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

• ClinicalTrials.gov Identifier: NCT01324596
• Recruitment Status: Completed
• First Posted: March 29, 2011
• Last Update Posted: April 15, 2016
• Sponsor: University Hospital Southampton NHS Foundation Trust
• Collaborator: Janssen-Cilag Ltd.
• Information provided by (Responsible Party): University Hospital Southampton NHS Foundation Trust

Tracking Information

• First Submitted Date: March 25, 2011
• First Posted Date: March 29, 2011
• Last Update Posted Date: April 15, 2016
• Study Start Date: April 2011
• Actual Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: March 28, 2011): Progression Free Survival [ Time Frame: 2 years ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 15, 2011)

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

Original Secondary Outcome Measures (submitted: March 28, 2011)

• Overall survival [ Time Frame: 5 years ]
• Event-free survival [ Time Frame: 5 years ]
• Disease-free survival [ Time Frame: 5 years ]
• Time to progression [ Time Frame: 5 years ]
• Response duration [ Time Frame: 5 years ]
• Complete and overall response rates [ Time Frame: 5 years ]
• Evaluation of toxicity (according to CTCAE version 3.0) [ Time Frame: 5 years ]
• Quality of life and assessment of peripheral neuropathy [ Time Frame: 5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Lymphoma, Large B-Cell, Diffuse

Intervention

• Drug: Intravenous
  Chemoimmunotheraphy
  Other Names:

  • Rituximab
  • cyclophosphamide
  • doxorubicin
  • vincristine
  • prednisolone
• Drug: Bortezomib
  Chemoimmunotheraphy
  Other Names:

  • rituximab
  • cyclophosphamide
  • doxorubicin
  • vincristine
  • prednisolone

Study Arms

• 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
  Intervention: Drug: Intravenous
• 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

  .

  Intervention: Drug: Bortezomib

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 24, 2015): 1132
• Original Estimated Enrollment (submitted: March 28, 2011): 940
• Actual Study Completion Date: June 2015
• Actual Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Switzerland, United Kingdom

Administrative Information

• NCT Number: NCT01324596
• Other Study ID Numbers: RHMCAN0749
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes

• Current Responsible Party: University Hospital Southampton NHS Foundation Trust
• Original Responsible Party: Director of R&D, Southampton University Hopsitals NHS Trust
• Current Study Sponsor: University Hospital Southampton NHS Foundation Trust
• Original Study Sponsor: Same as current
• Collaborators: Janssen-Cilag Ltd.

Investigators

• Principal Investigator: Prof Peter Johnson; University Hospital Southampton NHS Foundation Trust

• PRS Account: University Hospital Southampton NHS Foundation Trust
• Verification Date: April 2016