1 Molecular Imaging of Sarcoma and Normal Tissues: A Mouse-Human Phase I Co-Clinical Trial 1 Melodi Javid Whitley CTOS 2014 Berlin, Germany.

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Presentation transcript:

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

All Rights Reserved, Duke Medicine 2011 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

All Rights Reserved, Duke Medicine 2011 Targeting Cathepsin Proteases in Cancer 4 SarcomasMuscle (Mito JK, et al. Cancer 2012)(Cuneo KC, Mito JK, Whitley MJ et al. Cancer 2012)

All Rights Reserved, Duke Medicine 2011 LUM015: A Cathepsin-Activatable Fluorescent Probe 5 CTS

All Rights Reserved, Duke Medicine 2011 LUM015: A Cathepsin-Activatable Fluorescent Probe 6

All Rights Reserved, Duke Medicine 2011 Tumor Specificity 77 (Mito JK, et al. Cancer 2012) Tumor Muscle

All Rights Reserved, Duke Medicine 2011 A Phase I Study of the Safety and Activation of a Cathepsin- Activatable Fluorescent Cancer-Specific Probe LUM Primary Objective To 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 mg/kg No Adverse Pharmacological Activity (APA)

All Rights Reserved, Duke Medicine 2011 A Phase I Study of the Safety and Activation of a Cathepsin- Activatable Fluorescent Cancer-Specific Probe LUM Primary Objective To determine a safe and recommended phase II dose of LUM015 that labels tumors in human patients Secondary Objectives 1)To image tumor and normal tissue 2)To obtain PK/PD information 3)To analyze cathepsin protease expression in tumors

All Rights Reserved, Duke Medicine 2011 Study Design 10 Safety Evaluations Safety Evaluations + PK Studies

All Rights Reserved, Duke Medicine 2011 Tissue Fluorescence 30 Hours After IV LUM Cohort 2a 1.0 mg/kg LUM hours Cohort mg/kg LUM hours Human

All Rights Reserved, Duke Medicine 2011 Human and Mouse LUM015 Plasma Pharmacokinetic Profiles are Nearly Identical 12

All Rights Reserved, Duke Medicine 2011 Tissue Fluorescence 6 vs 30 Hours After IV LUM Cohort 2a 1.0 mg/kg LUM hours Cohort 1a 0.5 mg/kg LUM hours Cohort mg/kg LUM015 6 hours Cohort 2b 1.0 mg/kg LUM015 6 hours Cohort 1b 0.5 mg/kg LUM015 6 hours Human

All Rights Reserved, Duke Medicine 2011 Tumor Fluorescence is Significantly Higher than Normal Tissue Fluorescence 14

All Rights Reserved, Duke Medicine 2011 Tumor: Normal Fluorescence Ratios are Independent of Dose 15

All Rights Reserved, Duke Medicine 2011 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

All Rights Reserved, Duke Medicine 2011 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 17

18

All Rights Reserved, Duke Medicine 2011 Phase I Case Study 19

All Rights Reserved, Duke Medicine 2011 Patient #2: 38 year old female with core biopsy proven pleomorphic undifferentiated high-grade sarcoma s/p neoadjuvant radiation therapy 20

All Rights Reserved, Duke Medicine 2011 Patient #2 21 Potentially viable tumor Grossly necrotic tumor Muscle Skin

All Rights Reserved, Duke Medicine 2011 Patient #2 TEXT 22 Viable Tumor Necrosis Myxoid Tumor

All Rights Reserved, Duke Medicine 2011 Patient #2 23 Skin Muscle

All Rights Reserved, Duke Medicine 2011 Patient #2 24

All Rights Reserved, Duke Medicine 2011 TITLE TEXT 25

All Rights Reserved, Duke Medicine 2011 PHASE I TABLE TEXT 26

All Rights Reserved, Duke Medicine 2011 Can Residual Fluorescence Predict Local Recurrence? 27 CRE Lum015 TumorTumor Bed (+) Residual Fluorescence Tumor Bed (-) Residual -Fluorescence Follow for Local Recurrence Braf Ca ; p53 fl/fl

All Rights Reserved, Duke Medicine Increase Dose: Dose Level 2 Dose Level 3 is established as a safe dose for future phase II studies Dose Level 1 Decrease Dose: Dose Level -1 Trial stops w/o safe dose for future phase II studies Dose Expansion: 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: Dose Level 3 Dose Expansion: Dose Level 3 Decrease Dose: Dose Level 1 Decrease Dose: 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

All Rights Reserved, Duke Medicine 2011 Dose Escalation 29 Dose LevelLUM015 (mg/kg) /3 2/3 No Adverse Pharmacological Events