1 molecular imaging of sarcoma and normal tissues: a mouse-human phase i co-clinical trial 1 melodi...
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Molecular Imaging of Sarcoma and Normal Tissues: A Mouse-Human Phase I Co-Clinical Trial
1
Melodi Javid WhitleyCTOS 2014
Berlin, Germany
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Disclosure
• Patent for imaging device• Lumicell Inc.
– Scientific Advisory Board– Stock– Small Business Innovation Research (SBIR) Grant
from the NCI, NSF
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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
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Targeting Cathepsin Proteases in Cancer
4
Sarcomas Muscle
(Mito JK, et al. Cancer 2012) (Cuneo KC, Mito JK, Whitley MJ et al. Cancer 2012)
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LUM015: A Cathepsin-Activatable Fluorescent Probe
5
Quencher
Fluorophore
PEG
CTS
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LUM015: A Cathepsin-Activatable Fluorescent Probe
6
Quencher
Fluorophore
PEG
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Tumor Specificity
77
(Mito JK, et al. Cancer 2012)Tumor Muscle
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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)
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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
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Study Design
10
Safety Evaluations
Safety Evaluations
+ PK Studies
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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
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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)
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Tissue Fluorescence 6 vs 30 Hours After IV LUM015
13
Cohort 2a3 @ 1.0 mg/kg LUM015
Image @ 30 hours
Cohort 1a3 @ 0.5 mg/kg LUM015
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
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Tumor Fluorescence is Significantly Higher than Normal Tissue Fluorescence
14
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Tumor: Normal Fluorescence Ratios are Independent of Dose
15
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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
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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
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Patient #2: 38 year old female with core biopsy proven pleomorphic undifferentiated high-grade sarcoma s/p neoadjuvant radiation therapy
2020
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Patient #2
2121
Potentially viable tumor
Grossly necrotic tumor
MuscleSkin
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Patient #2
TEXT
2222
Viable Tumor Necrosis Myxoid Tumor
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Patient #2
2323
SkinMuscle
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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)
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TITLE
TEXT
2525
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PHASE I TABLE
TEXT
2626
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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
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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
Dose Level 2 is established as a safe dose for future phase II studies
≥1 subjects with adverse pharmacologic activity
No subjects with adverse pharmacological activity
START HERE
Dose Level 1 is established as a safe dose for future phase II studies
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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