Clinical trial NCT01324596: A Randomised Evaluation of Molecular Guided Therapy for Diffuse Large B-cell Lymphoma With Bortezomib
Official title: A Randomised Evaluation of Molecular Guided Therapy for Diffuse Large B-cell Lymphoma With Bortezomib
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lymphoma, Large B-Cell, Diffuse
Keywords: Lymphoma, Large B-Cell, Diffuse
Bortezomib
R-CHOP
Molecular profiling
Chemotherapy
Lead sponsor: University Hospital Southampton NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: Janssen-Cilag Ltd.
First posted: 2011-03-29
Enrollment: 1132
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Progression Free Survival
timeFrame: 2 years
Secondary outcomes:
measure: Overall survival
timeFrame: 5 years
measure: Event-free survival
timeFrame: 5 years
measure: Disease-free survival
timeFrame: 5 years
measure: Time to progression
timeFrame: 5 years
measure: Response duration
timeFrame: 5 years
measure: Complete and overall response rates
timeFrame: 5 years
measure: Evaluation of toxicity (according to CTCAE version 4.0)
timeFrame: 5 years
measure: Quality of life and assessment of peripheral neuropathy
timeFrame: 5 years
Other outcomes:
Locations:
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Basel
country: Switzerland
facility: Kantonsspital Liestal
city: Basel
country: Switzerland
facility: Universitatsspital Basel
city: Bellinzona
country: Switzerland
facility: Ospedale Regionale Bellinzona e Valli (IOSI)
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Bern
country: Switzerland
facility: STSAG Thun
city: Brig
country: Switzerland
facility: Spitalzenturm Oberwallis
city: Chur
country: Switzerland
facility: Kantonsspital Graubunden
city: Lucerne
country: Switzerland
facility: Luzerner Kantonsspital
city: Olten
country: Switzerland
facility: Kantonsspital Olten
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Zurich
country: Switzerland
facility: Stadtspital Triemli
city: Zurich
country: Switzerland
facility: UniversitatsSpital Zurich
city: Aintree
country: United Kingdom
facility: University Hospital Aintree
city: Airdrie
country: United Kingdom
facility: Monklands, Hairmyres and Whishaw Hospitals
city: Antrim
country: United Kingdom
facility: Antrim Area Hospital
city: Aylesbury
country: United Kingdom
facility: Stoke Mandeville Hospital and Wycombe Hospital
city: Bangor
country: United Kingdom
facility: Ysbyty Gwynedd Hospital
city: Basildon
country: United Kingdom
facility: Basildon Hospital
city: Basingstoke
country: United Kingdom
facility: North Hampshire & Basingstoke Hospital
city: Bath
country: United Kingdom
facility: Royal United Hospital
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Birkenhead
country: United Kingdom
facility: Arrowe Park
city: Birmingham
country: United Kingdom
facility: Good Hope Hosptial
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Birmingham
country: United Kingdom
facility: Sandwell General Hospital Birmingham
city: Blackpool
country: United Kingdom
facility: Victoria Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary
city: Burton upon Trent
country: United Kingdom
facility: Queen's Hospital Burton
city: Bury St. Edmunds
country: United Kingdom
facility: West Suffolk Hospital
city: Cardiff
country: United Kingdom
facility: Velindre Hospital
city: Chelmsford
country: United Kingdom
facility: Broomfield Hospital
city: Cheltenham
country: United Kingdom
facility: Cheltenham General Hospital and Gloucestershire Royal Infirmary
city: Chesterfield
country: United Kingdom
facility: Chesterfield Royal
city: Chichester
country: United Kingdom
facility: St Richard's Hospital
city: Colchester
country: United Kingdom
facility: Colchester General Hospital
city: Coventry
country: United Kingdom
facility: University Hospital Coventry
city: Dartford
country: United Kingdom
facility: Darent Valley Hospital
city: Derby
country: United Kingdom
facility: Royal Derby Hospitals
city: Doncaster
country: United Kingdom
facility: Doncaster Royal Infirmary
city: Dundonald
country: United Kingdom
facility: Ulster Hospital
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
city: Gateshead
country: United Kingdom
facility: Queen Elizabeth Hospital, Gateshead
city: Gillingham
country: United Kingdom
facility: Medway Maritime Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer centre
city: Grimsby
country: United Kingdom
facility: Diana Princess of Wales, Grimsby
city: Harrogate
country: United Kingdom
facility: Harrogate District Hospital
city: Hemel Hempstead and Watford
country: United Kingdom
facility: Hemel Hempstead General and Watford General
city: Huddersfield
country: United Kingdom
facility: Huddersfield Royal Infirmary
city: Hull
country: United Kingdom
facility: Castle Hill Hospital
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
city: Kent
country: United Kingdom
facility: Kent and Canterbury Hospital
city: King's Lynn
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Leeds
country: United Kingdom
facility: St James University Hospital
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital, Pilgrim Hospital, Grantham and District Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool
city: London
country: United Kingdom
facility: Barnet General Hospital
city: London
country: United Kingdom
facility: Ealing Hospital
city: London
country: United Kingdom
facility: Guy's Hospital
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: London
country: United Kingdom
facility: Hillingdon Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: Northwick Park Hospital
city: London
country: United Kingdom
facility: Princess Royal University Hospital
city: London
country: United Kingdom
facility: QE Woolwich
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: St Bartholomews Hospital
city: London
country: United Kingdom
facility: St George's Hospital
city: London
country: United Kingdom
facility: St Helier Hospital
city: London
country: United Kingdom
facility: The Royal Marsden
city: London
country: United Kingdom
facility: University College Hospital London
city: Luton
country: United Kingdom
facility: Luton and Dunstable Hospital
city: Maidstone
country: United Kingdom
facility: Maidstone Hospital and The Tunbridge Wells Hospital
city: Manchester
country: United Kingdom
facility: Christie Hospital
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital
city: Middlesbrough
country: United Kingdom
facility: The James Cook University Hospital
city: Milton Keynes
country: United Kingdom
facility: Milton Keynes General Hospital
city: Newcastle
country: United Kingdom
facility: Freeman Hospital, Newcastle
city: Northampton
country: United Kingdom
facility: Northampton General Hospital
city: Northwood
country: United Kingdom
facility: Mount Vernon Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Nuneaton
country: United Kingdom
facility: George Eliot Hospital
city: Oldham
country: United Kingdom
facility: Royal Oldham
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Poole
country: United Kingdom
facility: Poole General Hospital
city: Portadown
country: United Kingdom
facility: Craigavon Area Hospital
city: Portsmouth
country: United Kingdom
facility: Queen Alexandra Hospital
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
city: Rhyl
country: United Kingdom
facility: Glan Clwyd District General Hospital
city: Romford
country: United Kingdom
facility: Queen's Hospital
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
city: Scunthorpe
country: United Kingdom
facility: Scunthorpe General Hospital
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
city: Slough
country: United Kingdom
facility: Wexham Park
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Southend
country: United Kingdom
facility: Southend Hospital
city: Stafford
country: United Kingdom
facility: County Hospital
city: Stoke
country: United Kingdom
facility: Royal Stoke Hospital
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
city: Swindon
country: United Kingdom
facility: Great Western Hospital
city: Torbay
country: United Kingdom
facility: Torbay District General Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
city: Wakefield
country: United Kingdom
facility: Pinderfields Hospital, Dewsbury Hospital and Ponerfract Hospital
city: Warwick
country: United Kingdom
facility: Warwick Hospital
city: Worcester
country: United Kingdom
facility: Worcestershire Royal Hospital
city: Worthing
country: United Kingdom
facility: Worthing Hospital
Study officials:
affiliation: University Hospital Southampton NHS Foundation Trust
name: Prof Peter Johnson
role: PRINCIPAL_INVESTIGATOR
References:
citation: Davies A, Cummin TE, Barrans S, Maishman T, Mamot C, Novak U, Caddy J, Stanton L, Kazmi-Stokes S, McMillan A, Fields P, Pocock C, Collins GP, Stephens R, Cucco F, Clipson A, Sha C, Tooze R, Care MA, Griffiths G, Du MQ, Westhead DR, Burton C, Johnson PWM. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019 May;20(5):649-662. doi: 10.1016/S1470-2045(18)30935-5. Epub 2019 Apr 1.