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Waldenstrom’s: The Future

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Presentation on theme: "Waldenstrom’s: The Future"— Presentation transcript:

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

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 inhibitors Everolimus Perifosine Epigenetic modifiers Panobinostat Immunomodulators IMiDs Stem cell transplantation

5 The BCR study

6 Waldenstrom’s macroglobulinemia is somewhat similar to two other types of cancer,
multiple myeloma (plasma cell cancer) and non-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 Symptomatic untreated WM IV Bortezomib 1.6 mg/m2 on days 1, 8, 15
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/m2 on days 1, 8, 15 Oral Cyclophosphamide 250 mg/m2 on days 1, 8, 15 IV Rituximab 375 mg/m2 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 Possibility of s/c bortezomib
Randomised phase II FCR BCR v or DCR Possibility of s/c bortezomib

14 Side effects Bortezomib neurological Rituximab allergic / infections
Cyclophosphamide low 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 CRUK Aug 2010 April 2011
Decision by CRUK Nov 2010 July 2011 Expectation open May 2011 Jan 2012 Duration recruitment 2 years 2 years Duration follow up 5 years 5 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 Cartron, G. et al. Blood 2004;104:2635-2642
Main mechanisms of action of rituximab and ways to increase its clinical efficacy Cartron, G. et al. Blood 2004;104: Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

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 ORR 83.5% v 52.5% CR 38.5% v 16.2% grade 3/4 neutropenia similar

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

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 IMiDs Thalidomide + rituximab Lenalidomide + rituximab Pomolidomide
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 Ofatumumab anti-CD20 monoclonal Ab
Panobinostat epigenetic - HDACI Everolimus + BR mTOR inhibitor Belimumab monoclonal Ab Pomolidomide ImiD

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

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