Imaging to Guide Early Drug Trials

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Imaging to Guide Early Drug Trials

• David A. Mankoff, MD, PhD
• Seattle Cancer Care Alliance
• University of Washington
• Seattle, WA

work supported by NIH Grants CA42045, CA72064,
MH63641, CA90771, S10 RR17229
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Cautions

• Most of the imaging methods presented are
  considered investigational
• Discussion of results and possible applications
  is not a claim of clinical efficacy

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Imaging and Early Drug Trials

• Choosing the right patients
• Is the therapeutic target present?
• Choosing the right drug
• Does the drug reach the target?
• Getting the right result
• Is there a pharmacodynamic response?

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Early Drug Trials Why Imaging?

• Imaging samples the entire cancer
• Imaging is quantitative
• Imaging measures tumor heterogeneity
• Spatial
• Temporal (especially with Rx)
• Serial assay is feasible
• Complementary to in vitro assay

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Imaging and Early Drug Trials

• Choosing the right patients
• Is the therapeutic target present?
• Choosing the right drug
• Does the drug reach the target?
• Getting the right result
• Is there a pharmacodynamic response?

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F-18-Fluoroestradiol (FES) PET Estrogen
Receptor (ER) Imaging
FES
Estradiol
RBA (FES vs Estradiol)
ER 0.9
SHBG 0.8
(Kieswetter, J Nucl Med, 1984)
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FES Uptake Predicts Breast Cancer Response to
Hormonal Therapy
Post-Rx
Pre-Rx
Example 1

• Recurrent sternal lesion
• ER primary
• Recurrent Dz strongly FES

Excellent response after 6 wks Letrozole
FES
FDG
FDG
Example 2

• Newly Dxd met breast CA
• ER primary
• FES-negative bone mets

No response to several different hormonal Rxs
(Linden, J Clin Onc, 2006)
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FES Uptake Predicts Response of Advanced Breast
Cancer to Hormonal Therapy
LABC or Metastatic Br CA Primary Tamoxifen Rx
Recurrent or Metastatic Br CA Aromatase Inhibitor
Rx
FES SUV
Non-Responders
Responders
(Mortimer, J Clin Onc, 2001)
(Linden, J Clin Onc, 2006)
(P lt .01 for both)
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Imaging and Early Drug Trials

• Choosing the right patients
• Is the therapeutic target present?
• Choosing the right drug
• Does the drug reach the target?
• Getting the right result
• Is there a pharmacodynamic response?

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Resistance Due to Altered Drug Transport11C-Vera
pamil PET to Measure P-gp Drug Transport
Hypotheses
-P-gp limits drug transport
into the brain -Inhibiting P-gp will
increase brain transport
P-gp susceptible drug 11C-Verapamil
P-gp
P-gp susceptible drug 11C-Verapamil
x
inhibitor
(Hendrickse, Br j Pharmacol, 1998)
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Imaging P-gp Activity in Vivo in
Humans 11C-Verapamil images pre- and
post-cyclosporine (CSA)
88 /- 20 increase in verapamil AUC (N 12, P lt
.001)
(Sasongko, Clin Pharm Ther, 2005)
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Imaging and Early Drug Trials

• Choosing the right patients
• Is the therapeutic target present?
• Choosing the right drug
• Does the drug reach the target?
• Getting the right result
• Is there a pharmacodynamic response?

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FES PET Imaging Measures in Vivo Estrogen Binding
Antagonism by Tamoxifen
(thick sagittal planes)
Baseline
FDG
Glucose Metabolism
Estradiol Binding
FES
(Linden, SABCS, 2005)
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FES PET Measures Drug PharmacodynamicsStage IV
Breast Cancer Treated Using FulvestrantProgressiv
e Disease Despite Dose Increase
Pre-Rx
5 Months
1 month
Liver
SUV 7.4
SUV 3.2
SUV 3.1
Uterus
Post-Fulvestrant 250 mg qm
Post-Fulvestrant 500 mg qm
Pre-Fulvestrant
(Stable Dz, No Response)
(Dz Progression)
(FES PET, Coronal Slices)
(Linden, SABCS, 2005)
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Early Response of GIST to Imatinib Measured by
FDG PET
Annick Van Den Abbeele, Dana Farber, Boston
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Small Cell Lung Cancer PET Imaging Pre-and Post
One Cycle of Rx
7 days
(Shields, J Nucl Med, 1998)
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FLT Brain Tumor Imaging to Measure
ResponseKinetic Analysis (Muzi, J Nucl Med,
2006)
18F-Fluoro-L-thymidine (FLT)
Kinetic model
(Visvikis, Eur J Nucl Med Mol Imag, 2003 Muzi, J
Nucl Med, 2005)
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Special Considerations for Imaging and Early Drug
Trials
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Imaging Requirement for Biomarker
ImagingSimultaneously Localize and Characterize
Disease Sites
Functional/Anatomic Imaging
Functional Imaging Combinations
FES
FDG
PET/CT Fusion
FDG PET
Glucose Metabolism
Estradiol Binding
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Imaging Requirement for Biomarker Imaging Image
Acquisition and Quantitative Analysis

• Dynamic protocols
• Allows kinetic modeling
• Full range of analysis options
• But not for everyone

• Static protocols
• Clinically feasible, robust
• But only simple quantification possible

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Imaging and Early Drug Trials Summary

• Imaging complementary to tissue and blood assays
• Measure entire disease burden
• Quantitative
• Serial measures possible
• Guide early drug trials
• Measure target expression
• Measure drug delivery
• Measure early drug action

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Imaging and Early Drug Trials Collaborators

• UW Cancer PET Imaging
• Kenneth Krohn
• Janet Eary
• Jeanne Link
• Mark Muzi
• Joseph Rajendran
• Alex Spence
• Jash Unadkat

• SCCA/Breast Cancer
• Hannah Linden
• Robert Doot
• Lisa Dunnwald
• Brenda Kurland
• Lanell Peterson
• Erin Schubert
• Lavanya Sundarajan