Randomised phase 2 trial in Waldenstrőm's macroglobulinaemia R2W Randomised phase 2 trial in Waldenstrőm's macroglobulinaemia 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 OFF TRIAL SAMPLE SIZE: Stage I: 6 patients Stage II: 50 (33 BCR; 17 FCR) Total: 56 patients Assess response after 3 cycles 3 more cycles (total of 6) unless clinical contraindication to further treatment exist CR/VGPR/ PR/MR/SD Progression Follow-up Response/progression assessed every 3 months for 5 years Arm B: BCR (experimental) Bortezomib 1.6mg/m2 s.c d1,8,15 Cyclophosphamide 250mg/m2 po d1,8,15 Rituximab (c2&5) 375mg/m2 d 1/8/15/22 Cycle repeated every 28 days Arm A: FCR (control) Fludarabine 40mg/m2 po d1-3 Cyclophosphamide 250mg/m2 po d1-3 No excess toxicity observed Stage I: Safety run-in with BCR Previously untreated patients with symptomatic WM with measurable IgM paraprotein First 6 patients treated with BCR at 4 sites Bortezomib 1.6mg/m2 s.c days 1, 8, 15 Cyclophosphamide 250mg/m2 po days 1, 8, 15 Rituximab (c2 & c5) 375mg/m2 iv days 1/8/15/22 Regular safety data monitoring IDMC review after 6th patient reached C2 D1 Stage II: Randomisation BCR versus FCR 2:1 PATIENT ELIGIBILITY Trial endpoints MAIN INCLUSION CRITERIA Age ≥ 18 years WM with measurable IgM paraprotein Previously untreated disease requiring therapy 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 Performance status grade 0 - 2 Life expectancy of greater than 6 months MAIN EXCLUSION CRITERIA Lymphoplasmacytic lymphoma with no detectable IgM Severe pre-existing neuropathy (> grade 2) Autoimmune cytopenias Renal failure (creatinine clearance <30 ml/min) Severe impairment of liver function: alkaline phosphatase/bilirubin >2.5xULN, ALT/AST >2.5xULN not related to lymphoma Active systemic infection requiring treatment Severe or life-threatening cardiac, pulmonary, neurological, psychiatric or metabolic disease Please check protocol for further details Overall response rate Toxicity Complete response rate Speed and duration of response Time to next treatment Progression free survival Overall survival Quality of life Samples requirements during treatment & follow up Serum for SFLC & Hevylite assays sent for analysis to a Central Lab Peripheral blood for flow cytometry analysis at HMDS, Leeds Bone marrow aspirate and trephine for analysis at HMDS, Leeds Limited number of Sites for 1st safety stage: Barts Health NHS Trust, London Heart of England NHS Trust, Birmingham Leeds Teaching Hospitals NHS Trust University College London Hospitals NHS Trust Chief investigator Dr Rebecca Auer, St Barts SITE ELIGIBILITY Site registration form R&D approval Signed Clinical Trial Site Agreement Delegation log PI CV/GCP  ctc.r2w@ucl.ac.uk 0207 679 9860  0207 679 9861 R2W - Haematology Trials Group CR UK & UCL Cancer Trials Centre 90 Tottenham Court Rd, London, W1T 4TJ