Randomised Trial in Waldenstrom’s Macroglobulinaemia

Brief Title

Randomised Trial in Waldenstrom's Macroglobulinaemia

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

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.
    

Study Phase

Phase 2

Study Type

Interventional

Primary Outcome

Disease response

Secondary Outcome

 Toxicity of grade 3 or higher adverse event

Condition

Waldenstrom's Macroglobulinaemia

Intervention

Bortezomib

Study Arms / Comparison Groups

 bortezomib, cyclophosphamide, rituximab

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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Drug

Estimated Enrollment

60

Start Date

January 2013

Completion Date

August 2, 2020

Primary Completion Date

March 2017

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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Rebecca Auer, , 

Location Countries

United Kingdom

Location Countries

United Kingdom

NCT ID

NCT01592981

Organization ID

UCL/11/0353

Responsible Party

Sponsor

Study Sponsor

University College, London

Study Sponsor

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

Verification Date

June 2021