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

Cautions

• Most of the imaging methods presented are considered investigational

• Discussion of results and possible applications is not a claim of clinical efficacy

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?

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

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?

[F-18]-Fluoroestradiol (FES): PET Estrogen Receptor (ER) Imaging

FES Estradiol HO

OH HO

OH

F*

(Kieswetter, J Nucl Med, 1984)

RBA (FES vs Estradiol)

ER 0.9

SHBG 0.8

FES Uptake Predicts Breast Cancer Response to Hormonal Therapy

Pre-Rx Post-Rx

FES FDG FDG• Newly Dx’d met breast CA

• ER+ primary

• FES-negative bone mets

No response to several different

hormonal Rx’s

(Linden, J Clin Onc, 2006)

• Recurrent sternal lesion

• ER+ primary

• Recurrent Dz strongly FES+

Excellent response after 6 wks Letrozole

Example 1

Example 2

FES Uptake Predicts Response of Advanced Breast Cancer to Hormonal Therapy

(Mortimer, J Clin Onc, 2001)

0

2

4

6

8

10 HER2 NegHER2 Pos

Non-Responders

Responders

LABC or Metastatic Br CA Primary Tamoxifen Rx

Recurrent or Metastatic Br CA Aromatase Inhibitor Rx

(P < .01 for both)

FE

S S

UV

(Linden, J Clin Onc, 2006)

FE

S S

UV

Responders Non-Responders

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?

Resistance Due to Altered Drug Transport:11C-Verapamil PET to Measure P-gp Drug Transport

P-gpP-gp susceptible drug

11C-Verapamil

P-gpP-gp susceptible drug

11C-Verapamil xinhibitor

Hypotheses: -P-gp limits drug transport into the brain -Inhibiting P-gp will increase brain transport

(Hendrickse, Br j Pharmacol, 1998)

Imaging P-gp Activity in Vivo in Humans[11C]-Verapamil images pre- and post-cyclosporine (CSA)

Pre-CsA Post-CsAMRI

(Sasongko, Clin Pharm Ther, 2005)

88% +/- 20% increase in verapamil AUC (N= 12, P < .001)

P-gp P-gpx

Verapamil PET

Infuse CyclosporineVerapamil PET

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?

FES PET Imaging Measures in Vivo Estrogen Binding Antagonism by Tamoxifen

FDG

FES

Baseline2 monthsTamoxifen

(thick sagittal planes)

Glucose Metabolism

Estradiol Binding

(Linden, SABCS, 2005)

FES PET Measures Drug PharmacodynamicsStage IV Breast Cancer Treated Using Fulvestrant

Progressive Disease Despite Dose Increase

SUV= 7.4

Pre-Fulvestrant Post-Fulvestrant250 mg qm

Post-Fulvestrant500 mg qm

5 MonthsPre-Rx 1 month

(Stable Dz, No Response)

(Dz Progression)

Liver

SUV= 3.1

SUV= 3.2

Uterus

(FES PET, Coronal Slices)

(Linden, SABCS, 2005)

Baseline 3 days 23 days 3 months 7 months

Baseline 7 days 2 months 5.5 months24 hours

Early Response of GIST to Imatinib

Measured by FDG PET

Annick Van Den Abbeele, Dana Farber, Boston

FDG(Glucose

Metabolism)

3

424

845

1266

1687

cts/pix

Dr ShieldsMO**FDG -

01/27/9400:00

@ +00:31:0000:30:00IP 12

Lo -108Hi 1743 3

262

522

781

1040

cts/pix

MO**FDG -

02/03/9400:00

@ +00:31:0000:30:00IP 11

Lo -48Hi 1040

Thymidine(proliferation)

3

59

116

172

229

cts/pix

Dr ShieldsMO**Thymi

01/27/9400:00

@ +00:36:0000:25:00IP 11

Lo -21Hi 250

3

31

60

88

117

cts/pix

MO**Thymi

02/03/9400:00

@ +00:21:0000:40:00IP 11

Lo -13Hi 117

Marrow (with mets)

Post-RxPre-Rx

Tumor

Small Cell Lung Cancer: PET Imaging Pre-and Post One Cycle of Rx

7 days(Shields, J Nucl Med, 1998)

FLT Brain Tumor Imaging to Measure Response:Kinetic Analysis (Muzi, J Nucl Med, 2006)

Plasma Tissue

[FLT]pK1FLT

k2FLT

k3FLT

k4FLT

FreeFLT

FLT-MP

FluxFLT =K1FLT k3FLT

k2FLT + k3 FLT

Kinetic model:

(Visvikis, Eur J Nucl Med Mol Imag, 2003;

Muzi, J Nucl Med, 2005)

Post-RT

0.10

0.0

mL

/g/m

in

1 )

Parametric Imaging:Transport

FluxFLT

Summed

MRI

Pre-RT

N

NH

O

O

OHO

*F

N

NH

O

O

H3C

OHO

OH

[F-18]FLT

2-[C-11]Thymidine or [C-11]methyl-Thymidine

*

*

N

NH

O

O

H3C

OHO

OH

F

*

*

[C-11]methyl-FMAU or [F-18]FMAU

N

NH

O

O

F

OHO

HO F

FFUdR

N

NH

O

O

X

OHO

OH

N H

NH

O

O

F

BUdR, IUdR

FU

N

NH

O

O

H 3C

OHO

N 3

AZT

N NH

O

O

H 3C

OHO

OH

2'-Deoxy-pseudo- thymidine

**

18F-Fluoro-L-thymidine (FLT)

Special Considerations for Imaging and Early Drug Trials

Imaging Requirement for Biomarker Imaging:Simultaneously Localize and Characterize Disease Sites

FDG PET

PET/CT Fusion

FESFDG

Glucose Metabolism

Estradiol Binding

Functional/Anatomic Imaging

Functional Imaging Combinations

Imaging Requirement for Biomarker Imaging: Image Acquisition and Quantitative Analysis

Time

Dynamic Imaging

Blood

Tissue

Region-of-Interest Analysis

Time-Activity Curves

Parameter Estimates

Kinetic Modeling

Tumor

Ventricle

Inject Tracer

Static Image

Static Uptake

Measure (SUV)

• Dynamic protocols• Allows kinetic modeling• Full range of analysis

options• But … not for everyone

• Static protocols• Clinically feasible, robust

• But … only simple quantification possible

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

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