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1 Preliminary Analysis Of Phase I, First- In-Human, Cathepsin Activated Tumor Imaging Probe Brian Brigman November 1, 2013 1.

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Presentation on theme: "1 Preliminary Analysis Of Phase I, First- In-Human, Cathepsin Activated Tumor Imaging Probe Brian Brigman November 1, 2013 1."— Presentation transcript:

1 1 Preliminary Analysis Of Phase I, First- In-Human, Cathepsin Activated Tumor Imaging Probe Brian Brigman November 1,

2 All Rights Reserved, Duke Medicine 2011 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)

3 All Rights Reserved, Duke Medicine 2011 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? 3

4 All Rights Reserved, Duke Medicine 2011 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 Margin: Recurrence 5/14 (36%) - Margin: Recurrence in 20/72 (28%) 4

5 All Rights Reserved, Duke Medicine 2011 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 Fibrosis/Edema Osteonecrosis/Fracture Radiation associated malignancy Wound healing complications

6 All Rights Reserved, Duke Medicine 2011 Who needs radiation? “Wide” Resection alone –~66% local control in high grade sarcoma Radiation Therapy with Surgery –~10% recurrence with surgery and radiation 6 Only 25% of patients benefit from Radiation

7 All Rights Reserved, Duke Medicine 2011 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

8 All Rights Reserved, Duke Medicine Multiple Cathepsin Proteases are Overexpressed in Soft Tissue Sarcomas 8 SarcomasMuscle (Mito JK, et al. Cancer 2012)(Cuneo KC, et al. IJROBP 2013)

9 All Rights Reserved, Duke Medicine 2011 Cathepsin Activated Near Infra-red Fluorescent Probe Lum015 9

10 All Rights Reserved, Duke Medicine LUM015 NIR Fluorescent Probe 10 QUENCHER CY5 FLUOROPHORE PEG MW~22,000 g/mol Cathepsin Cleavage Site

11 All Rights Reserved, Duke Medicine Intraoperative Imaging System 11 (Mito JK, et al. Cancer 2012)

12 All Rights Reserved, Duke Medicine 2011 Tumor and Tumor Bed Imaging in Genetically Engineered Mouse model of Soft Tissue Sarcoma 12 (Mito JK, et al. Cancer 2012)

13 All Rights Reserved, Duke Medicine Genetically Engineered Mouse Model of Soft tissue Sarcoma treated with surgery alone with or without Fluorescent imaging 13 Standard Margin Assessment Intra-operative Fluor Imaging

14 All Rights Reserved, Duke Medicine 2011 De novo Canine tumor imaging trial data (mean f/u >1 year) 14 (Eward WE et al. CORR) 2012

15 All Rights Reserved, Duke Medicine A Phase I Study of the Safety and Activation of a Cathepsin- Activatable Fluorescent Probe LUM 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

16 All Rights Reserved, Duke Medicine 2011 Mathematical Simulations of LUM015 Revision 15: 4/2/201216

17 All Rights Reserved, Duke Medicine Increase Dose: 1.0 mg/kg 1.5 mg/kg is established as a safe dose for future phase II studies 0.5 mg/kg Decrease Dose: 0.25 mg/kg Trial stops w/o safe dose for future phase II studies Dose Expansion: 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: 1.5 mg/kg Dose Expansion: 1.5 mg/kg Decrease Dose: 1.0 mg/kg Decrease Dose: 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

18 All Rights Reserved, Duke Medicine Dose Escalation 18 Dose LevelLUM015 (mg/kg) /3 No Adverse Pharmacological Events

19 All Rights Reserved, Duke Medicine Phase I Case Study

20 All Rights Reserved, Duke Medicine year old female with biopsy proven UPS s/p pre- operative radiation therapy 20

21 All Rights Reserved, Duke Medicine Case Study: Gross 21 Potentially viable tumor Grossly necrotic tumor Muscle Skin

22 All Rights Reserved, Duke Medicine Case Study: Fluorescent Imaging TEXT 22 Viable Tumor Necrosis Myxoid TumorMuscle

23 All Rights Reserved, Duke Medicine Case Study: Relative Fluorescent Signal

24 All Rights Reserved, Duke Medicine Phase I Summary to Date 24 Patient #Tumor TypeTumor:Normal Signal Ratio 1LPS2.65 2UPS7.05 3UPS2.01 4MPNST1.98 5MFS1.11 6UPS1.91

25 All Rights Reserved, Duke Medicine 2011 Pharmacokinetics of Human vs. Mice – serum clearance 25

26 All Rights Reserved, Duke Medicine 2011 Mouse vs. Human Trials MouseHuman Dose (mg/kg) Imaging Time (hours) 630 Absolute Fluorescence (counts/s/cm 2 ) Tumor:Normal Ratio Question: What fluorescence values will we see in mice if we use the human clinical trial dose and imaging time parameters?

27 All Rights Reserved, Duke Medicine Back to the Mouse: Comparison of 6 h vs. 30 h Imaging 27

28 All Rights Reserved, Duke Medicine 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 28

29 All Rights Reserved, Duke Medicine 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 29 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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