3/9/2011
Clinical Trials: Why they're important and
why you should consider participating in one
IMF
March 10, 2011
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Joseph Mikhael, MD, MEd, FRCPC
Staff Hematologist, Mayo Clinic Arizona
Objectives
1. Introduce the subject of clinical trials
2. Describe the types and "phases" of clinical
trials
3. Discuss the importance of clinical trials in
the care of all cancer patients, especially in
myeloma
4. Highlight current clinical trials, with
emphasis on two novel agents
(pomalidomide and carlfilzomib)
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3/9/2011
Clinical Trials
Remember some of the important principles
of clinical trials:
· The drive of research has brought us to
where we are
· No one is expected to be a "guinea pig"
· Research is under very tight supervision
and standards
· Open, clear communication between the
physician and the patient is fundamental
Clinical Trials Why Me??
· Every patient is unique and must be viewed that
way
· Benefits of trials are numerous and include:
· Early access to "new" therapy
· Delay use of standard therapy
· Contribution to myeloma world present and
future
· Financial access to certain agents
· Must be balanced with potential risks
· "toxicity" of side effects
· Possibility of lack of efficacy
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Clinical Trials Categories in MM
· Upfront therapy
· Relapsed therapy
· Supportive Care
· Transplant related trials
· Conditioning, Consolidation,
Maintenance
Agents used in combination
Single agent trials
Importance of Research
· From "Bench" to "Bedside"
· Better understanding of the disease
allows for better drugs
· Targets to treat
· Interaction with other aspects of
bone marrow (microenvironment)
· Has already proven impact on better
survival...
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Types of Trials
· Phase 1: designed to test the safety
of a drug (possibly efficacy)
· Phase 2: test efficacy of established
drug
· Phase 3: test the agent in direct
comparison with the current standard
of care
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Clinical Trials in the
Treatment of Myeloma
Phase I
Phase II
Phase III
Tests safety
Tests how well
Compares new
treatment works
treatment to
standard treatment
Even Before Phase I
· Most agents are tested in lab models
· Various "myeloma cell lines" = in vitro
· Next step is animal model
· We are more like mice than you think!!
· Earliest study in phase I is called "First in
Human"
· Often uses extremely low dose of drug
to ensure safety
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In Vitro Activity
Murine Activity
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Phase 2
· This is the lion share of clinical trials
· Some are very small, but others large
· Single center to multi-center
· Safe drugs (from Phase 1), prove
their efficacy in Phase 2
Phase 3
· The true Gold Standard clinical trial
· Randomized and compared to
standard of care
· Usually required to result in FDA
approval
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Clinical Trials
· Information available at:
www.clinicaltrials.gov
· Currently 1323 listed under myeloma!
· 521 still accruing
· 35 open clinical trials at Mayo Clinic
· NB: the drugs that I will discuss are
not yet FDA approved
IMF
IMF Website for clinical trials
· http://myeloma.org/ResearchMatrix.a
ction?tabId=4&menuId=206&queryPa
geId=14
· Also note the Clinical Trial "Fact
Sheets"
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Clinical Trials with Current Drugs
· Often trials will explore combinations of
agents already in use
· Which combination is best (safe and
efficacious)?
· Several open now combining:
· Dexamethasone
· Cyclophosphamide (cytoxan)
· Thalidomide
· Bortezomib (Velcade)
· Lenalidomide (Revlimid)
Lenalidomide and Dexamethasone With or
Without Bortezomib in Treating Patients With
Previously Untreated Multiple Myeloma
· Arm I: Active Comparator Patients receive oral dexamethasone
once daily on days 1, 8, 15, and 22 and oral lenalidomide once
daily on days 1-21.
· Treatment repeats every 28 days for 6 courses in the
absence of disease progression or unacceptable toxicity.
· Arm II: Experimental Patients receive oral dexamethasone once
daily on days 1, 2, 4, 5, 8, 9, 11, and 12; oral lenalidomide
once daily on days 1-14; and bortezomib IV over 3-5 seconds
on days 1, 4, 8, and 11.
· Treatment repeats every 21 days for 8 courses in the
absence of disease progression or unacceptable toxicity.
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SWOG/ECOG trial # 0777 contd.
· Estimated Enrollment: 440
· Study Start Date: April 2008
· Estimated Primary Completion Date: June
2011
· Note:
· Both treatment arms have been
previously "validated"
· Stem cell harvesting occurs after third
cycle
Novel Agents
· "newer" versions of current drugs
· Pomalidomide
· Carlfizomib
· Newer proteasome inhibitors
· Novel agents
· Bendamustine
· Perifosine
· Vorinostat
· LBH589
· RAD001
· SGN 40
· Obatoclax
· HGF inhibitors
· BHQ
· AUY922
· Monoclonal antibodies (esp CD38)
· Dasatinib
· Vaccines
· cdk Inhibitor SCH 727965
· MLN8237 (Aurora A Kinase Inhibitor)
· TAK-901
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Clinical Trials
Key Agents:
· Pomalidomide "new" version of
lenalidomide (revlimid)
· Less neuropathy than thalidomide
· Less "myelosuppression" (low
blood counts) than lenalidomide
· Phase 1 trials complete
· Many phase 2 trials ongoing
· Combination studies underway
Clinical Trials
· Carlfilzomib "new" version of
bortezomib (=velcade) ie. Proteasome
inhibitor
· IV drug given twice a week
· No reported neuropathy
· Completed many phase 2
· Phase 3 - OPEN
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Phase 3 Study Comparing Carfilzomib, Lenalidomide,
and Dexamethasone (CRd) vs. Lenalidomide and
Dexamethasone (Rd)
in Subjects with Relapsed Multiple Myeloma
· carfilzomib:
http://clinicaltrials.gov/ct2/results?ter
m=carfilzomib+AND+myeloma
· pomalidomide:
http://clinicaltrials.gov/ct2/results?ter
m=pomalidomide+AND+myeloma
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Treatment sequence
Front line treatment
Maintenance
Relapsed
Induction
Consolidation
Maintenance
Rescue
Nothing
VAD
SCT
Prednisone
Few options
DEX
Thalidomide
Treatment sequence
Bortezomib
Lenalidomide
Thal/Dex
Thalidomide
Rev/Dex
Carlfilzomib
SCT
Nothing
Vel/Dex
Pomalidomide
NEW
VD/VRD
Thalidomide?
CyBorD
HSP90
MPT?
Bortezomib?
IGFR1
Vel/Doxil
VMP?
Lenalidomide?
HDAC
RevVel
Elotuzumab
VTD
Monoclonal Abs
Front line treatment
Maintenance
Relapsed
Post
Induction
Consolidation
Rescue
consolidation
Nothing
OLD VAD
SCT
Prednisone
Few options
DEX
Thalidomide
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Conclusions
· Clinical trials are a critical part of
advancing care in multiple myeloma
· There is a spectrum of trials from Phase 1
to Phase 3
· Selecting a trial is dependent on many
patient and disease factors and must be
discussed openly
· There are many new agents that provide
great promise for patients with multiple
myeloma
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