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

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma, Large B-Cell, Diffuse
• Intervention / Treatment: Drug: Intravenous; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 1132
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Arm A: R-CHOP; 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	Drug: Intravenous; Chemoimmunotheraphy; Other Names: Rituximab; prednisolone; cyclophosphamide; doxorubicin; vincristine
EXPERIMENTAL: Arm B: RB-CHOP; 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 .	Drug: Bortezomib; Chemoimmunotheraphy; Other Names: prednisolone; cyclophosphamide; doxorubicin; rituximab; vincristine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression Free Survival	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	5 years
Disease-free survival	5 years
Time to progression	5 years
Event-free survival	5 years
Response duration	5 years
Complete and overall response rates	5 years
Evaluation of toxicity (according to CTCAE version 4.0)	5 years
Quality of life and assessment of peripheral neuropathy	5 years

Collaborators and Investigators

• Sponsor: University Hospital Southampton NHS Foundation Trust
• Collaborators: Janssen-Cilag Ltd.
• Investigators: Principal Investigator: Prof Peter Johnson, University Hospital Southampton NHS Foundation Trust

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (ACTUAL): April 1, 2015
• Study Completion (ACTUAL): June 1, 2015

Study Registration Dates

• First Submitted: March 25, 2011
• First Submitted That Met QC Criteria: March 28, 2011
• First Posted (ESTIMATE): March 29, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): April 15, 2016
• Last Update Submitted That Met QC Criteria: April 14, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: Chemotherapy; Bortezomib; R-CHOP; Lymphoma, Large B-Cell, Diffuse; Molecular profiling
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Cyclophosphamide; Rituximab; Bortezomib; Doxorubicin; Liposomal doxorubicin; Vincristine
• Other Study ID Numbers: RHMCAN0749

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES