Imaging in Oncology Clinical Trials Susan Galbraith Clinical Discovery Bristol-Myers Squibb.
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Transcript of 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
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
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
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
Transaxial
Pre Flutamide Post Flutamide
Patient with prostate cancer and bony metastasis - Right ilium
MIR Mallinckrodt Instituteof 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• 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
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
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
MIR Mallinckrodt Instituteof Radiology
tumor
TransverseCoronal
tumor
Coronal
tumor
Transverse
1 h-post injection 2 h-post injection
tumor
bladder
heart
heart
bladder
18F-FLT PET Images before Treatment
intestineintestine
heart
liver
MIR Mallinckrodt Instituteof Radiology
18F-FLT microPET®; Monitoring Therapy
DES
tumor
tumor
Castration
Before 1 week 2 week 3 week
Control
tumor
By week 3 all control mice were euthanized following Institutional Regulations on tumor burden.
MIR Mallinckrodt Instituteof Radiology
Change in Tumor Volume
Change of Tumor Volume
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DES
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* only n=2 survived to week 2** no animals survived
Change of 18F-FLT Uptake in Tumor
MIR Mallinckrodt Instituteof Radiology
Ratios of Tumor vs. Muscle with Backgroud: At 1 hr
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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– 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