Randomised Trial in Waldenstrom's Macroglobulinaemia (R2W)

June 17, 2021 updated by: University College, London

Subcutaneous Bortezomib, Cyclophosphamide and Rituximab (BCR) Versus Fludarabine, Cyclophosphamide and Rituximab (FCR) for Initial Therapy of Waldenstrőm's Macroglobulinaemia (WM): a Randomized Phase II Trial

The purpose of this trial is to assess tolerability and efficacy of the Bortezomib, Cyclophosphamide and Rituximab combination as initial therapy for previously untreated patients with symptomatic Waldenstrom's macroglobulinaemia.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Waldenstrom macroglobulinaemia (WM) is a low grade nonHodgkin lymphoma characterised by bone marrow infiltration and the presence of an abnormal protein in the blood (IgM paraprotein. Most patients require treatment at presentation but there is no agreed standard of first line therapy. Current treatment is unsatisfactory with responses often incomplete and slow to attain, while recurrence is inevitable.

The aim of this study is to find out whether a new combination of Bortezomib (Velcade®), Cyclophosphamide and Rituximab (MabThera), is well tolerated and effective for patients with WM. R2W is a randomised, noncomparative, phase II trial of subcutaneous bortezomib, cyclophosphamide, rituximab (BCR, experimental arm) versus fludarabine, cyclophosphamide, rituximab (FCR, control arm) for initial therapy of WM. This is a two stage trial where six patients will be treated initially with BCR to assess tolerability. If BCR is considered tolerable, a further 50 patients will be randomised between BCR and FCR (2:1) in the second stage of the trial. Patients will receive 3 cycles of treatment and then be reassessed. Those with evidence of progression will stop trial treatment. All other patients will continue with a further 3 cycles (to a total of 6) unless there is a clear clinical contraindication to further treatment.

Study Type

Interventional

Enrollment (Actual)

60

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • Basingstoke, United Kingdom
        • Basingstoke & North Hampshire Hospital
      • Bath, United Kingdom
        • Royal United Hospital
      • Birmingham, United Kingdom, B9 5SS
        • Birmingham Heartlands Hospital
      • Birmingham, United Kingdom
        • City Hospital
      • Boston, United Kingdom
        • Pilgrim Hospital
      • Colchester, United Kingdom
        • Colchester General Hospital
      • Dartford, United Kingdom
        • Darent Valley Hospital
      • Dewsbury, United Kingdom
        • Dewsbury and District Hospital
      • Exeter, United Kingdom
        • Royal Devon and Exeter Hospital
      • Grantham, United Kingdom
        • Grantham and District Hospital
      • Leeds, United Kingdom, LS9 7TF
        • St James University Hospital
      • Leicester, United Kingdom
        • Leicester Royal Infirmary
      • Lincoln, United Kingdom
        • Lincoln County Hospital
      • Liverpool, United Kingdom
        • Royal Liverpool University Hospital
      • London, United Kingdom
        • Northwick Park Hospital
      • London, United Kingdom, NW1 2BU
        • University College Hospital
      • London, United Kingdom
        • King's College Hospital
      • London, United Kingdom
        • Royal Free Hospital
      • London, United Kingdom, EC1A 7BE
        • St Bartolomew's Hospital
      • Maidstone, United Kingdom
        • Maidstone Hospital
      • Plymouth, United Kingdom
        • Derriford Hospital
      • Pontefract, United Kingdom
        • Pontefract Hospital
      • Romford, United Kingdom
        • Queen's Hospital
      • Salisbury, United Kingdom
        • Salisbury District Hospital
      • Taunton, United Kingdom
        • Musgrove Park Hospital
      • Torquay, United Kingdom
        • Torbay Hospital
      • Tunbridge Wells, United Kingdom
        • Tunbridge Wells Hospital
      • Wakefield, United Kingdom
        • Pinderfields Hospital
      • West Bromwich, United Kingdom
        • Sandwell Hospital
      • Winchester, United Kingdom
        • Royal Hampshire County Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  • Age ≥ 18 years
  • Confirmed diagnosis of WM (according to consensus panel / WHO criteria) with measurable IgM paraprotein

  • Previously untreated disease at any stage requiring therapy at the discretion of the treating physician. Suggested criteria for initiating treatment include:

    • haematological suppression to Hb <10 g/dl, or neutrophils <1.5x109/l or platelets <150x109/l
    • clinical evidence of hyperviscosity
    • bulky lymphadenopathy and/or bulky splenomegaly
    • presence of B symptoms
  • No previous chemotherapy (prior plasma exchange and steroids are permissible)
  • Performance status grade 0 - 2
  • Life expectancy of greater than 6 months
  • Informed consent
  • Agreed compliance with recommended contraceptive precautions where appropriate

Exclusion Criteria:

  • Lymphoplasmacytic lymphoma with no detectable serum IgM paraprotein
  • Severe pre-existing neuropathy (> grade 2)
  • Autoimmune cytopenias
  • Evidence of active Hepatitis B or C infection (patients with evidence of past HepB infection may be eligible - see appendix 6)
  • Serological positivity for HIV
  • Pregnant or lactating women
  • Life expectancy severely limited by other illness
  • Renal failure (creatinine clearance <30 ml/min)
  • Severe impairment of liver function: alkaline phosphatase/bilirubin >2.5 times upper limit of normal (ULN), ALT/AST >2.5 times ULN not related to lymphoma (patients with Gilbert syndrome are eligible)
  • History of allergic reaction to compounds containing boron or mannitol
  • Known hypersensitivity to murine compounds.
  • Diagnosed or treated for a malignancy other than WM within 5 years before day 1 of Cycle 1 with the exception of complete resection of basal cell carcinoma, squamous cell carcinoma of the skin or any other in situ malignancy
  • Active systemic infection requiring treatment
  • Concurrent treatment with another investigational agent
  • Severe or life-threatening cardiac, pulmonary, neurological, psychiatric or metabolic disease

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: bortezomib, cyclophosphamide, rituximab

Bortezomib:1.6 mg/m2 s.c; days 1, 8, 15 of each cycle. Cyclophosphamide:250 mg/m2 oral; days 1, 8, 15 of each cycle. Rituximab: 375 mg/m2 i.v. infusion; days 1, 8, 15 and 22 of cycles 2 and 5 only.

Cycle repeated every 28 days. After 3 cycles of treatment, patients are reassessed and those with evidence of progression stop trial treatment. All other patients continue with further 3 cycles (to a total of 6) unless a clear clinical contradiction to further treatment exist.
Drug: Bortezomib
1.6 mg/m2 subcutaneous bortezomib on days1, 8 and 15 of 28 days cycle
Other Names:
  • Velcade
Drug: Cyclophosphamide

Cyclophosphamide:250 mg/sq m, oral, days 1, 8 and 15 of each cycle in the experimental arm.

Cyclophosphamide:250 mg/sq m, oral, days 1, 2 and 3 of each cycle in the control arm.

Biological: Rituximab
Rituximab: 375 mg/m2 i.v. infusion; days 1, 8, 15 and 22 of cycles 2 and 5 only
Other Names:
  • MabThera
Active Comparator: fludarabine, cyclophosphamide, rituximab

Fludarabine:40 mg/sq m, oral, days 1,2 and 3 of each cycle. Cyclophosphamide:250 mg/sq m; oral, days 1, 2 and 3 of each cycle. Rituximab: 375 mg/sq m i.v. infusion days 1, 8, 15 and 22 of cycles 2 and 5 only.

Cycle repeated every 28 days.After 3 cycles of treatment, patients are reassessed and those with evidence of progression stop trial treatment. All other patients continue with further 3 cycles (to a total of 6) unless a clear clinical contradiction to further treatment exist.
Drug: Cyclophosphamide

Cyclophosphamide:250 mg/sq m, oral, days 1, 8 and 15 of each cycle in the experimental arm.

Cyclophosphamide:250 mg/sq m, oral, days 1, 2 and 3 of each cycle in the control arm.

Biological: Rituximab
Rituximab: 375 mg/m2 i.v. infusion; days 1, 8, 15 and 22 of cycles 2 and 5 only
Other Names:
  • MabThera
Drug: Fludarabine
Fludarabine: 40 mg/sq m, oral, days 1, 2 and 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease response
Time Frame: 6 months (end of treatment)
Number and percentage of patients who achieve disease response
6 months (end of treatment)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Toxicity of grade 3 or higher adverse event
Time Frame: Up to 6 months after treatment start
The number and percentage of patients who experience grade 3 or higher adverse event
Up to 6 months after treatment start
Progression free survival
Time Frame: up to 5 years after treatment start
Time from date of randomisation to the date of first progression, relapse or death from any cause
up to 5 years after treatment start
Overall survival
Time Frame: up to 5 years after treatment start
Time form date of randomisation to the date of death from any cause
up to 5 years after treatment start
Quality of life (EQ-5D score)
Time Frame: at 3 and 6 months after treatment start
Quality of life will be measured using patient-completed EQ-5D questionnaire
at 3 and 6 months after treatment start

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University College, London

Investigators

  • Principal Investigator: Rebecca Auer, St. Bartholomew's Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2013

Primary Completion (Actual)

March 1, 2017

Study Completion (Actual)

August 2, 2020

Study Registration Dates

First Submitted

May 3, 2012

First Submitted That Met QC Criteria

May 4, 2012

First Posted (Estimate)

May 7, 2012

Study Record Updates

Last Update Posted (Actual)

June 18, 2021

Last Update Submitted That Met QC Criteria

June 17, 2021

Last Verified

June 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • UCL/11/0353

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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