Imaging to Guide Early Drug Trials

1. Imaging to Guide Early Drug Trials David A. Mankoff, MD, PhD Seattle Cancer Care Alliance University of Washington Seattle, WA work supported by NIH Grants CA42045, CA72064, MH63641, CA90771, S10 RR17229

2. Cautions • Most of the imaging methods presented are considered investigational • Discussion of results and possible applications is not a claim of clinical efficacy

3. Imaging and Early Drug Trials • Choosing the right patients • Is the therapeutic target present? • Choosing the right drug • Does the drug reach the target? • Getting the right result • Is there a pharmacodynamic response?

4. Early Drug Trials: Why Imaging? • Imaging samples the entire cancer • Imaging is quantitative • Imaging measures tumor heterogeneity • Spatial • Temporal (especially with Rx) • Serial assay is feasible • Complementary to in vitro assay

5. Imaging and Early Drug Trials • Choosing the right patients • Is the therapeutic target present? • Choosing the right drug • Does the drug reach the target? • Getting the right result • Is there a pharmacodynamic response?

6. * [F-18]-Fluoroestradiol (FES): PET Estrogen Receptor (ER) Imaging FES Estradiol (Kieswetter, J Nucl Med, 1984)

7. FES Uptake Predicts Breast Cancer Response to Hormonal Therapy Post-Rx Pre-Rx Example 1 • Recurrent sternal lesion • ER+ primary • Recurrent Dz strongly FES+ Excellent response after 6 wks Letrozole FES FDG FDG Example 2 • Newly Dx’d met breast CA • ER+ primary • FES-negative bone mets No response to several different hormonal Rx’s (Linden, J Clin Onc, 2006)

8. FES SUV Responders Non-Responders FES Uptake Predicts Response of Advanced Breast Cancer to Hormonal Therapy LABC or Metastatic Br CA Primary Tamoxifen Rx Recurrent or Metastatic Br CA Aromatase Inhibitor Rx FES SUV Responders Non-Responders (Mortimer, J Clin Onc, 2001) (Linden, J Clin Onc, 2006) (P < .01 for both)

9. Imaging and Early Drug Trials • Choosing the right patients • Is the therapeutic target present? • Choosing the right drug • Does the drug reach the target? • Getting the right result • Is there a pharmacodynamic response?

10. P-gp Resistance Due to Altered Drug Transport:11C-Verapamil PET to Measure P-gp Drug Transport Hypotheses: -P-gp limits drug transport into the brain -Inhibiting P-gp will increase brain transport P-gp susceptible drug 11C-Verapamil P-gp P-gp susceptible drug 11C-Verapamil x inhibitor (Hendrickse, Br j Pharmacol, 1998)

11. P-gp x Infuse Cyclosporine Verapamil PET Verapamil PET Pre-CsA Post-CsA MRI P-gp Imaging P-gp Activity in Vivo in Humans [11C]-Verapamil images pre- and post-cyclosporine (CSA) 88% +/- 20% increase in verapamil AUC (N= 12, P < .001) (Sasongko, Clin Pharm Ther, 2005)

12. Imaging and Early Drug Trials • Choosing the right patients • Is the therapeutic target present? • Choosing the right drug • Does the drug reach the target? • Getting the right result • Is there a pharmacodynamic response?

13. 2 months Tamoxifen FES PET Imaging Measures in Vivo Estrogen Binding Antagonism by Tamoxifen (thick sagittal planes) Baseline FDG Glucose Metabolism Estradiol Binding FES (Linden, SABCS, 2005)

14. FES PET Measures Drug PharmacodynamicsStage IV Breast Cancer Treated Using FulvestrantProgressive Disease Despite Dose Increase Pre-Rx 1 month 5 Months Liver SUV= 7.4 SUV= 3.2 SUV= 3.1 Uterus Post-Fulvestrant 500 mg qm Post-Fulvestrant 250 mg qm Pre-Fulvestrant (Stable Dz, No Response) (Dz Progression) (FES PET, Coronal Slices) (Linden, SABCS, 2005)

15. 24 hours 7 days 2 months 5.5 months Baseline Baseline 3 days 23 days 3 months 7 months Early Response of GIST to Imatinib Measured by FDG PET Annick Van Den Abbeele, Dana Farber, Boston

16. Post-Rx Pre-Rx Thymidine (proliferation) Tumor Marrow (with mets) FDG (Glucose Metabolism) Small Cell Lung Cancer:PET Imaging Pre-and Post One Cycle of Rx 7 days (Shields, J Nucl Med, 1998)

17. Parametric Imaging: Transport MRI FLT Summed Flux ) 1 0.10 Pre-RT mL/g/min Post-RT 0.0 FLT Brain Tumor Imaging to Measure Response:Kinetic Analysis(Muzi, J Nucl Med, 2006) 18F-Fluoro-L-thymidine (FLT) Kinetic model: (Visvikis, Eur J Nucl Med Mol Imag, 2003; Muzi, J Nucl Med, 2005)

18. Special Considerations for Imaging and Early Drug Trials

19. Imaging Requirement for Biomarker Imaging:Simultaneously Localize and Characterize Disease Sites Functional/Anatomic Imaging Functional Imaging Combinations FES FDG PET/CT Fusion FDG PET Glucose Metabolism Estradiol Binding

20. Region-of-Interest Analysis Dynamic Imaging Tumor Time Ventricle Time-Activity Curves Kinetic Modeling Tissue Parameter Estimates Blood Static Image Static Uptake Measure (SUV) Inject Tracer Imaging Requirement for Biomarker Imaging:Image Acquisition and Quantitative Analysis • Dynamic protocols • Allows kinetic modeling • Full range of analysis options • But … not for everyone • Static protocols • Clinically feasible, robust • But … only simple quantification possible

21. Imaging and Early Drug Trials: Summary • Imaging complementary to tissue and blood assays • Measure entire disease burden • Quantitative • Serial measures possible • Guide early drug trials • Measure target expression • Measure drug delivery • Measure early drug action

22. UW Cancer PET Imaging Kenneth Krohn Janet Eary Jeanne Link Mark Muzi Joseph Rajendran Alex Spence Jash Unadkat SCCA/Breast Cancer Hannah Linden Robert Doot Lisa Dunnwald Brenda Kurland Lanell Peterson Erin Schubert Lavanya Sundarajan Imaging and Early Drug Trials: Collaborators