Transcript Clinical Trials - Myeloma Canada

Myeloma Research in Canada
Myeloma Canada National
Conference
Donna E. Reece, M.D.
Princess Margaret Hospital
24 September 2011
Myeloma Research
Clinical Trials
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Phase 1
Phase II
Phase III
Laboratory Studies
Translational research
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Different drugs and
combinations
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Different points in disease
course (new diagnosis,
early relapse, advanced
relapse)
Phases of Clinical Trials
In-vitro and In-vivo studies
Phase I: Safety and dosing
Phase II: How well does it
work?
Phase III: How well does it work
compared to previous treatments?
Phase IV: Post marketing
surveillance
Phases of Clinical Trials
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Phase I
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Usually a relatively small, “dose escalation” study to
determine the maximum tolerated dose (“MTD”)
Can provide clues as to the anti-tumor effect of the
drug
Phase II
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The MTD is evaluated in a specific disease for
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Response rate
Time to progression (TTP)
Progression free survival (PFS)
Overall survival
Toxicity
Phases of Clinical Trials (cont)
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Phase III
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Phase IV
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Randomized trial to establish a new drug is equivalent to
or better than the previous standard therapy
Often needed for regulatory approval (“Registration
trial”)
Usually large study
Important endpoints are PFS and overall survival
Post marketing surveillance
Expanded access programs—very important in
Canada until drug is approved by Health Canada!
Who sponsors a clinical trial?
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National Cancer Institute of Canada (NCIC)
Industry (pharmaceutical companies)
Investigator-initiated trial
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Requires funding source, such as industry
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Trials may be single or multi-institutional
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Trials are EXPENSIVE!
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Comptetitive research grants do not cover clinical trials
Steps in Starting a Clinical Trial
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Appropriate design
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Health Canada approval
Local Research Ethics Board (REB, IRB) review and approval of
trial and consent form
Once started:
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Feasibility
Statistical considerations
Establish funding
Continuous monitoring of side-effects and periodic review of results
Monitoring visits by sponsor
Audits by Health Canada, FDA, NCIC
Need to keep track of the data
Where we were 5-10 years ago….
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NCIC trial MY-10
 Phase III trial of maintenance after ASCT with
thalidomide + prednisone vs observation
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A few industry sponsored trials
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Pamidronate and zolendronic acid trials
Canadian centers active in phase III trials for the new
myeloma drugs bortezomib (Velcade) and lenalidomide
(Revlimid) for relapsed/refractory myeloma
Progress in Myeloma Research
Myeloma Cells
Microenvironment
Progress in Myeloma Research
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Identification of key signalling pathways in cancer cells
Importance of microenvironment
Myeloma subtypes
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Cytogenetics
Molecular studies
17p del (loss of p53)
t(4;14)
Laboratory Research: From Bench to
Bedside
Identify
target
Validate
target
Develop/
identify
drug
against
target
Clinical
Trial
Step 1-Identify the Target and Patients
other
46 mo
18 mo
t(4;14)
Detection of t(4;14)
FGFR3 on Surface of
Myeloma Tumor Cells
t(4;14)
other
Step 2-Validate the Target
Trudel S et. al, Blood, 2004
Step 3: Develop drugs against the target
FGFR3
F
N
N
N
N
N
N
O
TKI-258
TKI-258
Tumor Regression
Placebo
TKI-258 or
Placebo
TKI-258
Increased Survival
More step 3: R3Mab Antibody against
FGFR3
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Qing J, el al. J Clin Invest 2009; 119: 1216-1229
Unique anti-FGFR3
monoclonal antibody
(Genentech)
Advantage of selectivity
Anti-tumor activity
mediated in part via ADCC
PMH is lead site for phase
I-II trial in t(4;14) myeloma
Are there drugs already out there that we
can use?
Purchase libraries
of FDA-approved
drugs, natural compounds
High throughput screening
Results of HTS
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Screen 50,000 chemicals
“hit” (decreased fluorescence or viability)
No effect of compound
Myeloma Research in Canada
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Good basic science already ongoing in
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Calgary
Edmonton
Montreal
St John
Toronto
Winnipeg
But, limited opportunities for investigators to interact and
brainstorm
Myeloma Canada sponsored first Scientific Roundtable in
Canada in November 2010
Enhancing Myeloma Research in Canada
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Myeloma Canada Scientific
Roundtable in Montreal,
QC in November 2010
Representatives from
Canadian centres
presented their laboratory
work in myeloma
Summary
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We have talent!
Tangible results
Enhancing Myeloma Research in Canada
Myeloma Canada Research Network
(MCRN)
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Provides umbrella for Canadian consensus guidelines for
myeloma management
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Provides framework for collaborative trials across Canada
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First study t(4;14) trial of bortezomib-based therapy in newly
diagnosed patients without planned ASCT
Upcoming study for transplant-eligible newly diagnosed
patients
MCRN 001 Schema for Trial in Newly Diagnosed
Transplant-eligible Myeloma Patients
Bortezomibbased
induction
therapy
High- dose
melphalan
+ busulfex
+ ASCT
Measure
MRD at
day + 100
Lenalidomide
maintenance
MCRN 001 Trial: Laboratory Correlates
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FISH cytogenetics, free light chain included at baseline
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Use multiparameter flow cytometry to measure minimal
residual disease (MRD), which is better than older ways
to measure response
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After induction
After BuMel + ASCT
During maintenance
Follow HeavyLite chain assay throughout therapy
PMH Clinical Trials in Myeloma
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Goal is to have trials for different disease setting
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First line therapy
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Post-transplant therapy (i.e., maintenance)
Relapsed myeloma
So called “double refractory” myeloma
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Induction before ASCT
Initial therapy for patients not eligible for ASCT
Defined as progression after both bortezomib and lenalidomide
Aim for a spectrum of phase I,II and III trials
Seek to have investigator-initiated trials
Laboratory component is a high priority
Current/Future Myeloma Trials at PMH
Newly diagnosed patients
Eligible for ASCT
Study candidate
yes
t(4;14)
study
Len + Dex
(Renal validation
study)
no
Len + Dex +
MLN 9807
ASCT
CyBorD
Current/Future Myeloma Trials at PMH
Newly diagnosed patients
Not Eligible for ASCT
Study candidate
yes
t(4;14)
study
Len + Dex +
MLN 9807
no
Len + Dex +/Elotuzomab
VMP
MPT
Other
Current/Future Myeloma Trials at PMH
Relapsed/Refractory Disease
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After 1-3 prior regimens
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Relapsed/refractory
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Bortezomib + dex +/- panobinostat (histone deactylase inhibitor)
Lenalidomide + dex +/- carfilzomib (proteasome inhibitor)
Lenalidomide + dex + +/- elotuzomab (antibody against myeloma cells)
NCIC 191—aurora kinase inhibitor
Pomalidomide + dex vs dex alone (IMiD)
Pomalidomide + dex
AKT inhibitor + bortezomib
AKT inhibitor
Targeting t(4;14)
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TKI 253 (Novartis)
Monoclonal antibody against FGFR3(Genentech)
Myeloma Research in Canada
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Laboratory and transitional research is ongoing
Myeloma Canada research grant offers opportunities
for young investigators
New research organization under Myeloma Canada
umbrella: MCRN
Second Myeloma Canada Scientific Roundtable in
Montreal, QC in November 2011
WE CAN DO THIS TOGETHER
TO WORK TOWARDS A CURE!