Myeloma Research in Canada

Myeloma Canada National Conference Donna E. Reece, M.D.

Princess Margaret Hospital 24 September 2011

Myeloma Research

Clinical Trials

   Phase 1 Phase II Phase III  Different drugs and combinations  Different points in disease course (new diagnosis, early relapse, advanced relapse)

Laboratory Studies

Translational research

Phases of Clinical Trials

In-vitro and In-vivo studies Phase I: Safety and dosing Phase II: How well does it work?

Phase IV: Post marketing surveillance Phase III: How well does it work compared to previous treatments?

Phases of Clinical Trials

   Phase I 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 The MTD is evaluated in a specific disease for      Response rate Time to progression (TTP) Progression free survival (PFS) Overall survival Toxicity

Phases of Clinical Trials (cont)

     Phase III 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   Phase IV Post marketing surveillance  Expanded access programs —very important in Canada until drug is approved by Health Canada!

Who sponsors a clinical trial?

   National Cancer Institute of Canada (NCIC) Industry (pharmaceutical companies)  Investigator-initiated trial Requires funding source, such as industry  Trials may be single or multi-institutional   Trials are EXPENSIVE!

Comptetitive research grants do not cover clinical trials

Steps in Starting a Clinical Trial

        Appropriate design Feasibility Statistical considerations Establish funding Health Canada approval Local Research Ethics Board (REB, IRB) review and approval of trial and consent form    Once started: 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….

 NCIC trial MY-10  Phase III trial of maintenance after ASCT with thalidomide + prednisone vs observation    A few industry sponsored trials 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

   Identification of key signalling pathways in cancer cells Importance of microenvironment Myeloma subtypes  Based on:

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

Detection of t(4;14) t(4;14) 18 mo t(4;14) other 46 mo other FGFR3 on Surface of Myeloma Tumor Cells

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 O

TKI-258

N

Tumor Regression TKI-258 Placebo TKI-258 TKI-258 or Placebo Increased Survival

More step 3: R3Mab Antibody against FGFR3  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 Qing J, el al. J Clin Invest 2009; 119: 1216-1229

Are there drugs already out there that we can use?

Purchase libraries High throughput screening of FDA-approved drugs, natural compounds

Results of HTS  Screen 50,000 chemicals

“hit” (decreased fluorescence or viability) No effect of compound

Myeloma Research in Canada          Good basic science already ongoing in 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    Myeloma Canada Scientific Roundtable in Montreal, QC in November 2010 Representatives from Canadian centres presented their laboratory work in myeloma   Summary We have talent!

Tangible results

Enhancing Myeloma Research in Canada

Myeloma Canada Research Network (MCRN)  Provides umbrella for Canadian consensus guidelines for myeloma management    Provides framework for collaborative trials across Canada 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

Bortezomib based induction therapy High- dose melphalan + busulfex + ASCT Measure MRD at day + 100 Lenalidomide maintenance

MCRN 001 Trial: Laboratory Correlates  FISH cytogenetics, free light chain included at baseline     Use multiparameter flow cytometry to measure minimal residual disease (MRD), which is better than older ways to measure response After induction After BuMel + ASCT During maintenance  Follow HeavyLite chain assay throughout therapy

PMH Clinical Trials in Myeloma

        Goal is to have trials for different disease setting First line therapy   Induction before ASCT Initial therapy for patients not eligible for ASCT Post-transplant therapy (i.e., maintenance) Relapsed myeloma So called “double refractory” myeloma  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 no t(4;14) study Len + Dex (Renal validation study) Len + Dex + MLN 9807 CyBorD ASCT

Current/Future Myeloma Trials at PMH Newly diagnosed patients Not Eligible for ASCT

Study candidate

yes no t(4;14) study Len + Dex + MLN 9807 Len + Dex +/ Elotuzomab VMP MPT Other

Current/Future Myeloma Trials at PMH Relapsed/Refractory Disease     After 1-3 prior regimens Bortezomib + dex +/- panobinostat (histone deactylase inhibitor) Lenalidomide + dex +/- carfilzomib (proteasome inhibitor) Lenalidomide + dex + +/- elotuzomab (antibody against myeloma cells)       Relapsed/refractory NCIC 191—aurora kinase inhibitor Pomalidomide + dex vs dex alone (IMiD) Pomalidomide + dex AKT inhibitor + bortezomib AKT inhibitor    Targeting t(4;14) TKI 253 (Novartis) Monoclonal antibody against FGFR3(Genentech)

Myeloma Research in Canada      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!