Transcript What you always wanted to know about clinical trials but

Clinical trials in brain tumours- What you always wanted to
know but were afraid to ask
Zarnie Lwin
Department of Medical Oncology, Mater Adult Hospital
November 2011
Stupp Treatment Schema
Concomitant
Adjuvant TMZ
TMZ/RT*
R
0
6
10
14
18
22
26
30
Weeks
RT Alone
Temozolomide 75 mg/m2 po qd for 6 weeks,
then 150–200 mg/m2 po qd d1–5 every 28 days for 6 cycles
Focal RT daily — 30 x 200 cGy
Total dose 60 Gy
*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.
Stupp Survival
What are the different types of trials ?
• Phase I
• Phase II
• Phase III
• Phase IV
How are clinical trials developed ?
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Current scientific literature
Gaps in knowledge
Postulates and hypothesis
Preliminary data on hypothesis
Is this logical ?
Think tanking and collaboration
Interstate, international, collaborative groups
discussions
What happens next ?
Trial protocol designed and written up
Scientific merit, novel idea, feasibility
Funding very important
Research ethics approval
Multi-instituion ? Need all institutions to
approve
• Hypothesis, objectives, outcomes
• Overall survival
• Statitician for clinically meaningful numbers
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Where are these trials available ?
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Approved and funded clinical trial
Selection of clinical sites / hospitals
Invited to participate
Review, feasibility, patient volume considered
Expression of interest
Approved at hospital X
How are these trials advertised ?
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Principal investigator responsible
Tumour boards
Interhospital referrals
Clinical trials registries
Am I eligible ?
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Inclusion criteria
Exclusion
Specific populations e.g elderly
Specific grade of tumour
Specific biomarkers in tumour tissue
Other cancers
Other medical problems
Enrolled in other trial and had other new
agents
Who will explain the trial design to me ?
• Initial consultation with Principal or
Subinvestigator at hospital X
• Consent very important
• Can never consent immediately
• Must be able to understand and have
independent capacity to consent
• Proxy consent not allowed in majority
• English versus non english speaking patients
and families
Why am I not getting the new treatment even
though I am on a trial ?
• Comparator/control arm
• Randomization centralized
• Low grade glioma trials may not require new
treatment to start immediately
• Must be compared to standard of care
• Sometimes in recurrent disease there is no
standard of care
Do I have to pay for anything ?
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Study drug will be supplied
Investigations will be covered in cost
Parking ?
CT scans ?
Emergency or hospital admissions ?
What is randomization ?
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Randomization vs. stratification
Centre, tumour biomarkers, ECOG
Blinding and unblinding
SAE and homeopathic medications
How do I know if the new drug is working ?
• Strict guidelines in study for follow up
appointments
• MRI scan intervals
• Quality of life questionnaires
• Mini mental or CogState tests
• Decrease in steroid dosages
What if I decide to discontinue ?
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Must inform oncologist
No clinical trial ever compulsary
Consent very important
Voluntary discontinuation versus toxicities
Will still be offered standard of care
Will not be turned away from clinic
When do I stop the new treatment ?
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As per protocol
Watch and wait
True progression
Trial discontinued due to safety reports in
interim analysis
When will I know the results of the trial ?
• Data analyses
• Data needs to mature
• Abstract presented at major scientific
meetings
• Scientific manuscript published
• Media release
Are all clinical trial results released to media?
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Positive versus negative results
Important negatives
Potential harm
Costs
What happens to the new treatment /drug ?
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Goes up one Phase
Phase II
Phase III
Phase IV
What happens to the new treatment /drug ?
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Various approvals
FDA
TGA
Access schemes
Patient covers the cost
PBS
Why are some new drugs unavailable to us ?
• Cost –effectiveness
• Different countries have different
thresholds
• Still requiring confirmation data from more
larger trials
• Not yet endorsed in standard treatment
guidelines
What should I do if hospital X is too far to
travel ?
• Satellite trial sites may open
• Hospital will adhere to follow up trial protocol
even after trial closes
• Discuss with oncologist
Why should I participate in clinical trials?
• The treatments of today are results of
previous
• Robust trial results require large numbers
• Access to newer agents as they are
investigated
• Brain tumours are still unmet need compared
to other solid tumours
Are clinical trials always open for me?
• Designated time frame or total numbers as
target
• Once accrued - trial closes for data
maturation and analyses
• Newer trials opening pending on approvals
Targeted Therapies for GBM
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EGFR inhibitors
– Gefitinib
– Erlotinib
– Cetuximab
– Nimotuzumab
PI3K-Akt-mTor-pathway
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Enzastaurin
Tamoxifen
Histone deacetylase inhibitors
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Vorinostat
Depsipeptide
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Bevacizumab
VEGF Trap
AZD2171
Vatalanib
Multitargeted TKIs
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Sunitinib (VEGFR2, PDGFR, C-Kit, FLT-3)
Sorafenib (Raf, VEGFR, PDGFR)
Lapatinib (EGFR, ERBB2/HER2)
Zactima (EGFR, VEGFR2)
Dasatinib (VEGFR, PDGFR, c-Kit, Src,
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EPHA2)
Integrin antagonists
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Imatinib mesylate
VEGF and VEGFR inhibitors
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Tipifarnib
Lonafarnib
Protein kinase C inhibitors
PDGFR inhibitors
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Ras-MAPK pathway
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Sirolimus
Temsirolimus
Everolimus
AP23573
perifosine
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Cilengitide
Proteosome inhibitors
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Bortezomib
Targeted Therapy for Glioblastoma: Preliminary Results
• Most trials have evaluated targeted therapeutics in
recurrent glioblastoma
• Most trials have evaluated targeted therapeutics as
monotherapy
• Drugs have generally been well-tolerated
Challenges to the Development of
Targeted Therapeutics for Gliomas
• Target must be expressed by tumor in study population
• Target must play a critical role in tumor growth
– Genetic heterogeneity within tumor
– Importance of target fluctuates as disease evolves
• Targeted agent must reach target
– Role of enzyme inducing anticonvulsants
– Role of blood-brain-barrier
• Targeted pathway must be silenced
– Signaling cascades often redundant and overlapping
• Challenges of Clinical Trials Design
– Novel clinical trials design for selecting appropriate patients,
measuring response, surrogate molecular markers for
outcome, acquisition of tissue for correlative studies
WE NEED TO HAVE A BETTER UNDERSTANDING OF THE
BIOLOGY OF GLIOMAS!
• Questions ?