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.

Clinical trials in brain tumours- What you always wanted to know but were afraid to ask

Zarnie LwinDepartment of Medical Oncology, Mater Adult

Hospital

November 2011

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 cGyTotal dose 60 Gy

TMZ/RT*

Adjuvant TMZ

Weeks6 10 14 18 22 26 30

RT Alone

R

Stupp Treatment Schema

0

*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.

Concomitant

Stupp Survival

What are the different types of trials ?

• Phase I

• Phase II

• Phase III

• Phase IV

How are clinical trials developed ?

• 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

Where are these trials available ?

• 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 ?

• Principal investigator responsible• Tumour boards• Interhospital referrals• Clinical trials registries

Am I eligible ?

• 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 ?

• Study drug will be supplied• Investigations will be covered in cost• Parking ?• CT scans ?• Emergency or hospital admissions ?

What is randomization ?

• 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 ?

• 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 ?

• 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?

• Positive versus negative results• Important negatives • Potential harm• Costs

What happens to the new treatment /drug ?

• Goes up one Phase• Phase II• Phase III• Phase IV

What happens to the new treatment /drug ?

• 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

• EGFR inhibitors– Gefitinib– Erlotinib– Cetuximab– Nimotuzumab

• PI3K-Akt-mTor-pathway– Sirolimus– Temsirolimus– Everolimus– AP23573– perifosine

• Ras-MAPK pathway– Tipifarnib– Lonafarnib

• Protein kinase C inhibitors– Enzastaurin– Tamoxifen

• Histone deacetylase inhibitors– Vorinostat– Depsipeptide

• PDGFR inhibitors– Imatinib mesylate

• VEGF and VEGFR inhibitors– Bevacizumab– VEGF Trap– AZD2171– Vatalanib

• Multitargeted TKIs– Sunitinib (VEGFR2, PDGFR, C-Kit, FLT-3)

– Sorafenib (Raf, VEGFR, PDGFR)– Lapatinib (EGFR, ERBB2/HER2)– Zactima (EGFR, VEGFR2)– Dasatinib (VEGFR, PDGFR, c-Kit, Src,– EPHA2)

• Integrin antagonists– Cilengitide

• Proteosome inhibitors– 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 ?