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

This study is currently recruiting participants.
Verified September 2013 by University Hospital Southampton NHS Foundation Trust.
Sponsor:
Collaborator:
Janssen-Cilag Ltd.
Information provided by (Responsible Party):
University Hospital Southampton NHS Foundation Trust.
ClinicalTrials.gov Identifier:
NCT01324596
First received: March 25, 2011
Last updated: November 4, 2013
Last verified: September 2013
  Purpose

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.

Condition Intervention Phase
Lymphoma, Large B-Cell, Diffuse
Drug: Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone
Drug: Bortezomib, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomised Evaluation of Molecular Guided Therapy for Diffuse Large B-cell Lymphoma With Bortezomib

Resource links provided by NLM:


Further study details as provided by University Hospital Southampton NHS Foundation Trust.:

Primary Outcome Measures:
  • Progression Free Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Overall survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Event-free survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Disease-free survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Time to progression [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Response duration [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Complete and overall response rates [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Evaluation of toxicity (according to CTCAE version 4.0) [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
  • Quality of life and assessment of peripheral neuropathy [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 940
Study Start Date: April 2011
Estimated Study Completion Date: April 2020
Estimated Primary Completion Date: April 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A: R-CHOP
Participants receive 6 cycles of conventional R-CHOP chemotherapy on a standard 21 day schedule
Drug: Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone
Chemotherapy
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 with bortezomib.
Drug: Bortezomib, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone
Chemotherapy

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 800 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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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. REMoDL-B Protocol Version 2.0 6th January 2011.
  • 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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01324596

Contacts
Contact: Catherine Simpson 044 2380777222 ext 3785 Catherine.Simpson@soton.ac.uk
Contact: Debbie Hamid 044 2380795328 d.hamid@soton.ac.uk

Locations
United Kingdom
University Hospital Aintree Recruiting
Aintree, United Kingdom
Principal Investigator: Barbara Hammer         
North Hampshire & Basingstoke Hospital Recruiting
Basingstoke, United Kingdom
Principal Investigator: Alison Milne         
Royal Bournemouth Recruiting
Bournemouth, United Kingdom
Principal Investigator: Rachel Hall         
St Richard's Hospital Recruiting
Chichester, United Kingdom
Principal Investigator: Philip Bevan         
Colchester General Hospital Recruiting
Colchester, United Kingdom
Principal Investigator: Michael Hamblin         
Hemel Hempstead General and Watford General Recruiting
Hemel Hempstead and Watford, United Kingdom
Principal Investigator: Justin Harrison         
Kent and Canterbury Hospital Recruiting
Kent, United Kingdom
Principal Investigator: Christopher Pocock         
Royal Liverpool Recruiting
Liverpool, United Kingdom
Principal Investigator: Nagesh Kalakonda         
Guy's Hospital Recruiting
London, United Kingdom
Principal Investigator: Paul Fields         
Royal Free Hospital Recruiting
London, United Kingdom
Principal Investigator: Kate Cwynarski         
University College Hospital London Recruiting
London, United Kingdom
Principal Investigator: Kirit Ardeshna         
Christie Hospital Recruiting
Manchester, United Kingdom
Principal Investigator: John Radford         
Mount Vernon Hospital Recruiting
Northwood, United Kingdom
Principal Investigator: Jonathan Lambert         
Churchill Hospital Recruiting
Oxford, United Kingdom
Principal Investigator: Graham Collins         
Queen Alexandra Hospital Recruiting
Portsmouth, United Kingdom
Principal Investigator: Ann O'Callaghan         
Queen's Hospital Recruiting
Romford, United Kingdom
Principal Investigator: Alison Brownell         
Southampton General Hospital Recruiting
Southampton, United Kingdom
Contact: Andrea Lodge    02380 798448    a.lodge@southampton.ac.uk   
Principal Investigator: Peter Prof Johnson         
Southend Hospital Recruiting
Southend, United Kingdom
Principal Investigator: Paul Cervi         
Great Western Hospital Recruiting
Swindon, United Kingdom
Principal Investigator: Norbert Blessing         
Torbay District General Hospital Recruiting
Torbay, United Kingdom
Principal Investigator: Deborah Turner         
Royal Cornwall Hospital Recruiting
Truro, United Kingdom
Principal Investigator: Anton Kruger         
Worthing Hospital Recruiting
Worthing, United Kingdom
Principal Investigator: Santosh Narat         
Sponsors and Collaborators
University Hospital Southampton NHS Foundation Trust.
Janssen-Cilag Ltd.
Investigators
Principal Investigator: Prof Peter Johnson University Hospital Southampton NHS Foundation Trust.
  More Information

No publications provided

Responsible Party: University Hospital Southampton NHS Foundation Trust.
ClinicalTrials.gov Identifier: NCT01324596     History of Changes
Other Study ID Numbers: RHMCAN0749
Study First Received: March 25, 2011
Last Updated: November 4, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University Hospital Southampton NHS Foundation Trust.:
Lymphoma, Large B-Cell, Diffuse
Bortezomib
R-CHOP
Molecular profiling
Chemotherapy

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Cyclophosphamide
Rituximab
Bortezomib
Doxorubicin
Prednisolone
Methylprednisolone Hemisuccinate
Vincristine
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents

ClinicalTrials.gov processed this record on April 17, 2014