A Randomised Evaluation of Molecular Guided Therapy for Diffuse Large B-cell Lymphoma With Bortezomib
- Conditions
- Lymphoma, Large B-Cell, Diffuse
- Interventions
- Drug: Intravenous
- Registration Number
- NCT01324596
- Brief Summary
The aims of this study are:
* To evaluate the benefits of the addition of bortezomib to standard rituximab with cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) therapy in Diffuse Large B-cell Lymphoma (DLBCL).
* To determine whether molecular phenotype effects the benefits derived from the addition of bortezomib.
- Detailed Description
REMoDLB is a trial which aims to determine whether the addition of bortezomib (a drug that blocks the action of cellular complexes that break down proteins) to standard combination chemotherapy (called R-CHOP) improves how long patients with diffuse large B cell lymphoma survive without a recurrence of the disease. Results from recent research have suggested that patients can be divided into two biologically distinct subgroups labeled GCB (germinal centre derived B-cells like) and ABC (activated peripheral B-cells like).
GCB patients tend to do well with standard combination chemotherapy, but ABC patients have the majority of treatment failures. It is thought that ABC patients will benefit most from the addition of bortezomib.
The trial will be discussed with the patient. They will be asked to consent to molecular profiling of their tumour block whilst they have some time to consider whether they wish to enter the main trial. This will allow more time for this sample to be analysed and their particular biological subgroup to be determined.
All patients consenting to enter the main study will be given an initial cycle of RCHOP chemotherapy. Within each subgroup (ABC or GCB) patients will be randomly assigned to receive either RCHOP or RCHOP and bortezomib to ensure that the same number of each biological subgroup will receive the two treatments. All patients will then have 5 cycles of their assigned treatment regimen (either RCHOP or RCHOP and bortezomib). All patients will be followed up for a period of five years once they have completed their chemotherapy. The GCB group receiving RCHOP and bortezomib will be regularly checked to see if the new treatment is improving survival without recurrence of the disease. If the addition of bortezomib is not found to be beneficial for this group of patients this part of the trial will be stopped and all GCB patients will receive the standard treatment only (RCHOP).
It is anticipated that between 560 and 892 patients will be randomly allocated to the two treatments, the exact number depends on whether the GCB group receiving RCHOP and bortezomib is stopped or not.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1132
- Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material should be available to forward to Haematological Malignancies Diagnostic Service (HMDS) for gene expression profiling and central pathology review. Core biopsies are acceptable, however the molecular profiling success rate is inferior compared to larger surgically acquired tissue samples. Best diagnostic practice encourages investigators to seek the latter approach whenever clinically appropriate.
- Measurable disease of at least 15mm.
- Not previously treated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative intent.
- Age > 18 years.
- Stage IAX (bulk defined as lymph node diameter > 10cm) to stage IV disease and deemed to require a full course of chemotherapy.
- ECOG performance status 0-2.
- Adequate bone marrow function with platelets > 100x109/L; neutrophils >1.0x109/L at study entry, unless lower figures are attributable to lymphoma.
- Serum creatinine < 150μmol/L, measured or calculated creatinine clearance > 30mls/min, serum bilirubin < 35μmol/L and transaminases < 2.5x upper limit of normal at the time of study entry, unless attributable to lymphoma.
- Cardiac function sufficient to tolerate 300mg/m2 of doxorubicin. A pre-treatment echocardiogram is not mandated, but recommended in patients considered at higher risk of anthracycline cardiotoxicity.
- No concurrent uncontrolled medical condition.
- Life expectancy > 3 months.
- Adequate contraceptive precautions for all patients of child bearing potential.
- A negative serum pregnancy test for females of child bearing potential or those < 2 years after the onset of the menopause.
- Patients will have provided written informed consent.
- Previous history of treated or untreated indolent lymphoma. However newly diagnosed patients with DLBCL who are found to also have small cell infiltration of the bone marrow or other diagnostic material (discordant lymphoma) will be eligible.
- Diagnosis of primary mediastinal lymphoma
- Uncontrolled systemic infection.
- History of cardiac failure of uncontrolled angina.
- Clinical CNS involvement.
- Serological positivity for Hepatitis C, B or known HIV infection. Viral serological testing is not mandated for study entry, but considered standard of care. (• Positive test results for chronic HBV infection (defined as positive HBsAg serology) will not be eligible. • Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) will not be eligible as one would normally monitor HBV DNA serially and add lamivudine if copy number became detectable. There is an interaction between lamivudine and bortezomib. Reactivation of latent infection has been reported with the use of bortezomib in this population (along obviously with the well recognised reactivation following R-CHOP). For these patient safety reasons, these patients should be excluded. • Patients who have protective titres of hepatitis B surface antibody (HBSAb) after vaccination are eligible. • Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing) will not be eligible.)
- Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give informed consent.
- Active malignancy other than fully excised squamous or basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix in the preceding 5 years.
- History of allergic reaction to substances containing boron or mannitol.
- Patient unwilling to abstain from green tea and preparations made from green tea as bortezomib may interact with these.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A: R-CHOP Intravenous Participants receive 6 cycles of conventional R-CHOP chemotherapy on a standard 21 day schedule: Rituximab 375mg/m2 intravenous Cyclophosphamide 750mg/m2 Intravenous Doxorubicin 50mg/m2 Intravenous Vincristine intravenous Prednisolone 100mg od orally Arm B: RB-CHOP Bortezomib Participants in this arm will receive 1 cycle of conventional R-CHOP chemotherapy, followed by 5 cycles of R-CHOP: Cyclophosphamide 750mg/m2 Intravenous Doxorubicin 50mg/m2 Intravenous Vincristine intravenous bortezomib - Intravenous Prednisolone 100mg od orally .
- Primary Outcome Measures
Name Time Method Progression Free Survival 2 years
- Secondary Outcome Measures
Name Time Method Response duration 5 years Complete and overall response rates 5 years Disease-free survival 5 years Evaluation of toxicity (according to CTCAE version 4.0) 5 years Quality of life and assessment of peripheral neuropathy 5 years Time to progression 5 years Overall survival 5 years Event-free survival 5 years
Trial Locations
- Locations (108)
Ysbyty Gwynedd Hospital
🇬🇧Bangor, United Kingdom
Doncaster Royal Infirmary
🇬🇧Doncaster, United Kingdom
Queen Elizabeth Hospital, Gateshead
🇬🇧Gateshead, United Kingdom
Hemel Hempstead General and Watford General
🇬🇧Hemel Hempstead and Watford, United Kingdom
Huddersfield Royal Infirmary
🇬🇧Huddersfield, United Kingdom
Princess Royal University Hospital
🇬🇧London, United Kingdom
Christie Hospital
🇬🇧Manchester, United Kingdom
Wythenshawe Hospital
🇬🇧Manchester, United Kingdom
Northampton General Hospital
🇬🇧Northampton, United Kingdom
George Eliot Hospital
🇬🇧Nuneaton, United Kingdom
Churchill Hospital
🇬🇧Oxford, United Kingdom
Derriford Hospital
🇬🇧Plymouth, United Kingdom
Poole General Hospital
🇬🇧Poole, United Kingdom
Glan Clwyd District General Hospital
🇬🇧Rhyl, United Kingdom
Queen's Hospital
🇬🇧Romford, United Kingdom
Scunthorpe General Hospital
🇬🇧Scunthorpe, United Kingdom
Royal Hallamshire Hospital
🇬🇧Sheffield, United Kingdom
County Hospital
🇬🇧Stafford, United Kingdom
Royal Stoke Hospital
🇬🇧Stoke, United Kingdom
Royal Cornwall Hospital
🇬🇧Truro, United Kingdom
Pinderfields Hospital, Dewsbury Hospital and Ponerfract Hospital
🇬🇧Wakefield, United Kingdom
Warwick Hospital
🇬🇧Warwick, United Kingdom
Kantonsspital Aarau
🇨🇭Aarau, Switzerland
West Suffolk Hospital
🇬🇧Bury St. Edmunds, United Kingdom
Broomfield Hospital
🇬🇧Chelmsford, United Kingdom
Royal Derby Hospitals
🇬🇧Derby, United Kingdom
University Hospital Coventry
🇬🇧Coventry, United Kingdom
Ealing Hospital
🇬🇧London, United Kingdom
Hammersmith Hospital
🇬🇧London, United Kingdom
Hillingdon Hospital
🇬🇧London, United Kingdom
Northwick Park Hospital
🇬🇧London, United Kingdom
St George's Hospital
🇬🇧London, United Kingdom
Manchester Royal Infirmary
🇬🇧Manchester, United Kingdom
The James Cook University Hospital
🇬🇧Middlesbrough, United Kingdom
Milton Keynes General Hospital
🇬🇧Milton Keynes, United Kingdom
Freeman Hospital, Newcastle
🇬🇧Newcastle, United Kingdom
STSAG Thun
🇨🇭Bern, Switzerland
Kantonsspital Olten
🇨🇭Olten, Switzerland
Kantonsspital St. Gallen
🇨🇭St. Gallen, Switzerland
University Hospital Aintree
🇬🇧Aintree, United Kingdom
Antrim Area Hospital
🇬🇧Antrim, United Kingdom
Kantonsspital Liestal
🇨🇭Basel, Switzerland
Inselspital Bern
🇨🇭Bern, Switzerland
Luzerner Kantonsspital
🇨🇭Lucerne, Switzerland
Universitatsspital Basel
🇨🇭Basel, Switzerland
Spitalzenturm Oberwallis
🇨🇭Brig, Switzerland
Monklands, Hairmyres and Whishaw Hospitals
🇬🇧Airdrie, United Kingdom
Ospedale Regionale Bellinzona e Valli (IOSI)
🇨🇭Bellinzona, Switzerland
Kantonsspital Graubunden
🇨🇭Chur, Switzerland
Belfast City Hospital
🇬🇧Belfast, United Kingdom
Stadtspital Triemli
🇨🇭Zurich, Switzerland
UniversitatsSpital Zurich
🇨🇭Zurich, Switzerland
Stoke Mandeville Hospital and Wycombe Hospital
🇬🇧Aylesbury, United Kingdom
Royal Bournemouth
🇬🇧Bournemouth, United Kingdom
Bradford Royal Infirmary
🇬🇧Bradford, United Kingdom
Basildon Hospital
🇬🇧Basildon, United Kingdom
Royal United Hospital
🇬🇧Bath, United Kingdom
Arrowe Park
🇬🇧Birkenhead, United Kingdom
Good Hope Hosptial
🇬🇧Birmingham, United Kingdom
North Hampshire & Basingstoke Hospital
🇬🇧Basingstoke, United Kingdom
Queen Elizabeth Hospital
🇬🇧King's Lynn, United Kingdom
Victoria Hospital
🇬🇧Blackpool, United Kingdom
Sandwell General Hospital Birmingham
🇬🇧Birmingham, United Kingdom
Cheltenham General Hospital and Gloucestershire Royal Infirmary
🇬🇧Cheltenham, United Kingdom
Chesterfield Royal
🇬🇧Chesterfield, United Kingdom
Colchester General Hospital
🇬🇧Colchester, United Kingdom
Queen's Hospital Burton
🇬🇧Burton upon Trent, United Kingdom
Darent Valley Hospital
🇬🇧Dartford, United Kingdom
Velindre Hospital
🇬🇧Cardiff, United Kingdom
St Richard's Hospital
🇬🇧Chichester, United Kingdom
Ulster Hospital
🇬🇧Dundonald, United Kingdom
Royal Devon and Exeter Hospital
🇬🇧Exeter, United Kingdom
Royal Liverpool
🇬🇧Liverpool, United Kingdom
Medway Maritime Hospital
🇬🇧Gillingham, United Kingdom
Lincoln County Hospital, Pilgrim Hospital, Grantham and District Hospital
🇬🇧Lincoln, United Kingdom
Beatson West of Scotland Cancer centre
🇬🇧Glasgow, United Kingdom
St James University Hospital
🇬🇧Leeds, United Kingdom
Diana Princess of Wales, Grimsby
🇬🇧Grimsby, United Kingdom
Harrogate District Hospital
🇬🇧Harrogate, United Kingdom
Barnet General Hospital
🇬🇧London, United Kingdom
Kent and Canterbury Hospital
🇬🇧Kent, United Kingdom
Royal Free Hospital
🇬🇧London, United Kingdom
Raigmore Hospital
🇬🇧Inverness, United Kingdom
The Royal Marsden
🇬🇧London, United Kingdom
University College Hospital London
🇬🇧London, United Kingdom
King's College Hospital
🇬🇧London, United Kingdom
Luton and Dunstable Hospital
🇬🇧Luton, United Kingdom
Maidstone Hospital and The Tunbridge Wells Hospital
🇬🇧Maidstone, United Kingdom
St Helier Hospital
🇬🇧London, United Kingdom
QE Woolwich
🇬🇧London, United Kingdom
St Bartholomews Hospital
🇬🇧London, United Kingdom
Craigavon Area Hospital
🇬🇧Portadown, United Kingdom
Queen Alexandra Hospital
🇬🇧Portsmouth, United Kingdom
Mount Vernon Hospital
🇬🇧Northwood, United Kingdom
Nottingham City Hospital
🇬🇧Nottingham, United Kingdom
Royal Oldham
🇬🇧Oldham, United Kingdom
Salisbury District Hospital
🇬🇧Salisbury, United Kingdom
Wexham Park
🇬🇧Slough, United Kingdom
Royal Berkshire Hospital
🇬🇧Reading, United Kingdom
Southampton General Hospital
🇬🇧Southampton, United Kingdom
Southend Hospital
🇬🇧Southend, United Kingdom
Sunderland Royal Hospital
🇬🇧Sunderland, United Kingdom
Great Western Hospital
🇬🇧Swindon, United Kingdom
Torbay District General Hospital
🇬🇧Torbay, United Kingdom
Worcestershire Royal Hospital
🇬🇧Worcester, United Kingdom
Worthing Hospital
🇬🇧Worthing, United Kingdom
Guy's Hospital
🇬🇧London, United Kingdom
Castle Hill Hospital
🇬🇧Hull, United Kingdom