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 - 15 O -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 - K trans

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. FDHT-PET Pre-flutamidePost-flutamide MIR Mallinckrodt Institute of Radiology

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

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 before measurement 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, K trans, k ep, v e 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 tumor TransverseCoronal tumor Coronal tumor Transverse 1 h-post injection2 h-post injection tumor bladder heart bladder 18 F-FLT PET Images before Treatment intestine heart liver

27. MIR Mallinckrodt Institute of Radiology 18 F-FLT microPET ® ; Monitoring Therapy DES tumor Castration Before1 week2 week3 week Control tumor By week 3 all control mice were euthanized following Institutional Regulations on tumor burden.

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

29. Change of 18 F-FLT Uptake in Tumor MIR Mallinckrodt Institute of Radiology * 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