What the pharmaceutical industry wants from novel imaging ...
Imaging in Oncology Clinical Trials Susan Galbraith Clinical Discovery Bristol-Myers Squibb What can we see? Microvasculature
Blood volume - MRI, PET Vessel permeability - MRI Blood flow - PET, MRI, SPECT Hypoxia - MRI, PET VEGF - PET 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 Imaging Blood Flow -15O -PET Yamaguchi et al Cancer 2000
CT PET -Anatomy and Glucose Metabolism Ken Krohn University of Washington 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 Imaging Proliferation Grant Macarthur - Peter Mac, Australia 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
DCE-MRI - Ktrans 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 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 ? Objectives of Phase I Oncology Trials Safety Pharmacokinetics
Dose selection cytotoxics - maximum tolerated dose targeted drugs - optimal biological dose 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 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 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 FDHT-PET Pre-flutamide Post-flutamide MIR
Mallinckrodt Institute of Radiology FDHT-PET Pre Flutamide Post Flutamide Transaxial Patient with prostate cancer and bony metastasis - Right ilium MIR
Mallinckrodt Institute of Radiology 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
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 Reproducibility studies NMR in Biomed 2002, 15, p132-142
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 ROIs etc Learning curve for technique Project cohort size needed for measurement of treatment effect 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
DCE-MRI response to CA4P Galbraith et al J Clin Oncol In Press Choice of patient population Homogeneous tumor type, site Ability to obtain good quality images respiration/movement artefact Ability to accrue trial within reasonable time 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 18 F-FLT PET Images before Treatment Coronal
bladder 2 h-post injection MIR Mallinckrodt Institute of Radiology F-FLT microPET; Monitoring Therapy 18
DES tumor Castration tumor By week 3 all control mice were euthanized following Institutional Regulations on tumor burden. Control tumor
Before 1 week 2 week MIR 3 week Institute Mallinckrodt of Radiology
Change in Tumor Volume Tumor Volume (mm3) Change of Tumor Volume 4000 3500 3000 2500 2000 1500 1000 500
0 DES Castration * Control ** 0w 1w
2w 3w * only n=2 survived to week 2 ** no animals survived MIR Mallinckrodt Institute of Radiology
Change of 18F-FLT Uptake in Tumor Ratios of Tumor vs. Muscle with Backgroud: At 1 hr Tumor/Mucle Ratios 5 4 DES 3 Castration
* Control 2 1 ** 0 0 week
1 week 2 week 3 week * only n=2 survived to week 2 ** no animals survived MIR Mallinckrodt Institute of Radiology
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 Will FLT be more informative than FDG for response assessment? FDG
FLT Grant Macarthur - Peter Mac, Australia Phase II/III - response prediction Whole tumor imaging characteristics vs tissue biopsy Implications of tumor heterogeneity Serial non-invasive images vs serial biopsies 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 How do we get there? Collaboration with academia - long term limits of the technologies possible now translational studies whats 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
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