Department of Medical Oncology, Mater Adult Hospital 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 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. 2

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 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 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

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 ?