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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

Phase 2
18 Years
Open (Enrolling)
Waldenstrom's Macroglobulinaemia

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Trial Information

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

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.

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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Disease response

Outcome Description:

Number and percentage of patients who achieve disease response

Outcome Time Frame:

6 months (end of treatment)

Safety Issue:



United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

January 2013

Completion Date:

July 2021

Related Keywords:

  • Waldenstrom's Macroglobulinaemia
  • Waldenstrom's macroglobulinaemia
  • bortezomib
  • cyclophosphamide
  • rituximab
  • Waldenstrom Macroglobulinemia