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Barts Cancer Institute Rebecca Auer Waldenstrom’s: The Future.

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Presentation on theme: "Barts Cancer Institute Rebecca Auer Waldenstrom’s: The Future."— Presentation transcript:

1 Barts Cancer Institute Rebecca Auer Waldenstrom’s: The Future

2 WM treatment WM1 recently closed No other UK trials No standard treatment Difficult to achieve CR New agents

3 Development pathway

4 Novel strategies Combinations including rituximab and/or bortezomib Novel anti-CD20 Abs / proteasome inhibitors Bendamustine Novel signal inhibitorsEverolimus Perifosine Epigenetic modifiersPanobinostat ImmunomodulatorsIMiDs Stem cell transplantation

5 The BCR study

6 Waldenstrom’s macroglobulinemia is somewhat similar to two other types of cancer, multiple myelomamultiple myeloma (plasma cell cancer) and non-Hodgkin's lymphomanon-Hodgkin's lymphoma (a group of cancers of lymphocytes).

7 Bortezomib plasma cells Rituximab B cells

8 Bortezomib in WM Predominantly in phase II trials in the relapsed or refractory setting Alone or in combination Rapid responses As a salvage treatment option - Fourth International Workshop on WM treatment recommendations

9 Rituximab Minimal myelosuppression Single agent RR 40-50% Combination –chemotherapy –IMiDs

10 Bortezomib & Rituximab in WM Barts study in relapsed lymphoma –9 of 10 patients with WM responded 2 studies in USA in untreated WM –BDR twice a week 83% responded –BR once a week 65% responded Complete response/near-complete response = 22%

11 A phase II trial of bortezomib, rituximab and cyclophosphamide in patients with symptomatic, untreated Waldenstrom macroglobulinemia To determine the efficacy and safety of bortezomib, rituximab and cyclophosphamide Symptomatic untreated WM IV Bortezomib 1.6 mg/m 2 on days 1, 8, 15 Oral Cyclophosphamide 250 mg/m 2 on days 1, 8, 15 IV Rituximab 375 mg/m 2 d1, 8, 15, 22 of cycles 2 and 4 –this will be repeated every 28 days for 6 cycles in responding patients. 1° endpoint: Response rate 2° endpoint: Toxicity, complete response rate, duration of response, speed of response, time to next treatment, progression free survival

12 Study design Run in phase 6 patients Multicentre phase 33 patients Recruit over 2 years 6 centres –Barts, Leeds, Mid-Yorkshire, Heartlands, King’s, UCH, Plymouth Plan to follow on with a phase III –BCR versus FCR

13 Randomised phase II FCR BCR v or DCR Possibility of s/c bortezomib

14 Side effects Bortezomibneurological Rituximaballergic / infections Cyclophosphamidelow blood counts

15 Assessments Blood tests every cycle Bone marrow and CT scans at start, midway, at completion Blood and BM assays to look for better markers of response Research samples to look at some of the genetic & protein changes in WM

16 Timelines Application to CRUKAug 2010April 2011 Decision by CRUKNov 2010July 2011 Expectation openMay 2011Jan 2012 Duration recruitment2 years2 years Duration follow up5 years5 years

17 New proteasome inhibitors s/c Bortezomib –less neurotoxicity but as active Carfilzomib –phase I data –no grade 3/4 neuropathy –activity Marizomib –phase I studies recruiting

18 Copyright ©2004 American Society of Hematology. Copyright restrictions may apply. Cartron, G. et al. Blood 2004;104: Main mechanisms of action of rituximab and ways to increase its clinical efficacy

19 Novel anti-CD20 Abs GA101 Ofatumumab And other Abs to other proteins eg. Belimumab

20 Bendamustine

21 StiL Group - Rummel BR versus R-CHOP first line n=549 –WM n=42 –ORR similar BUT CR, PFS, TTNT all significantly better with BR –Progressive disease in 2/23 BR versus 7/17 R-CHOP –Less grade 3/4 neutropenia with BR

22 StiL Group - Rummel BR versus FR relapse n=219 –BR higher ORR83.5% v 52.5% CR38.5% v 16.2% –grade 3/4 neutropenia similar

23 Overactive in WM cells Everolimus Perifosine PI3K/Akt/mTOR cell signalling pathway

24 Everolimus Oral ORR – 70% –PR 42% MR 28% Median PFS and duration response not reached Toxicities –Grade 3 or higher in 56% –Lung toxicity in 10%

25 Perifosine Oral ORR - 35% Median PFS 12.6 months Toxicities –cytopenias –GI –Arthritis flare

26 IMiDs

27 Thalidomide + rituximab –dose reductions required in all patients –neuropathy Lenalidomide + rituximab –study discontinued due to unexpected clinically significant anaemia Pomolidomide

28 HDACI Eg. Panobinostat

29 Open studies O fatumumabanti-CD20 monoclonal Ab Panobinostatepigenetic - HDACI Everolimus + BRmTOR inhibitor Belimumab monoclonal Ab PomolidomideImiD

30 Chemotherapy Biologic agent Monoclonal Ab Waldenstrom’s: The Future


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