Randomised Trial in Waldenstrom's Macroglobulinaemia
- Conditions
- Waldenstrom's Macroglobulinaemia
- Interventions
- Registration Number
- NCT01592981
- Lead Sponsor
- University College, London
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 60
-
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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description bortezomib, cyclophosphamide, rituximab 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. fludarabine, cyclophosphamide, rituximab 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. bortezomib, cyclophosphamide, rituximab Bortezomib 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. bortezomib, cyclophosphamide, rituximab Cyclophosphamide 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, cyclophosphamide, rituximab Fludarabine 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. fludarabine, cyclophosphamide, rituximab Cyclophosphamide 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.
- Primary Outcome Measures
Name Time Method Disease response 6 months (end of treatment) Number and percentage of patients who achieve disease response
- Secondary Outcome Measures
Name Time Method Progression free survival up to 5 years after treatment start Time from date of randomisation to the date of first progression, relapse or death from any cause
Quality of life (EQ-5D score) at 3 and 6 months after treatment start Quality of life will be measured using patient-completed EQ-5D questionnaire
Overall survival up to 5 years after treatment start Time form date of randomisation to the date of death from any cause
Toxicity of grade 3 or higher adverse event Up to 6 months after treatment start The number and percentage of patients who experience grade 3 or higher adverse event
Trial Locations
- Locations (30)
University College Hospital
🇬🇧London, United Kingdom
King's College Hospital
🇬🇧London, United Kingdom
Maidstone Hospital
🇬🇧Maidstone, United Kingdom
St Bartolomew's Hospital
🇬🇧London, United Kingdom
Pontefract Hospital
🇬🇧Pontefract, United Kingdom
Birmingham Heartlands Hospital
🇬🇧Birmingham, United Kingdom
Derriford Hospital
🇬🇧Plymouth, United Kingdom
Salisbury District Hospital
🇬🇧Salisbury, United Kingdom
Pinderfields Hospital
🇬🇧Wakefield, United Kingdom
Sandwell Hospital
🇬🇧West Bromwich, United Kingdom
Basingstoke & North Hampshire Hospital
🇬🇧Basingstoke, United Kingdom
Pilgrim Hospital
🇬🇧Boston, United Kingdom
Darent Valley Hospital
🇬🇧Dartford, United Kingdom
Royal United Hospital
🇬🇧Bath, United Kingdom
City Hospital
🇬🇧Birmingham, United Kingdom
Leicester Royal Infirmary
🇬🇧Leicester, United Kingdom
Musgrove Park Hospital
🇬🇧Taunton, United Kingdom
Queen's Hospital
🇬🇧Romford, United Kingdom
Grantham and District Hospital
🇬🇧Grantham, United Kingdom
Northwick Park Hospital
🇬🇧London, United Kingdom
Torbay Hospital
🇬🇧Torquay, United Kingdom
Tunbridge Wells Hospital
🇬🇧Tunbridge Wells, United Kingdom
Royal Hampshire County Hospital
🇬🇧Winchester, United Kingdom
Colchester General Hospital
🇬🇧Colchester, United Kingdom
Dewsbury and District Hospital
🇬🇧Dewsbury, United Kingdom
Royal Devon and Exeter Hospital
🇬🇧Exeter, United Kingdom
St James University Hospital
🇬🇧Leeds, United Kingdom
Lincoln County Hospital
🇬🇧Lincoln, United Kingdom
Royal Free Hospital
🇬🇧London, United Kingdom
Royal Liverpool University Hospital
🇬🇧Liverpool, United Kingdom