Transcript Slide 1

Preliminary Analysis Of Phase I, FirstIn-Human, Cathepsin Activated Tumor
Imaging Probe
Brian Brigman
November 1, 2013
Disclosures
• Patent for imaging device held by MIT and Duke
• Lumicell Diagnostics
– Scientific Advisory Board (DK)
– Own Stock (DK, JF)
– Employee (JF)
• Preclinical research supported by:
– NSF (DK, WE)
– NCI SBIR (Subcontract - BB)
– CTSA (BB)
• Phase I study supported by
– ASCO Advanced Clinical Research Award (DK)
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What is the problem?
• Local recurrence of soft tissue sarcoma after wide
resection
• Presumably due to residual tumor left in tumor bed
• We use margin assessment as a surrogate for our
real question – is there tumor left in the tumor bed?
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What is the problem?
• Multiple studies of surgery alone for high grade STS
show recurrence rates of 30-40%
– Prospective trial of surgery alone for STS
• Pisters et al. JCO 1996
• + Margin: Recurrence 5/14 (36%)
• - Margin: Recurrence in 20/72 (28%)
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Isn’t that what Radiation is for?
• Radiation does decrease local recurrence
significantly
• Morbidity of radiation therapy
– O’Sullivan et al. Lancet 2002
– Davis et al. Radiother Onc 2005
Fibrosis/Edema
Osteonecrosis/Fracture
Radiation associated malignancy
Wound healing complications
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Who needs radiation?
• “Wide” Resection alone
– ~66% local control in high grade sarcoma
• Radiation Therapy with Surgery
– ~10% recurrence with surgery and radiation
Only 25% of patients benefit from Radiation
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Optical Imaging of Microscopic Residual Cancer
• A system for intra-operative margin assessment that can detect
microscopic residual disease within the tumor bed
• If successful:
– Intensify therapy for patients with residual cancer
– Minimize RT for patients with no residual cancer
– Reduce rates of repeat resection
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Multiple Cathepsin Proteases are Overexpressed in
Soft Tissue Sarcomas
Sarcomas
(Mito JK, et al. Cancer 2012)
Muscle
(Cuneo KC, et al. IJROBP 2013)
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Cathepsin Activated Near Infra-red
Fluorescent Probe Lum015
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LUM015 NIR Fluorescent Probe
QUENCHER
Cathepsin Cleavage Site
PEG
MW~22,000 g/mol
CY5 FLUOROPHORE
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Intraoperative Imaging System
(Mito JK, et al. Cancer 2012)
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Tumor and Tumor Bed Imaging in Genetically
Engineered Mouse model of Soft Tissue Sarcoma
(Mito JK, et al. Cancer 2012)
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Genetically Engineered Mouse Model of Soft tissue Sarcoma
treated with surgery alone with or without Fluorescent imaging
Standard Margin Assessment
Intra-operative Fluor Imaging
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De novo Canine tumor imaging trial data
(mean f/u >1 year)
(Eward WE et al. CORR) 2012
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A Phase I Study of the Safety and Activation of a CathepsinActivatable Fluorescent Probe LUM015
Primary Objective
To determine a safe and recommended phase II intravenous dose of LUM015
that labels tumors in human patients with sarcoma.
Secondary Objectives
1) To obtain imaging data of the tumor and any adjacent normal appearing
tissue in pathology suite – No imaging of patient tumor beds
2) To obtain PK/PD data regarding LUM015 when administered IV in patients
3) To analyze cathepsin protease expression in tumors.
Modified 3+3 design with up to 3 dosing levels
Starting probe dose (0.5 mg/kg) and time to tumor
visualization (>24 h) based on allometric scaling from mouse
data and mathematical simulations of Lum015 in humans
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Mathematical Simulations of LUM015
Tumor Signal in Mice
700
80
600
LUM015 Data
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LUM015 Sim
500
LUM015 EpiFluor
Signal (nM)
Signal (nM)
Tumor Signal in Humans
90
400
300
60
50
40
30
200
20
100
10
0
0
-2
8
18
Time (hrs)
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38
48
0
TBR in Mice
25
8
16
24
Time (hrs)
32
40
48
TBR in Humans
10
9
20
Tumor to Backgrounc Ratio
Tumor to Backgrounc Ratio
LUM015 Sim
LUM015 Sim
LUM015 Data
15
10
5
8
7
6
5
4
LUM015 Sim
3
2
1
0
0
8
16
24
Time (hrs)
32
40
48
Revision 15: 4/2/2012
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0
0
8
16
24(hrs)
Time
32
40
48
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1.0 mg/kg is
established as a
safe dose for future
phase II studies
Trial stops w/o safe
dose for future phase II
studies
Decrease Dose:
3 @ 0.25 mg/kg
3 @ 0.5 mg/kg
Decrease Dose:
3@ 1.0 mg/kg
Increase Dose:
3 @ 1.0 mg/kg
Trial stops w/o safe
dose for future phase
II studies
Dose Expansion:
3@ 0.25 mg/kg
0.25 mg/kg is established as a safe
dose for future phase II studies
START HERE
≥1 subjects with adverse pharmacologic activity
No subjects with adverse pharmacological
activity
Decrease Dose:
3@ 1.0 mg/kg
1.0 mg/kg is
established as a
safe dose for future
phase II studies
Increase Dose:
3 @ 1.5 mg/kg
Dose Expansion:
3 @ 1.5 mg/kg
1.5 mg/kg is established as a safe
dose for future phase II studies
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Dose Escalation
Dose Level
LUM015 (mg/kg)
-1
0.25
1
0.50
2
1.0
3
1.5
3/3
3/3
No Adverse Pharmacological
Events
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Phase I Case Study
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38 year old female with biopsy proven UPS s/p preoperative radiation therapy
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Case Study: Gross
Skin
Muscle
Potentially
viable
tumor
Grossly
necrotic
tumor
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Case Study: Fluorescent Imaging
TEXT
Viable
Tumor
Necrosis
Myxoid Tumor
Muscle
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Case Study: Relative Fluorescent Signal
6E+10
Mean Fluorescence Intensity (counts/s/cm^2)
5E+10
4E+10
3E+10
2E+10
1E+10
0
Muscle
Tumor
Necrosis
Tissue Type
Myxoid Tumor
Skin
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Phase I Summary to Date
Patient #
Tumor Type
Tumor:Normal
Signal Ratio
1
LPS
2.65
2
UPS
7.05
3
UPS
2.01
4
MPNST
1.98
5
MFS
1.11
6
UPS
1.91
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Pharmacokinetics of Human vs. Mice – serum clearance
120%
Normalized concentration [C(t)/Cmax]
Patient 1 (0.5 mg/kg)
100%
Patient 2 (0.5 mg/kg)
80%
Patient 3 (0.5 mg/kg)
60%
Patient 4 (1.0 mg/kg)
40%
Patient 5 (1.0 mg/kg)
Mice (3.5 mg/kg)
20%
0%
0
10
20
30
40
Hours post administration of LUM015
50
60
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Mouse vs. Human Trials
Dose (mg/kg)
Imaging Time (hours)
Absolute Fluorescence
(counts/s/cm2)
Tumor:Normal Ratio
Mouse
Human
3.5
0.5-1.5
6
30
1012
1010
5-10
1.1-7
Question: What fluorescence values will we see
in mice if we use the human clinical trial dose
and imaging time parameters?
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Back to the Mouse: Comparison of 6 h vs. 30 h Imaging
6E+11
5E+11
Tumor
4E+11
Muscle
3E+11
Fat
2E+11
1E+11
0
1.5 mg/kg 6 hr
1.5 mg/kg 30 hr
3.5 mg/kg 6 hr
3.5 mg/kg 30 hr
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Summary and Plan
We have administered a novel, cathepsin activated fluorescent
imagine probe to 6 patients with sarcoma
No adverse pharmacologic events
Able to image tumors, but with decreased overall signal intensity and
tumor:normal ratio than in mice
Probe serum half-life in humans same as in mice
Revising the Protocol
Change imaging time from minimum 24 h to 6 h
-Approved by IRB
Patients 7 and 8 scheduled in next 30 days
Additional research site under consideration
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Acknowledgements
•
•
•
Kirsch Lab
• David Kirsch
• Melodi Javid
• Jeff Mito
• Kyle Cuneo
• Nerissa Williams
MIT
• Moungi Bawendi
• Linda Griffith
Lumicell Diagnostics
• Jorge Ferrer
• David Strasfeld
• David Lee
•Clinical research team
•
Brian Brigman
•
Will Eward
•
Diana Cardona
•
Dan Blazer
•
Paul Mosca
•
Joan Cahill
•
Erin O’Reilly
•DCI Clinical Pharmacology Laboratory
•
Ivan Spasojevic
•Duke BME
•
Jenna Mueller
•Statistical Support
•
Bercedis Peterson
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