey Hospital
state: England
city: Aylesbury
country: United Kingdom
facility: Stoke Mandeville Hospital
state: England
city: Basingstoke
country: United Kingdom
facility: Basingstoke and North Hampshire NHS Foundation Trust
state: England
city: Bath
country: United Kingdom
facility: Royal United Hospital
state: England
city: Birmingham
country: United Kingdom
facility: Good Hope Hospital
state: England
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
state: England
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
state: England
city: Carshalton
country: United Kingdom
facility: St. Helier Hospital
state: England
city: Cheltenham
country: United Kingdom
facility: Gloucestershire Oncology Centre at Cheltenham General Hospital
state: England
city: Chichester
country: United Kingdom
facility: Saint Richards Hospital
state: England
city: Colchester
country: United Kingdom
facility: Essex County Hospital
state: England
city: Colchester
country: United Kingdom
facility: Colchester General Hospital
state: England
city: Cosham
country: United Kingdom
facility: Queen Alexandra Hospital
state: England
city: Croydon
country: United Kingdom
facility: Mayday University Hospital
state: England
city: Darlington
country: United Kingdom
facility: Darlington Memorial
state: England
city: Dartford
country: United Kingdom
facility: Darent Valley Hospital
state: England
city: Dewsbury
country: United Kingdom
facility: Dewsbury and District Hospital
state: England
city: Dudley
country: United Kingdom
facility: Russells Hall Hospital
state: England
city: Durham
country: United Kingdom
facility: Bishop Auckland Hospital
state: England
city: Epsom
country: United Kingdom
facility: Epsom General Hospital
state: England
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
state: England
city: Gateshead
country: United Kingdom
facility: Queen Elizabeth Hospital
state: England
city: Gillingham
country: United Kingdom
facility: Medway Maritime Hospital
state: England
city: Gloucester
country: United Kingdom
facility: Gloucestershire Royal Hospital
state: England
city: Hereford
country: United Kingdom
facility: Hereford Hospitals
state: England
city: High Wycombe
country: United Kingdom
facility: Wycombe General Hospital
state: England
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary
state: England
city: Leeds
country: United Kingdom
facility: Cancer Research UK Clinical Centre at St. James's University Hospital
state: England
city: London
country: United Kingdom
facility: Saint Bartholomew's Hospital
state: England
city: Maidstone
country: United Kingdom
facility: Mid Kent Oncology Centre at Maidstone Hospital
state: England
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
state: England
city: Manchester
country: United Kingdom
facility: Christie Hospital
state: England
city: Margate
country: United Kingdom
facility: Queen Elizabeth The Queen Mother Hospital
state: England
city: Newcastle-Upon-Tyne
country: United Kingdom
facility: Newcastle Upon Tyne Hospitals NHS Trust
state: England
city: Northwood
country: United Kingdom
facility: Mount Vernon Cancer Centre at Mount Vernon Hospital
state: England
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
state: England
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
state: England
city: Pontefract
country: United Kingdom
facility: Pontefract General Infirmary
state: England
city: Portsmouth
country: United Kingdom
facility: Portsmouth Oncology Centre at St Mary's Hospital
state: England
city: Prescot
country: United Kingdom
facility: Whiston Hospital
state: England
city: Preston
country: United Kingdom
facility: Rosemere Cancer Centre at Royal Preston Hospital
state: England
city: Redhill
country: United Kingdom
facility: East Surrey Hospital
state: England
city: Royal Tunbridge Wells
country: United Kingdom
facility: Pembury Hospital
state: England
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Cancer Research Centre at Weston Park Hospital
state: England
city: Southampton
country: United Kingdom
facility: Royal South Hants Hospital
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden - Surrey
state: England
city: Swindon
country: United Kingdom
facility: Great Western Hospital
state: England
city: Torquay
country: United Kingdom
facility: Torbay Hospital
state: England
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
state: England
city: Tunbridge Wells
country: United Kingdom
facility: Kent and Sussex Hospital
state: England
city: Wolverhampton
country: United Kingdom
facility: New Cross Hospital
state: England
city: Yeovil
country: United Kingdom
facility: Yeovil District Hospital
state: England
city: Airdrie
country: United Kingdom
facility: Monklands General Hospital
state: Scotland
city: East Kilbride
country: United Kingdom
facility: Hairmyres Hospital
state: Scotland
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
state: Scotland
city: Wakefield
country: United Kingdom
facility: Pinderfields General Hospital
state: Scotland
city: Wishaw
country: United Kingdom
facility: Wishaw General Hospital
state: Scotland
city: Bangor
country: United Kingdom
facility: Ysbyty Gwynedd
state: Wales
city: Amersham
country: United Kingdom
facility: Amersham Hospital
city: Taunton
country: United Kingdom
facility: Musgrove Park Hospital
Study officials:
affiliation: Derriford Hospital
name: Simon Rule, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rule S, Smith P, Johnson PW, Bolam S, Follows G, Gambell J, Hillmen P, Jack A, Johnson S, Kirkwood AA, Kruger A, Pocock C, Seymour JF, Toncheva M, Walewski J, Linch D. The addition of rituximab to fludarabine and cyclophosphamide chemotherapy results in a significant improvement in overall survival in patients with newly diagnosed mantle cell lymphoma: results of a randomized UK National Cancer Research Institute trial. Haematologica. 2016 Feb;101(2):235-40. doi: 10.3324/haematol.2015.128710. Epub 2015 Nov 26.