1 Molecular Imaging of Sarcoma and Normal Tissues: A Mouse-Human Phase I Co-Clinical Trial 1 Melodi...

Molecular Imaging of Sarcoma and Normal Tissues: A Mouse-Human Phase I Co-Clinical Trial

1

Melodi Javid WhitleyCTOS 2014

Berlin, Germany

All Rights Reserved, Duke Medicine 2011

Disclosure

• Patent for imaging device• Lumicell Inc.

– Scientific Advisory Board– Stock– Small Business Innovation Research (SBIR) Grant

from the NCI, NSF


Proposed Solution

A system for optical intra-operative detection of microscopic residual disease within the tumor bed

Clinical Problem

After limb-sparing surgery alone, 1/3 of STS will recur locally

Method

1. Molecularly label tumor cells with a fluorescent agent

2. Detect residual fluorescence using a handheld imaging device


Targeting Cathepsin Proteases in Cancer

4

Sarcomas Muscle

(Mito JK, et al. Cancer 2012) (Cuneo KC, Mito JK, Whitley MJ et al. Cancer 2012)


LUM015: A Cathepsin-Activatable Fluorescent Probe

5

Quencher

Fluorophore

PEG

CTS


LUM015: A Cathepsin-Activatable Fluorescent Probe

6

Quencher

Fluorophore

PEG


Tumor Specificity

77

(Mito JK, et al. Cancer 2012)Tumor Muscle


A Phase I Study of the Safety and Activation of a Cathepsin-Activatable Fluorescent Cancer-Specific Probe LUM015

88

Primary ObjectiveTo determine a safe and recommended phase II dose of LUM015 that labels tumors in human patients.

• 15 patients enrolled (12 STS, 3 Breast Cancer)• IV LUM015 @ 0.5-1.5 mg/kg• No Adverse Pharmacological Activity (APA)


A Phase I Study of the Safety and Activation of a Cathepsin-Activatable Fluorescent Cancer-Specific Probe LUM015

99

Primary ObjectiveTo determine a safe and recommended phase II dose of LUM015 that labels tumors in human patients

Secondary Objectives1) To image tumor and normal tissue2) To obtain PK/PD information3) To analyze cathepsin protease expression in tumors


Study Design

10

Safety Evaluations

Safety Evaluations

+ PK Studies


Tissue Fluorescence 30 Hours After IV LUM015

11

Cohort 2a3 @ 1.0 mg/kg LUM015

Image @ 30 hours

Cohort 13 @ 0.5 mg/kg LUM015

Image @ 30 hours

Human


Human and Mouse LUM015 Plasma Pharmacokinetic Profiles are Nearly Identical

12

0 5 10 15 20 25 30 35 40 45 500

10

20

30

40

Human Av-erageMouse Av-erage

Hours after IV administration of LUM015

[LU

M0

15

] p

las

ma

(µ

g/m

L)


Tissue Fluorescence 6 vs 30 Hours After IV LUM015

13


Image @ 30 hours


Image @ 30 hours

Cohort 33 @ 1.5 mg/kg LUM015

Image @ 6 hours

Cohort 2b3 @ 1.0 mg/kg LUM015

Image @ 6 hours

Cohort 1b3 @ 0.5 mg/kg LUM015

Image @ 6 hours Human


Tumor Fluorescence is Significantly Higher than Normal Tissue Fluorescence

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Tumor: Normal Fluorescence Ratios are Independent of Dose

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In Summary

• 12 STS, 3 Breast Cancer patients received LUM015 without APA

• Co-clinical studies identified an optimal imaging time of 6 hours after LUM015 injection

• Human tumor-specific fluorescence can be detected with the LUM imaging device

• Tumor-to-normal contrast is dose-independent within the tested dose range

• 0.5 mg/kg LUM015 will be used in further clinical studies

16


Acknowledgements

• Kirsch Lab• David Kirsch, MD, PhD• Jeff Mito, MD, PhD• Kyle Cuneo, MD• Nerissa Williams• Yan Ma

• MIT• Moungi Bawendi, PhD• Linda Griffith, PhD

• Lumicell Inc.• Jorge Ferrer, PhD• David Strasfeld, PhD• David Lee, MS

• Duke MSTP

• Clinical research team• Brian Brigman, MD• Diana Cardona, MD• Joan Cahill, RSCN, RGN, OCN• Erin O’Reilly, PhD• Alex Lazarides, BSc• Dan Blazer, MD• Will Eward, MD• Douglas Tyler, MD• Shelley Hwang, MD, MPH• Rachel A. Greenup, MD, MPH• Paul Mosca, MD, PhD• Nicole Larrier, MD• Richard Riedel, MD

• DCI PK/PD Core Laboratory• Ivan Spasojevic, PhD

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Phase I Case Study

1919


Patient #2: 38 year old female with core biopsy proven pleomorphic undifferentiated high-grade sarcoma s/p neoadjuvant radiation therapy

2020


Patient #2

2121

Potentially viable tumor

Grossly necrotic tumor

MuscleSkin


Patient #2

TEXT

2222

Viable Tumor Necrosis Myxoid Tumor


Patient #2

2323

SkinMuscle


Patient #2

2424

Muscle Tumor Necrosis Myxoid Tumor Skin0

5000000000

10000000000

15000000000

20000000000

25000000000

30000000000

35000000000

40000000000

45000000000

50000000000

Tissue Type

Mea

n F

luo

resc

ence

In

ten

sity

(co

un

ts/s

/cm

^2)


TITLE

TEXT

2525


PHASE I TABLE

TEXT

2626


Can Residual Fluorescence Predict Local Recurrence?

2727

CRE Lum015

Tumor Tumor Bed(+) Residual Fluorescence

Tumor Bed(-) Residual

- Fluorescence

Follow for Local

Recurrence

Braf Ca; p53 fl/fl


2828

Increase Dose:3 @ Dose Level 2

Dose Level 3 is established as a safe dose for future phase II studies

3 @ Dose Level 1

Decrease Dose: 3 @ Dose Level -1

Trial stops w/o safe dose for future phase II

studies

Dose Expansion:3@ Dose Level -1

Trial stops w/o safe dose for future phase

II studies

Dose Level -1 is established as a safe dose for future phase II studies

Increase Dose:3 @ Dose Level 3

Dose Expansion:3 @ Dose Level 3

Decrease Dose:3@ Dose Level 1

Decrease Dose:3@ Dose Level 2


≥1 subjects with adverse pharmacologic activity

No subjects with adverse pharmacological activity

START HERE



Dose Escalation

2929

Dose Level LUM015 (mg/kg)-1 0.25

1 0.50

2 1.0

3 1.5

3/3

2/3

No Adverse Pharmacological Events

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