barts cancer institute rebecca auer [email protected] waldenstrom’s: the future
TRANSCRIPT
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Barts Cancer InstituteRebecca Auer
www.cancer.qmul.ac.uk
Waldenstrom’s: The Future
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WM treatment
• WM1 recently closed
• No other UK trials
• No standard treatment
• Difficult to achieve CR
• New agents
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Development pathway
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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
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The BCR study
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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).
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Bortezomib
plasma cells
Rituximab
B cells
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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
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Rituximab
• Minimal myelosuppression
• Single agent RR 40-50%
• Combination – chemotherapy– IMiDs
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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%
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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
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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
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Randomised phase II
FCRBCR v or
DCR
Possibility of s/c bortezomib
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Side effects
• Bortezomib neurological
• Rituximab allergic / infections
• Cyclophosphamide low blood counts
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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
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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
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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
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Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.
Cartron, G. et al. Blood 2004;104:2635-2642
Main mechanisms of action of rituximab and ways to increase its clinical efficacy
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Novel anti-CD20 Abs
• GA101
• Ofatumumab
And other Abs to other proteins eg. Belimumab
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Bendamustine
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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
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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
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Overactive in WM cells
EverolimusPerifosine
PI3K/Akt/mTOR cell signalling pathway
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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%
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Perifosine
• Oral
• ORR - 35%
• Median PFS 12.6 months
• Toxicities– cytopenias– GI– Arthritis flare
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IMiDs
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IMiDs
• Thalidomide + rituximab– dose reductions required in all patients – neuropathy
• Lenalidomide + rituximab– study discontinued due to unexpected
clinically significant anaemia
• Pomolidomide
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HDACIEg. Panobinostat
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Open studies
Ofatumumab anti-CD20 monoclonal Ab
Panobinostat epigenetic - HDACI
Everolimus + BR mTOR inhibitor
Belimumab monoclonal Ab
Pomolidomide ImiD
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Chemotherapy
Biologic agent
Monoclonal Ab
Waldenstrom’s: The Future