Randomised Trial in Waldenstrom's Macroglobulinaemia

Waldenstrom's Macroglobulinaemia Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01592981
• Other study ID #: UCL/11/0353
• Status: Completed
• Phase: Phase 2
• Start date: January 2013
• Est. completion date: August 2, 2020

Study information

• Verified date: June 2021
• Source: University College, London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: August 2, 2020
• Est. primary completion date: March 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Waldenstrom Macroglobulinemia
• Waldenstrom's Macroglobulinaemia

Intervention

Drug:
• Bortezomib
1.6 mg/m2 subcutaneous bortezomib on days1, 8 and 15 of 28 days cycle
• 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

Drug:
• Fludarabine
Fludarabine: 40 mg/sq m, oral, days 1, 2 and 3

Locations

Country	Name	City	State
United Kingdom	Basingstoke & North Hampshire Hospital	Basingstoke
United Kingdom	Royal United Hospital	Bath
United Kingdom	Birmingham Heartlands Hospital	Birmingham
United Kingdom	City Hospital	Birmingham
United Kingdom	Pilgrim Hospital	Boston
United Kingdom	Colchester General Hospital	Colchester
United Kingdom	Darent Valley Hospital	Dartford
United Kingdom	Dewsbury and District Hospital	Dewsbury
United Kingdom	Royal Devon and Exeter Hospital	Exeter
United Kingdom	Grantham and District Hospital	Grantham
United Kingdom	St James University Hospital	Leeds
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	Lincoln County Hospital	Lincoln
United Kingdom	Royal Liverpool University Hospital	Liverpool
United Kingdom	King's College Hospital	London
United Kingdom	Northwick Park Hospital	London
United Kingdom	Royal Free Hospital	London
United Kingdom	St Bartolomew's Hospital	London
United Kingdom	University College Hospital	London
United Kingdom	Maidstone Hospital	Maidstone
United Kingdom	Derriford Hospital	Plymouth
United Kingdom	Pontefract Hospital	Pontefract
United Kingdom	Queen's Hospital	Romford
United Kingdom	Salisbury District Hospital	Salisbury
United Kingdom	Musgrove Park Hospital	Taunton
United Kingdom	Torbay Hospital	Torquay
United Kingdom	Tunbridge Wells Hospital	Tunbridge Wells
United Kingdom	Pinderfields Hospital	Wakefield
United Kingdom	Sandwell Hospital	West Bromwich
United Kingdom	Royal Hampshire County Hospital	Winchester

Sponsors (1)

Lead Sponsor	Collaborator
University College, London

Country where clinical trial is conducted

United Kingdom, 

Outcome

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