preliminary analysis of phase i, first-in-human, cathepsin activated tumor imaging probe

Preliminary Analysis Of Phase I, First-In-Human, Cathepsin Activated Tumor Imaging Probe

Brian BrigmanNovember 1, 2013

1

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

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?


4

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%)


5

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


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


• 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

Multiple Cathepsin Proteases are Overexpressed in Soft Tissue Sarcomas

8

Sarcomas Muscle

(Mito JK, et al. Cancer 2012) (Cuneo KC, et al. IJROBP 2013)


9

Cathepsin Activated Near Infra-red Fluorescent Probe Lum015


10

LUM015 NIR Fluorescent Probe

10

QUENCHER

CY5 FLUOROPHORE

PEG

MW~22,000 g/mol

Cathepsin Cleavage Site


11

Intraoperative Imaging System

11

(Mito JK, et al. Cancer 2012)


12

Tumor and Tumor Bed Imaging in Genetically Engineered Mouse model of Soft Tissue Sarcoma

(Mito JK, et al. Cancer 2012)


13

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


De novo Canine tumor imaging trial data (mean f/u >1 year)

14

(Eward WE et al. CORR) 2012


15

A Phase I Study of the Safety and Activation of a Cathepsin-Activatable Fluorescent Probe LUM015

15

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


Mathematical Simulations of LUM015

Revision 15: 4/2/2012

0

5

10

15

20

25

0 8 16 24 32 40 48

Tum

or to

Bac

kgro

unc

Ratio

Time (hrs)

TBR in Mice

LUM015 Sim

LUM015 Data

0

100

200

300

400

500

600

700

-2 8 18 28 38 48

Sign

al (n

M)

Time (hrs)

Tumor Signal in Mice

LUM015 DataLUM015 SimLUM015 EpiFluor

0

1

2

3

4

5

6

7

8

9

10

0 8 16 24 32 40 48

Tum

or to

Bac

kgro

unc

Ratio

Time (hrs)

TBR in Humans

LUM015 Sim

0

10

20

30

40

50

60

70

80

90

0 8 16 24 32 40 48

Sign

al (n

M)

Time (hrs)

Tumor Signal in Humans

LUM015 Sim

16


1717

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


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 subjects with adverse pharmacologic activity

No subjects with adverse pharmacological activity

START HERE



18

Dose Escalation

18

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


1919

Phase I Case Study


20

38 year old female with biopsy proven UPS s/p pre-operative radiation therapy

20


21

Case Study: Gross

21

Potentially viable tumor

Grossly necrotic tumor

MuscleSkin


22

Case Study: Fluorescent Imaging

TEXT

22

Viable Tumor Necrosis Myxoid Tumor Muscle


2323

Muscle Tumor Necrosis Myxoid Tumor Skin0

5000000000

10000000000

15000000000

20000000000

25000000000

30000000000

35000000000

40000000000

45000000000

50000000000

Tissue Type

Mea

n Fl

uore

scen

ce In

tens

ity (c

ount

s/s/

cm^2

)

Case Study: Relative Fluorescent Signal


24

Phase I Summary to Date

24

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


25

Pharmacokinetics of Human vs. Mice – serum clearance

0 10 20 30 40 50 600%

20%

40%

60%

80%

100%

120%

Patient 1 (0.5 mg/kg)





Mice (3.5 mg/kg)

Hours post administration of LUM015

Norm

aliz

ed c

once

ntra

tion

[C(t)

/Cm

ax]


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?


27

Back to the Mouse: Comparison of 6 h vs. 30 h Imaging

27

1.5 mg/kg 6 hr 1.5 mg/kg 30 hr 3.5 mg/kg 6 hr 3.5 mg/kg 30 hr0

50000000000

100000000000

150000000000

200000000000

250000000000

300000000000

350000000000

400000000000

450000000000

500000000000

Tumor Muscle

Fat


28

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

28


29

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

preliminary analysis of phase i, first-in-human, cathepsin activated tumor imaging probe

Documents

tumor bed imaging

residual tumor

fluorescent imaging

recurrence rates

handheld imaging device11tumor

operative margin assessment

human patients

microscopic residual