# Presentation: 126581

## 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

**Notes:**
Noninvasive imaging of lymphatic function induced by vascular hyperpermeability was achieved by following the distribution of albumin triple-labeled with biotin, fluorescein, and gadolinium-diethylene triamine pentaacetic acid. This contrast material allowed for multimodality imaging using magnetic resonance imaging (MRI), confocal microscopy, and histology.
Overexpression of VEGF in C6-pTET-VEGF165 tumors, inoculated in hind limbs of nude mice, elevated vascular permeability, interstitial convection, and lymphatic drain. These were manifested in dynamic MRI measurements by outward flux of the contrast material, the rat of which correlated with tumor volume followed by directional flow toward the popliteal lymph node. Avidin-chase, namely i.v. administration of avidin, was applied for inducing rapid clearance of the intravascular biotinylated contrast material, thus allowing early experimental separation between vascular leak and lymphatic drain. Repeated MRI measurements of the same mice were conducted 48 h after withdrawal of VEGF by addition of tetracycline to the drinking water. VEGF withdrawal decreased tumor blood-plasma volume  fraction by 43%, reduced tumor permeability by 75%, and abolished interstitial convection of the contrast material.

## 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

**FDHT-PET**

- Pre-flutamide

- Post-flutamide

## FDHT-PET

- Transaxial

- Pre Flutamide

- Post Flutamide

- Patient with prostate cancer and bony metastasis - Right ilium

## 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 ‘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

## 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

## 18F-FLT PET Images before Treatment

- tumor

- Transverse

- Coronal

- tumor

- Coronal

- tumor

- Transverse

- 1 h-post injection

- 2 h-post injection

- tumor

- bladder

- heart

- heart

- bladder

- 18F-FLT PET Images before Treatment

- intestine

- intestine

- heart

- liver

## 18F-FLT microPET®; Monitoring Therapy

- 18F-FLT microPET®; Monitoring Therapy

- Before

- 1 week

- 2 week

- 3 week

- Control

- tumor

**By week 3 all control mice**
** ****were euthanized following**
** ****Institutional Regulations **
**on tumor burden.**

## Change in Tumor Volume

- *

- **

- * only n=2 survived to week 2
- ** no animals survived

## Change of 18F-FLT Uptake in Tumor

- * only n=2 survived to week 2
- ** no animals survived

- *

- **

## 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