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  1. Imaging in Oncology Clinical Trials Susan Galbraith Clinical Discovery Bristol-Myers Squibb

  2. What can we see? • Microvasculature • Blood volume - MRI, PET • Vessel permeability - MRI • Blood flow - PET, MRI, SPECT • Hypoxia - MRI, PET • VEGF - PET

  3. What can we see? • Gene expression - optical imaging, PET • Enzyme activation - optical imaging, MRI • Receptor expression/occupancy - PET, MRI • Apoptosis - MRI, PET, SPECT • Cell proliferation - PET • Glucose metabolism - PET • Membrane turnover - PET

  4. Imaging Blood Flow -15O -PET Yamaguchi et al Cancer 2000

  5. CT PET -Anatomy and Glucose Metabolism Ken Krohn University of Washington

  6. FLT PET - Imaging Proliferation • FLT (3’- deoxy-3’ – fluorothymidine) is phosphorylated by thymidine kinase 1 and trapped within cells • Since TK-1 levels increase around 10-fold in S-phase, retention should theoretically reflect DNA synthesis Shields et al. Nature Med 1998

  7. Imaging Proliferation Grant Macarthur - Peter Mac, Australia

  8. DCE-MRI • Using Gd-DTPA - composite of vessel permeability, surface area and blood flow • Using high molecular weight contrast agents - permeability, blood volume • Need arterial input function to determine blood flow

  9. DCE-MRI - Ktrans

  10. MRI - Imaging of permeability and blood volume • Need high molecular weight contrast agent • Albumin- GdDTPA - Overexpression of VEGF 165 drives peritumor interstitial convection and induces lymphatic drain (Dafni et al Cancer Res 2002) • Superparamagnetic iron oxide contrast agents

  11. What can imaging do for you?…. Novel imaging technology has the potential to • assist lead compound selection • enable earlier Go/No Go decisions • have greater confidence about those decisions • save patients from treatment with drugs destined to fail • save money How to utilize this potential to truly affect decisions in drug development ?

  12. Objectives of Phase I Oncology Trials • Safety • Pharmacokinetics • Dose selection • cytotoxics - ‘maximum tolerated dose’ • ‘targeted’ drugs - ‘optimal biological dose’

  13. What answers would help a novel ‘targeted’ oncology drug? • Pre-clinical/Phase 1 • does the drug hit the target in the tumor • what is the exposure response / time course of response • Phase I/II • how does hitting target relate to anti-tumor efficacy • any early indicators of toxicity • Phase II/III • can tumor response be predicted by target expression/ activation • differentiation from competitors

  14. Definition of Go/No Go • Drug does not hit target • Do not achieve desired effect size at tolerable doses • Selectivity of effect in tumor/normal tissues

  15. Where does imaging fit in development? • SAD (if TI allows) - rapidly define single dose PK, tolerability, ability to reach exposure range for efficacy • MAD - imaging or other biomarker to demonstrate biological activity, dose response and PK/PD relationship

  16. MIR Mallinckrodt Institute of Radiology FDHT-PET Pre-flutamide Post-flutamide

  17. MIR Mallinckrodt Institute of Radiology FDHT-PET Pre Flutamide Post Flutamide Transaxial Patient with prostate cancer and bony metastasis - Right ilium

  18. Phase I trial • Dose escalate ? To MTD (depends on TI) • Expand cohorts for imaging studies (n depends on reproducibility and effect size of interest) • Need same imaging protocol implemented at all sites • Quality control • Centralized data analysis

  19. Implications • Technology used - relatively established vs ‘cutting edge’ • Definition of every stage of imaging process • Reproducibility studies needed beforemeasurement of treatment effect • SDV as detailed as for clinical aspects of study • Site selection • Consensus on methodology e.g. EORTC FDG PET recommendations 1999

  20. Reproducibility studies NMR in Biomed 2002, 15, p132-142

  21. Reproducibility Studies • Determine 95% limits of change for individuals and for groups • Identify ‘key determinants’ of reproducibility - how much is dependent on subjective definition of ‘ROI’s etc • Learning curve for technique • Project cohort size needed for measurement of treatment effect

  22. Choice of parameter • DCE-MRI - gradient, enhancement, AUC, Ktrans, kep, ve • FDG PET - dynamic, SUV - which SUV? • Balance - • reproducibility • sensitivity to treatment effect • validity of assumptions • availability • heterogeneity effect

  23. DCE-MRI response to CA4P Galbraith et al J Clin Oncol In Press

  24. Choice of patient population • Homogeneous tumor type, site • Ability to obtain good quality images - respiration/movement artefact • Ability to accrue trial within reasonable time

  25. Phase II - Efficacy • Is stable disease indicative of anti-tumor efficacy? • Effects on tumor metabolism/ proliferation/ microvasculature seen before effects on tumor size • Are changes in proliferation/ metabolism seen in higher proportion of patients than proportion with PR/CR

  26. MIR Mallinckrodt Institute of Radiology 18F-FLT PET Images before Treatment Coronal Transverse Coronal Transverse heart tumor liver tumor heart heart tumor tumor intestine intestine bladder bladder 1 h-post injection 2 h-post injection

  27. DES tumor Castration tumor MIR Mallinckrodt Institute of Radiology 18F-FLT microPET®; Monitoring Therapy Control By week 3 all control mice were euthanized following Institutional Regulations on tumor burden. tumor Before 1week 2 week 3 week

  28. MIR Mallinckrodt Institute of Radiology Change in Tumor Volume * ** * only n=2 survived to week 2 ** no animals survived

  29. MIR Mallinckrodt Institute of Radiology Change of 18F-FLT Uptake in Tumor * ** * only n=2 survived to week 2 ** no animals survived

  30. Rationale for use of FDG PET for response assessment • Earlier response assessment • Better predictor of clinical benefit than conventional imaging - biology rather than anatomy • ? Increased number of responders - more information on ‘stable disease’

  31. Will FLT be more informative than FDG for response assessment? FDG FLT Grant Macarthur - Peter Mac, Australia

  32. Phase II/III - response prediction • Whole tumor imaging characteristics vs tissue biopsy • Implications of tumor heterogeneity • Serial non-invasive images vs serial biopsies

  33. Potential utility of imaging.. • Imaging of receptor occupancy/ enzyme inhibition • Pre-clinical correlation with anti-tumor effect • Understanding of PK/PD relationship • Translatable technology from pre-clinic to clinic • Determination of reproducibility in clinic • High quality, multi-site imaging in trials • Early indication of efficacy • Response prediction

  34. How do we get there? • Collaboration with academia - long term • limits of the technologies possible now • translational studies • what’s around the corner? • Work on QA/ imaging monitoring/analysis • delivery of high quality imaging in trials • Develop internal understanding of and expertise in imaging technology