Randomised Trial in Waldenstrom's Macroglobulinaemia

Study Overview
=================
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.

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

Conditions
-----------------
Waldenstrom's Macroglobulinaemia

Intervention / Treatment
-----------------
* Drug: Bortezomib
* Drug: Cyclophosphamide
* Biological: Rituximab
* Drug: Fludarabine


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: bortezomib, cyclophosphamide, rituximab<br>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. | Drug: Bortezomib<br>* 1.6 mg/m2 subcutaneous bortezomib on days1, 8 and 15 of 28 days cycle<br>* Other names: Velcade;Drug: Cyclophosphamide<br>* 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.<br>Biological: Rituximab<br>* Rituximab: 375 mg/m2 i.v. infusion; days 1, 8, 15 and 22 of cycles 2 and 5 only<br>* Other names: MabThera;|
| Active Comparator: fludarabine, cyclophosphamide, rituximab<br>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. | Drug: Cyclophosphamide<br>* 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.<br>Biological: Rituximab<br>* Rituximab: 375 mg/m2 i.v. infusion; days 1, 8, 15 and 22 of cycles 2 and 5 only<br>* Other names: MabThera;Drug: Fludarabine<br>* Fludarabine: 40 mg/sq m, oral, days 1, 2 and 3<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease response | Number and percentage of patients who achieve disease response | 6 months (end of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| Overall survival | Time form date of randomisation to the date of death from any cause | up to 5 years after treatment start | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Waldenstrom's macroglobulinaemia, bortezomib, cyclophosphamide, rituximab