A Randomised Evaluation of Molecular Guided Therapy for Diffuse Large B-cell Lymphoma With Bortezomib

Lymphoma, Large B-Cell, Diffuse Clinical Trial

— REMoDL-B  

Official title:

A Randomised Evaluation of Molecular Guided Therapy for Diffuse Large B-cell Lymphoma With Bortezomib

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01324596
• Other study ID #: RHMCAN0749
• Status: Completed
• Phase: Phase 3
• First received: March 25, 2011
• Last updated: April 14, 2016
• Start date: April 2011
• Est. completion date: June 2015

Study information

• Verified date: April 2016
• Source: University Hospital Southampton NHS Foundation Trust.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 1132
• Est. completion date: June 2015
• Est. primary completion date: April 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse

Intervention

Drug:
• Intravenous
Chemoimmunotheraphy
• Bortezomib
Chemoimmunotheraphy

Locations

Country	Name	City	State
Switzerland	Kantonsspital Aarau	Aarau
Switzerland	Kantonsspital Liestal	Basel
Switzerland	Universitatsspital Basel	Basel
Switzerland	Ospedale Regionale Bellinzona e Valli (IOSI)	Bellinzona
Switzerland	Inselspital Bern	Bern
Switzerland	STSAG Thun	Bern
Switzerland	Spitalzenturm Oberwallis	Brig
Switzerland	Kantonsspital Graubunden	Chur
Switzerland	Luzerner Kantonsspital	Lucerne
Switzerland	Kantonsspital Olten	Olten
Switzerland	Kantonsspital St. Gallen	St. Gallen
Switzerland	Stadtspital Triemli	Zurich
Switzerland	UniversitatsSpital Zurich	Zurich
United Kingdom	University Hospital Aintree	Aintree
United Kingdom	Monklands, Hairmyres and Whishaw Hospitals	Airdrie
United Kingdom	Antrim Area Hospital	Antrim
United Kingdom	Stoke Mandeville Hospital and Wycombe Hospital	Aylesbury
United Kingdom	Ysbyty Gwynedd Hospital	Bangor
United Kingdom	Basildon Hospital	Basildon
United Kingdom	North Hampshire & Basingstoke Hospital	Basingstoke
United Kingdom	Royal United Hospital	Bath
United Kingdom	Belfast City Hospital	Belfast
United Kingdom	Arrowe Park	Birkenhead
United Kingdom	Good Hope Hosptial	Birmingham
United Kingdom	Queen Elizabeth Hospital	Birmingham
United Kingdom	Sandwell General Hospital Birmingham	Birmingham
United Kingdom	Victoria Hospital	Blackpool
United Kingdom	Royal Bournemouth	Bournemouth
United Kingdom	Bradford Royal Infirmary	Bradford
United Kingdom	Queen's Hospital Burton	Burton upon Trent
United Kingdom	West Suffolk Hospital	Bury St. Edmunds
United Kingdom	Velindre Hospital	Cardiff
United Kingdom	Broomfield Hospital	Chelmsford
United Kingdom	Cheltenham General Hospital and Gloucestershire Royal Infirmary	Cheltenham
United Kingdom	Chesterfield Royal	Chesterfield
United Kingdom	St Richard's Hospital	Chichester
United Kingdom	Colchester General Hospital	Colchester
United Kingdom	University Hospital Coventry	Coventry
United Kingdom	Darent Valley Hospital	Dartford
United Kingdom	Royal Derby Hospitals	Derby
United Kingdom	Doncaster Royal Infirmary	Doncaster
United Kingdom	Ulster Hospital	Dundonald
United Kingdom	Royal Devon and Exeter Hospital	Exeter
United Kingdom	Queen Elizabeth Hospital, Gateshead	Gateshead
United Kingdom	Medway Maritime Hospital	Gillingham
United Kingdom	Beatson West of Scotland Cancer centre	Glasgow
United Kingdom	Diana Princess of Wales, Grimsby	Grimsby
United Kingdom	Harrogate District Hospital	Harrogate
United Kingdom	Hemel Hempstead General and Watford General	Hemel Hempstead and Watford
United Kingdom	Huddersfield Royal Infirmary	Huddersfield
United Kingdom	Castle Hill Hospital	Hull
United Kingdom	Raigmore Hospital	Inverness
United Kingdom	Kent and Canterbury Hospital	Kent
United Kingdom	Queen Elizabeth Hospital	King's Lynn
United Kingdom	St James University Hospital	Leeds
United Kingdom	Lincoln County Hospital, Pilgrim Hospital, Grantham and District Hospital	Lincoln
United Kingdom	Royal Liverpool	Liverpool
United Kingdom	Barnet General Hospital	London
United Kingdom	Ealing Hospital	London
United Kingdom	Guy's Hospital	London
United Kingdom	Hammersmith Hospital	London
United Kingdom	Hillingdon Hospital	London
United Kingdom	King's College Hospital	London
United Kingdom	Northwick Park Hospital	London
United Kingdom	Princess Royal University Hospital	London
United Kingdom	QE Woolwich	London
United Kingdom	Royal Free Hospital	London
United Kingdom	St Bartholomews Hospital	London
United Kingdom	St George's Hospital	London
United Kingdom	St Helier Hospital	London
United Kingdom	The Royal Marsden	London
United Kingdom	University College Hospital London	London
United Kingdom	Luton and Dunstable Hospital	Luton
United Kingdom	Maidstone Hospital and The Tunbridge Wells Hospital	Maidstone
United Kingdom	Christie Hospital	Manchester
United Kingdom	Manchester Royal Infirmary	Manchester
United Kingdom	Wythenshawe Hospital	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	Northampton General Hospital	Northampton
United Kingdom	Mount Vernon Hospital	Northwood
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	George Eliot Hospital	Nuneaton
United Kingdom	Royal Oldham	Oldham
United Kingdom	Churchill Hospital	Oxford
United Kingdom	Derriford Hospital	Plymouth
United Kingdom	Poole General Hospital	Poole
United Kingdom	Craigavon Area Hospital	Portadown
United Kingdom	Queen Alexandra Hospital	Portsmouth
United Kingdom	Royal Berkshire Hospital	Reading
United Kingdom	Glan Clwyd District General Hospital	Rhyl
United Kingdom	Queen's Hospital	Romford
United Kingdom	Salisbury District Hospital	Salisbury
United Kingdom	Scunthorpe General Hospital	Scunthorpe
United Kingdom	Royal Hallamshire Hospital	Sheffield
United Kingdom	Wexham Park	Slough
United Kingdom	Southampton General Hospital	Southampton
United Kingdom	Southend Hospital	Southend
United Kingdom	County Hospital	Stafford
United Kingdom	Royal Stoke Hospital	Stoke
United Kingdom	Sunderland Royal Hospital	Sunderland
United Kingdom	Great Western Hospital	Swindon
United Kingdom	Torbay District General Hospital	Torbay
United Kingdom	Royal Cornwall Hospital	Truro
United Kingdom	Pinderfields Hospital, Dewsbury Hospital and Ponerfract Hospital	Wakefield
United Kingdom	Warwick Hospital	Warwick
United Kingdom	Worcestershire Royal Hospital	Worcester
United Kingdom	Worthing Hospital	Worthing

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Southampton NHS Foundation Trust.	Janssen-Cilag Ltd.

Countries where clinical trial is conducted

Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival		2 years	No
Secondary	Overall survival		5 years	No
Secondary	Event-free survival		5 years	No
Secondary	Disease-free survival		5 years	No
Secondary	Time to progression		5 years	No
Secondary	Response duration		5 years	No
Secondary	Complete and overall response rates		5 years	No
Secondary	Evaluation of toxicity (according to CTCAE version 4.0)		5 years	Yes
Secondary	Quality of life and assessment of peripheral neuropathy		5 years	Yes