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Randomised Trial in Waldenstrom's Macroglobulinaemia (R2W)

Primary Purpose

Waldenstrom's Macroglobulinaemia

Status
Completed
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Bortezomib
Cyclophosphamide
Rituximab
Fludarabine
Sponsored by
University College, London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Waldenstrom's Macroglobulinaemia focused on measuring Waldenstrom's macroglobulinaemia, bortezomib, cyclophosphamide, rituximab

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Basingstoke & North Hampshire Hospital
  • Royal United Hospital
  • Birmingham Heartlands Hospital
  • City Hospital
  • Pilgrim Hospital
  • Colchester General Hospital
  • Darent Valley Hospital
  • Dewsbury and District Hospital
  • Royal Devon and Exeter Hospital
  • Grantham and District Hospital
  • St James University Hospital
  • Leicester Royal Infirmary
  • Lincoln County Hospital
  • Royal Liverpool University Hospital
  • St Bartolomew's Hospital
  • University College Hospital
  • King's College Hospital
  • Northwick Park Hospital
  • Royal Free Hospital
  • Maidstone Hospital
  • Derriford Hospital
  • Pontefract Hospital
  • Queen's Hospital
  • Salisbury District Hospital
  • Musgrove Park Hospital
  • Torbay Hospital
  • Tunbridge Wells Hospital
  • Pinderfields Hospital
  • Sandwell Hospital
  • Royal Hampshire County Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

bortezomib, cyclophosphamide, rituximab

fludarabine, cyclophosphamide, rituximab

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Disease response
Number and percentage of patients who achieve disease response

Secondary Outcome Measures

Toxicity of grade 3 or higher adverse event
The number and percentage of patients who experience grade 3 or higher adverse event
Progression free survival
Time from date of randomisation to the date of first progression, relapse or death from any cause
Overall survival
Time form date of randomisation to the date of death from any cause
Quality of life (EQ-5D score)
Quality of life will be measured using patient-completed EQ-5D questionnaire

Full Information

First Posted
May 3, 2012
Last Updated
June 17, 2021
Sponsor
University College, London
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1. Study Identification

Unique Protocol Identification Number
NCT01592981
Brief Title
Randomised Trial in Waldenstrom's Macroglobulinaemia
Acronym
R2W
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
January 2013 (undefined)
Primary Completion Date
March 2017 (Actual)
Study Completion Date
August 2, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University College, London

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Waldenstrom's Macroglobulinaemia
Keywords
Waldenstrom's macroglobulinaemia, bortezomib, cyclophosphamide, rituximab

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
60 (Actual)

8. Arms, Groups, and Interventions

Arm Title
bortezomib, cyclophosphamide, rituximab
Arm Type
Experimental
Arm Description
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.
Arm Title
fludarabine, cyclophosphamide, rituximab
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Bortezomib
Other Intervention Name(s)
Velcade
Intervention Description
1.6 mg/m2 subcutaneous bortezomib on days1, 8 and 15 of 28 days cycle
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
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.
Intervention Type
Biological
Intervention Name(s)
Rituximab
Other Intervention Name(s)
MabThera
Intervention Description
Rituximab: 375 mg/m2 i.v. infusion; days 1, 8, 15 and 22 of cycles 2 and 5 only
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Intervention Description
Fludarabine: 40 mg/sq m, oral, days 1, 2 and 3
Primary Outcome Measure Information:
Title
Disease response
Description
Number and percentage of patients who achieve disease response
Time Frame
6 months (end of treatment)
Secondary Outcome Measure Information:
Title
Toxicity of grade 3 or higher adverse event
Description
The number and percentage of patients who experience grade 3 or higher adverse event
Time Frame
Up to 6 months after treatment start
Title
Progression free survival
Description
Time from date of randomisation to the date of first progression, relapse or death from any cause
Time Frame
up to 5 years after treatment start
Title
Overall survival
Description
Time form date of randomisation to the date of death from any cause
Time Frame
up to 5 years after treatment start
Title
Quality of life (EQ-5D score)
Description
Quality of life will be measured using patient-completed EQ-5D questionnaire
Time Frame
at 3 and 6 months after treatment start

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rebecca Auer
Organizational Affiliation
St. Bartholomew's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Basingstoke & North Hampshire Hospital
City
Basingstoke
Country
United Kingdom
Facility Name
Royal United Hospital
City
Bath
Country
United Kingdom
Facility Name
Birmingham Heartlands Hospital
City
Birmingham
ZIP/Postal Code
B9 5SS
Country
United Kingdom
Facility Name
City Hospital
City
Birmingham
Country
United Kingdom
Facility Name
Pilgrim Hospital
City
Boston
Country
United Kingdom
Facility Name
Colchester General Hospital
City
Colchester
Country
United Kingdom
Facility Name
Darent Valley Hospital
City
Dartford
Country
United Kingdom
Facility Name
Dewsbury and District Hospital
City
Dewsbury
Country
United Kingdom
Facility Name
Royal Devon and Exeter Hospital
City
Exeter
Country
United Kingdom
Facility Name
Grantham and District Hospital
City
Grantham
Country
United Kingdom
Facility Name
St James University Hospital
City
Leeds
ZIP/Postal Code
LS9 7TF
Country
United Kingdom
Facility Name
Leicester Royal Infirmary
City
Leicester
Country
United Kingdom
Facility Name
Lincoln County Hospital
City
Lincoln
Country
United Kingdom
Facility Name
Royal Liverpool University Hospital
City
Liverpool
Country
United Kingdom
Facility Name
St Bartolomew's Hospital
City
London
ZIP/Postal Code
EC1A 7BE
Country
United Kingdom
Facility Name
University College Hospital
City
London
ZIP/Postal Code
NW1 2BU
Country
United Kingdom
Facility Name
King's College Hospital
City
London
Country
United Kingdom
Facility Name
Northwick Park Hospital
City
London
Country
United Kingdom
Facility Name
Royal Free Hospital
City
London
Country
United Kingdom
Facility Name
Maidstone Hospital
City
Maidstone
Country
United Kingdom
Facility Name
Derriford Hospital
City
Plymouth
Country
United Kingdom
Facility Name
Pontefract Hospital
City
Pontefract
Country
United Kingdom
Facility Name
Queen's Hospital
City
Romford
Country
United Kingdom
Facility Name
Salisbury District Hospital
City
Salisbury
Country
United Kingdom
Facility Name
Musgrove Park Hospital
City
Taunton
Country
United Kingdom
Facility Name
Torbay Hospital
City
Torquay
Country
United Kingdom
Facility Name
Tunbridge Wells Hospital
City
Tunbridge Wells
Country
United Kingdom
Facility Name
Pinderfields Hospital
City
Wakefield
Country
United Kingdom
Facility Name
Sandwell Hospital
City
West Bromwich
Country
United Kingdom
Facility Name
Royal Hampshire County Hospital
City
Winchester
Country
United Kingdom

12. IPD Sharing Statement

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Randomised Trial in Waldenstrom's Macroglobulinaemia

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