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

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

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?

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

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?

[F-18]-Fluoroestradiol (FES): PET Estrogen Receptor (ER) Imaging FES Estradiol * (Kieswetter, J Nucl Med, 1984) RBA (FES vs Estradiol) ER0.9 SHBG0.8

FES Uptake Predicts Breast Cancer Response to Hormonal Therapy Pre-Rx Post-Rx FES FDG 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) Recurrent sternal lesion ER+ primary Recurrent Dz strongly FES+ Excellent response after 6 wks Letrozole Example 1 Example 2

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

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?

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

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

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?

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

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

Baseline 3 days23 days 3 months 7 months Baseline 7 days2 months 5.5 months 24 hours Early Response of GIST to Imatinib Measured by FDG PET Annick Van Den Abbeele, Dana Farber, Boston

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

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

Special Considerations for Imaging and Early Drug Trials

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

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

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

Imaging and Early Drug Trials: Collaborators 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