Preliminary Analysis Of Phase I, First-In-Human, Cathepsin Activated Tumor Imaging Probe
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Preliminary Analysis Of Phase I, First-In-Human, Cathepsin Activated Tumor Imaging Probe
Brian BrigmanNovember 1, 2013
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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/EdemaOsteonecrosis/FractureRadiation associated malignancyWound 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
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Only 25% of patients benefit from Radiation
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• 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
Optical Imaging of Microscopic Residual Cancer
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Multiple Cathepsin Proteases are Overexpressed in Soft Tissue Sarcomas
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Sarcomas Muscle
(Mito JK, et al. Cancer 2012) (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
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QUENCHER
CY5 FLUOROPHORE
PEG
MW~22,000 g/mol
Cathepsin Cleavage Site
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Intraoperative Imaging System
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(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
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Standard Margin Assessment Intra-operative Fluor Imaging
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De novo Canine tumor imaging trial data (mean f/u >1 year)
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(Eward WE et al. CORR) 2012
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A Phase I Study of the Safety and Activation of a Cathepsin-Activatable Fluorescent Probe LUM015
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Primary ObjectiveTo determine a safe and recommended phase II intravenous dose of LUM015 that labels tumors in human patients with sarcoma.
Secondary Objectives1) To obtain imaging data of the tumor and any adjacent normal appearing
tissue in pathology suite – No imaging of patient tumor beds2) To obtain PK/PD data regarding LUM015 when administered IV in patients3) 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
Revision 15: 4/2/2012
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Increase Dose:3 @ 1.0 mg/kg
1.5 mg/kg is established as a safe dose for future phase II studies
3 @ 0.5 mg/kg
Decrease Dose: 3 @ 0.25 mg/kg
Trial stops w/o safe dose for future phase II
studies
Dose Expansion:3@ 0.25 mg/kg
Trial stops w/o safe dose for future phase
II studies
0.25 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
Decrease Dose:3@ 1.0 mg/kg
Decrease Dose:3@ 1.0 mg/kg
1.0 mg/kg 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
1.0 mg/kg is established as a safe dose for future phase II studies
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Dose Escalation
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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 pre-operative radiation therapy
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Case Study: Gross
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Potentially viable tumor
Grossly necrotic tumor
MuscleSkin
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Case Study: Fluorescent Imaging
TEXT
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Viable Tumor Necrosis Myxoid Tumor Muscle
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Muscle Tumor Necrosis Myxoid Tumor Skin0
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Tissue Type
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Case Study: Relative Fluorescent Signal
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Phase I Summary to Date
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Patient # Tumor Type Tumor:Normal Signal Ratio
1 LPS 2.652 UPS 7.053 UPS 2.014 MPNST 1.985 MFS 1.116 UPS 1.91
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Pharmacokinetics of Human vs. Mice – serum clearance
0 10 20 30 40 50 600%
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Patient 1 (0.5 mg/kg)
Patient 2 (0.5 mg/kg)
Patient 3 (0.5 mg/kg)
Patient 4 (1.0 mg/kg)
Patient 5 (1.0 mg/kg)
Mice (3.5 mg/kg)
Hours post administration of LUM015
Norm
aliz
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once
ntra
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[C(t)
/Cm
ax]
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Mouse vs. Human Trials
Mouse HumanDose (mg/kg) 3.5 0.5-1.5
Imaging Time (hours) 6 30
Absolute Fluorescence (counts/s/cm2)
1012 1010
Tumor:Normal Ratio 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
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1.5 mg/kg 6 hr 1.5 mg/kg 30 hr 3.5 mg/kg 6 hr 3.5 mg/kg 30 hr0
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Tumor Muscle
Fat
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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 miceProbe serum half-life in humans same as in mice
Revising the ProtocolChange imaging time from minimum 24 h to 6 h
-Approved by IRBPatients 7 and 8 scheduled in next 30 daysAdditional 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
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• 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