The NCI Comparative Oncology Program: Clinical Trials in Pet Dogs with Cancer and

Insight for HumansAmy LeBlanc, DVM DACVIM (Oncology)Director, Comparative Oncology Program

NIH/NCI/CCR

14th Joint Meeting of the Board of Scientific Advisors & National Cancer Advisory BoardDecember 3, 2019

The State of Comparative Oncology in North America

Intramural + Extramural NCI –Comparative Oncology Program

Focus on Cancer Drug Development and Translational

Tumor Biology

Comparative Cancer GenomicsBreen Lab – NCSU

TGenBroad Institute

Ostrander Laboratory- NIH/NHGRI

10 Veterinary Colleges with formal membership

and integration to NCI Comprehensive Cancer

Centers

Several with informal or individual interactions

Other cooperative veterinary clinical trial

groups (private practice and academic-led)

NIH or other National Funding/Philanthropy

for Comparative Oncology Research

Increasing support from

Pharma to conduct early phase studies

with novel cancer

therapeutics

Integration of Comparative

Oncology within the Cooperative Group

Structures

(Children’s Oncology Group; NCI-CTEP,

NeXT)

The NCI Comparative Oncology Trials

Consortium

Study of gene-environment and cancer-

associated risk factors

Approximately 78 million dogs in US households- Over 1 million will develop cancer each year

Many cancers are similar to those that occur in people:- Non-Hodgkin’s lymphoma, melanoma, osteosarcoma, soft tissue

sarcoma, muscle-invasive bladder cancer, brain tumorsOwners are increasingly interested in more advanced therapeutics and access to clinical trials for their pets

- Surgery, chemotherapy, radiation therapy, small molecule RTK inhibitors, canine-specific immunotherapies

Spontaneous cancer in dogs: why is it relevant?

Why consider a comparative oncology approach to cancer drug development?

Comparable genetic etiopathogenesis

Greater synteny between dog/human vs. rodent/humanSimilar gene expression alterations in cancer

Comparable signal transduction pathways

Similar druggable targets identifiedSimilar angiogenic and apoptotic pathways

Spontaneous tumors, outbred population

Recapitulates heterogeneity in human tumorsRecurrence, metastasis, resistance to therapy common

Lower relative costGMP quality material not always necessaryPre-IND work highly valuable, particularly for early efficacy signals

Population less heavily pretreated

Higher patient performance status, more accurate AE assessment and less acquired resistance

Body size of companion species

Similar imaging and treatment modalities usedOpportunity for repeated tissue and fluid sampling

One patient, many opportunities

Large-volume biologic samples collected routinely via validated SOPs during comparative oncology clinical trials

Access to canine-specific assays and reagents through the COTC Pharmacodynamic (PD) Core laboratory (Colorado State University)

A Comparative and Integrated Approach to Cancer Drug Development

Paoloni et al, PLOS One, 2009

Green: anti-CD31 Red: anti-phagePhase I study of TNFα adeno-expression cassette with RGD motif targeting αvβ3 integrin receptors on tumor neo-vessels.

Co-localization of RGD-TNF particles was present within tumor vascular endothelium, but not in the tumor cells or blood vessels in normal tissues.

hTNFα levels increased in post-treatment tumor biopsies compared to pre-treatment tumor biopsies.

Informed phase I trials in people.

COTC001: Evaluation of RGD targeted delivery of phage expressing TNF-α in tumor bearing dogs

8

Comparative oncology’s challenge: to move past observations and into action

The comparative approach impacts

human health

Data-driven research and discovery bridges human

and canine oncology

Naturally-occurring cancers in pet dogs are a novel model system for human cancers

1

2

3

• >10,000 middle-old age, large and giant breed dogs in the US/year vs. ~ 1000 pediatric/AYA cases

• Median Survival Time: 10-14 months - majority develop metastatic disease• Shares many clinical and molecular features with pediatric osteosarcoma• Canine model recognized as a key component of discovery process for new

therapies for children

Paoloni M., et al BMC Genomics 2009

Canine Osteosarcoma

Images courtesy of Nicola Mason/UPenn and Kristen Weishaar/CSU

In-depth genomic profiling of human OS allows generation and selection of appropriate PDX models, and rational testing of therapeutic strategy

Companion strategy in dogs can identify translationally-relevant canine OS subtypes for targeted recruitment into clinical trials

A Comparative Approach to Osteosarcoma Drug Development:Translational studies of agents designed to improve outcomes for

dogs and humans

Canine OS Trials

Minimal residual disease studies• Comparative Oncology Trials Consortium • Prioritize agents for human MRD/adjuvant

based studies of metastatic progression

Localized Primary Minimal ResidualDisease

Distant Gross Metastasis

12 Months

Later Phase Trials

Minimal ResidualDisease

Early Phase Trials

MeasurableDisease

Therapeutic approaches include: Novel biologics/vaccines

Rapalog inhibition of mTORMetabolic targeting of

metastatic cells

Enrolled ~450 canine patients on 3 trials over ~3.5 years

DOG2 project goals:

Build out a comprehensive comparative dataset describing the molecular landscape of canine OS Define molecular subtypes New druggable targets

Leverage existing canine OS biospecimen repository Tumor:normal; tumor:met; all treatment-

naïve and outcome-linked; same method of treatment

n = 72 36 each early failures/elite responders RNAseq, WES, low-pass and deep WGS

n = 25 tumor:met pairs

N = 157 dogs; Median Disease-free Interval (Intent to Treat) = 173 days (5.8 months)

Early failures (DFI < 90 days)

Elite responders (DFI > 360 days)

Define genomic landscape of canine OS with COP biospecimen

repository

Integrate with human OS data (NCI TARGET)

Identify new druggable targets

Interrogate with preclinical (mouse)

models

Prioritize therapeutic approaches to study in canine OS clinical trials

COG input

The National Cancer InstituteComparative Oncology Trials Consortium

A Comparative Approach:

Leveraging existing tools and expertise to

identify new approaches for

pediatric OS

NSC 743400

1. Can indenoisoquinolines be safely administered to tumor-bearing dogs?

2. What are the comparable toxicity profiles of the three indenoisoquinolines in tumor-bearing animals?

3. What are comparative PK profiles and correlative PD marker(s) for response?

4. Are indenoisoquinolines active in a naturally occurring canine model of non-Hodgkin’s lymphoma?

• Study sponsored by DCTD

• 400 & 776 most promising based on preclinical data

• Biomarker: Induction of γH2AX foci formation

Prioritization of a lead compound

Indenoisoquinolines: novel inhibitors of topoisomerase 1 (TOP1)

TOP1 empirically validated as target by success of camptothecin derivatives (topotecan and irinotecan)

Topoisomerase (Top1) relaxes DNA by generating single-stranded breaks in the DNA backbone, forming cleavage complexes

Top1 inhibition cytotoxicity:1. Drug binds reversibly to cleavage complex to slow down DNA re-ligation2. Upon collision with replication fork or transcription machinery, complex becomes irreversibly “trapped” and induces DS DNA breaks

Frederick National Laboratory

Why develop the indenoisoquinoline class?

Camptothecins (CPTs)

• Inactivated at physiologic pH by lactone hydrolysis

• Long infusion times needed to overcome reversibility of binding

• Drug efflux ABCG2 substrates

• Murine bone marrow progenitors resistant to CPTs

Indenoisoquinolines

• Stable in blood• Persistent enzyme-DNA

cleavage complexes at novel sites compared to CPTs

• Not/lesser substrates of ABCG2

• Animal models (mouse, dog) more predictive of toxicity profile

Indenoisoquinolines: γH2AX as pharmacodynamic (PD) readout

Predose Day 1, 2Hr Day 1, 6Hr Day 6

Frederick National Laboratory

COTC007b: A multicenter trial, open-label prospective preclinical trial of indenoisoquinolines in pet dogs with lymphoma

BiopsyTumor aspirateBM aspirate

Biopsy (2 & 6hr)Tumor aspirate (2, 4, & 6hr)24hr PK curve

Dosed daily IV for 5 days

Biopsy Tumor aspirateBM aspirate24hr PK curve

Weekly rechecksTumor measurements Tumor measurements

CR/PR Cycle 2

SD/PD

Off study

Dose Cohort (mg/m2/day) NSC 743400 NSC 706744 NSC 725776

1 8 25 3

2 16 50 6

3 24 75 9

4 40 125 15

5 50 150 20

0

25

50

75

100

125

8/14/08 8/14/09 8/14/10

NSC706744 Enrollment

patient entry

010203040506070

7/15/08 7/15/09 7/15/10

NSC743400 Enrollment

Patient Entry

0

5

10

15

20

5/13/08 5/13/09

NSC725776 Enrollment

Patient Entry

Grade 5 eventGrade 4 eventGrade 3 event

9 COTC sites; 84 dogs enrolledDose escalation complete: 69 dogs treatedCohort expansion complete: 13 dogs treated

mg/

m2

Patients

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

0901

0202

0902

0401

0210

0403

0501

0204

0205

0301

0217

1002

0405

0215

0502

0615

0211

0503

0609

0207

0601

0212

1603

1602

0413

0613

0209

1604

0607

0614

1003

0602

0506

0406

0608

0101

0507

0612

0605

0213

0411

0604

0504

0407

0206

0611

1601

1607

0404

0214

1606

0216

1608

1609

0402

0302

0509

**16

0502

0306

1005

1004

1210

01**

0208

Best Overall ResponseR

espo

nse

Asse

ssm

ent (

%)

PR

NSC725776 NSC743400 NSC706744NSC706744 25mg/m2

NSC706744 50mg/m2

NSC743400 8mg/m2

NSC743400 16mg/m2

NSC725776 3mg/m2

NSC725776 6mg/m2

NSC725776 20mg/m2

NSC725776 15mg/m2

NSC725776 17.5mg/m2

NSC725776 9mg/m2

NSC743400 24mg/m2

NSC743400 40mg/m2

NSC743400 50mg/m2

NSC706744 100mg/m2

NSC706744 125mg/m2

NSC706744 75mg/m2

NSC725776 NSC743400 NSC706744

NSC706744 25mg/m2

NSC706744 50mg/m2

NSC743400 8mg/m2

NSC743400 16mg/m2

NSC725776 3mg/m2

NSC725776 6mg/m2

NSC725776 20mg/m2

NSC725776 15mg/m2

NSC725776 17.5mg/m2

NSC725776 9mg/m2 NSC743400 24mg/m2

NSC743400 40mg/m2

NSC743400 50mg/m2

NSC706744 100mg/m2

NSC706744 125mg/m2

NSC706744 75mg/m2

(MTD not reached)

Overall response rate (PR or better)7/23 (30%) 9/23 (39%) 18/23 (78%)

Response at the MTD2/6 (33%) N/A 8/11 (73%)

• Evidence of dose response for LMP 776 & 400

• Early-cohort responders with LMP 744 suggest dose-response may be plateaued

• Non-responders (SD + PD) across dose range with LMP 776 & 400

020406080

100120

0 50 100 150Bes

t Res

pons

e (%

De

crea

se)

Dose (mg/m2)Red=Previously treated, blue=naïve disease

NSC706744

0

20

40

60

80

0 5 10 15 20 25

Best

Res

pons

e (%

Dec

reas

e)

Dose (mg/m2)

NSC725776

0.0

20.0

40.0

60.0

80.0

0 20 40 60 80

Best

Res

pons

e (%

Dec

reas

e)

Dose (mg/m2)

NSC743400

Dose vs. Best Clinical Response

gH2AX at pre-dose, 2 hr, 6 hr, Day 6

12/5/2014 Ji/NCTVL 23

Chart1

Pre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dose

D1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2h

D1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6h

D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6

0401* - Indeno 400, DL 2

0602* - Indeno 400, DL 2

0212* - Indeno 400, DL 3

0403 - Indeno 400, DL 3

0405 - Indeno 400, DL 3

0406 - Indeno 400, DL 3

0407 - Indeno 400, DL 3

0603 - Indeno 400, DL 3

0607 - Indeno 400, DL 4

0608 - Indeno 400, DL 4

1607 - Indeno 400, DL 4

0214 - Indeno 400, DL 5

0411 - Indeno 400, DL 5

0612 - Indeno 400, DL 5

0301 - Indeno 400, DL 6

0302 - Indeno 400, DL 6

0510 - Indeno 400, DL 6

0615 - Indeno 400, DL 6

1002 - Indeno 400, DL 6

1609 - Indeno 400, DL 6

0206* - Indeno 744, DL 2

γH2AX %NAP

LMP400

0

0

0

1.16

1.68

1.15

1.2

0

2.85

2.64

4.14

0

0

1.74

0

0

1.8

1.57

1.26

3.02

0

1.89

2.31

1.81

7.12

2.99

3.02

17.31

1

11.59

1

6.93

7.75

8.12

9.78

0

5.02

19.1

2.47

6.56

10.18

0

2.45

2.28

1.34

3.26

4.01

3.93

13.02

0

8.69

0

0

0

3.97

8.11

5.08

0

7.82

5.81

31.6

15.19

0

1.43

1.3

1

1.7

1

1.09

2.95

0

1.31

0

1.35

0

3.04

0

1

1.54

1.48

1

3.1

0

1

Patients

Dog IDNSCDose CohortNotemg/kgCohort

2024001201C 72577631

9014001204C 72577631

9024001205C 72577631

2104002207C 72577662

4014002209C 72577662

6024002211C 72577693

2124003No Pre-dose213C 725776154

4034003215C 72577617.54.5

4054003216C 72577617.54.5

4064003217C 72577617.54.5

4074003501C 72577631

6034003No Pre-dose502C 72577631

5084004503C 72577631

6074004504C 725776154

6084004507C 725776205

16074004509C 72577617.54.5

2144005609C 725776205

4114005611C 725776205

6124005613C 72577617.54.5

3014006614C 72577617.54.5

30240061602C 72577662

51040061603C 72577693

61540061604C 72577693

100240061606C 725776154

16094006101C 7067441003.5

2037441203C 706744251

6017441206C 706744502

16017441208C 706744502

2067442402C 706744502

2087442404C 706744753

4027442408C 7067441254

4047443412C 7067441003.5

6047443413C 7067441003.5

6057443505C 7067441254

1017443.5506C 7067441254

4127443.5601C 706744251

4137443.5604C 706744753

10017443.5605C 706744753

10037443.5610C 7067441254

16087443.51001C 7067441003.5

40874441003C 7067441003.5

50574441601C 706744251

50674441605C 7067441254

61074441608C 7067441003.5

16057444202C 74340081

2017761210C 743400162

2047761212C 743400243

2057761214C 743400505

5017761301C 743400656

5027761302C 743400656

5037761401C 743400162

2077762403C 743400243

2097762405C 743400243

16027762406C 743400243

2117763407C 743400243

16037763411C 743400505

16047763508C 743400404

2137764510C 743400656

5047764602C 743400162

16067764603C 743400243

2157764.5607C 743400404

2167764.5608C 743400404

2177764.5612C 743400505

5097764.5615C 743400656

6137764.5901C 74340081

6147764.5902C 74340081

50777651002C 743400656

60977651607C 743400404

61177651609C 743400656

Data

COTC007bpending QAmissing#N/A (TQ or QA Fail)ULQNC - not collected

Patient#NSCDose CohortPatientPre-doseD1-2hD1-6hD6

0401*40020401* - Indeno 400, DL 21.892.451.43

0602*40020602* - Indeno 400, DL 22.312.281.30

0212*40030212* - Indeno 400, DL 31.811.341.00

040340030403 - Indeno 400, DL 31.167.123.261.70

040540030405 - Indeno 400, DL 31.682.994.011.00

040640030406 - Indeno 400, DL 31.153.023.931.09

040740030407 - Indeno 400, DL 31.217.3113.022.95

060340030603 - Indeno 400, DL 31.00

060740040607 - Indeno 400, DL 42.8511.598.691.31

060840040608 - Indeno 400, DL 42.641.00

160740041607 - Indeno 400, DL 44.146.931.35

021440050214 - Indeno 400, DL 57.75

041140050411 - Indeno 400, DL 58.123.973.04

061240050612 - Indeno 400, DL 51.749.788.11

030140060301 - Indeno 400, DL 65.081.00

030240060302 - Indeno 400, DL 65.021.54

051040060510 - Indeno 400, DL 61.8019.107.821.48

061540060615 - Indeno 400, DL 61.572.475.811.00

100240061002 - Indeno 400, DL 61.266.5631.603.10

160940061609 - Indeno 400, DL 63.0210.1815.19

0206*74420206* - Indeno 744, DL 21.00

0402*74420402* - Indeno 744, DL 21.003.821.87

040474430404 - Indeno 744, DL 31.084.692.042.88

060474430604 - Indeno 744, DL 31.001.051.68

060574430605 - Indeno 744, DL 31.003.655.321.00

01017443.50101 - Indeno 744, DL 3.51.5010.331.72

04127443.50412 - Indeno 744, DL 3.51.064.822.371.40

04137443.50413 - Indeno 744, DL 3.5

10017443.51001 - Indeno 744, DL 3.51.723.164.531.48

10037443.51003 - Indeno 744, DL 3.51.151.891.001.00

16087443.51608 - Indeno 744, DL 3.51.571.43

040874440408 - Indeno 744, DL 41.834.803.72

050674440506 - Indeno 744, DL 41.711.311.982.28

061074440610 - Indeno 744, DL 41.192.774.421.69

0209*77620209* - Indeno 776, DL 21.001.621.00

021177630211 - Indeno 776, DL 32.141.00

160377631603 - Indeno 776, DL 31.031.221.511.00

160477631604 - Indeno 776, DL 32.662.641.83

021377640213 - Indeno 776, DL 43.583.7613.18

050477640504 - Indeno 776, DL 42.36

160677641606 - Indeno 776, DL 42.385.1216.30

02157764.50215 - Indeno 776, DL 4.51.001.001.961.73

02167764.50216 - Indeno 776, DL 4.58.4127.231.00

02177764.50217 - Indeno 776, DL 4.52.434.871.19

05097764.50509 - Indeno 776, DL 4.51.257.2810.971.00

06137764.50613 - Indeno 776, DL 4.51.001.221.301.00

06147764.50614 - Indeno 776, DL 4.51.361.33

050777650507 - Indeno 776, DL 51.427.127.272.72

060977650609 - Indeno 776, DL 51.002.723.251.00

061177650611 - Indeno 776, DL 54.812.314.82

Data

Pre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dose

D1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2h

D1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6h

D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6

0401* - Indeno 400, DL 2

0602* - Indeno 400, DL 2

0212* - Indeno 400, DL 3

0403 - Indeno 400, DL 3

0405 - Indeno 400, DL 3

0406 - Indeno 400, DL 3

0407 - Indeno 400, DL 3

0603 - Indeno 400, DL 3

0607 - Indeno 400, DL 4

0608 - Indeno 400, DL 4

1607 - Indeno 400, DL 4

0214 - Indeno 400, DL 5

0411 - Indeno 400, DL 5

0612 - Indeno 400, DL 5

0301 - Indeno 400, DL 6

0302 - Indeno 400, DL 6

0510 - Indeno 400, DL 6

0615 - Indeno 400, DL 6

1002 - Indeno 400, DL 6

1609 - Indeno 400, DL 6

0206* - Indeno 744, DL 2

γH2AX %NAP

LMP400

0

0

0

1.16

1.68

1.15

1.2

0

2.85

2.64

4.14

0

0

1.74

0

0

1.8

1.57

1.26

3.02

0

1.89

2.31

1.81

7.12

2.99

3.02

17.31

1

11.59

1

6.93

7.75

8.12

9.78

0

5.02

19.1

2.47

6.56

10.18

0

2.45

2.28

1.34

3.26

4.01

3.93

13.02

0

8.69

0

0

0

3.97

8.11

5.08

0

7.82

5.81

31.6

15.19

0

1.43

1.3

1

1.7

1

1.09

2.95

0

1.31

0

1.35

0

3.04

0

1

1.54

1.48

1

3.1

0

1

Pre vs D12h

Pre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dose

D1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2h

D1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6h

D6D6D6D6D6D6D6D6D6D6D6D6D6D6

0206* - Indeno 744, DL 2

0402* - Indeno 744, DL 2

0404 - Indeno 744, DL 3

0604 - Indeno 744, DL 3

0605 - Indeno 744, DL 3

0101 - Indeno 744, DL 3.5

0412 - Indeno 744, DL 3.5

0413 - Indeno 744, DL 3.5

1001 - Indeno 744, DL 3.5

1003 - Indeno 744, DL 3.5

1608 - Indeno 744, DL 3.5

0408 - Indeno 744, DL 4

0506 - Indeno 744, DL 4

0610 - Indeno 744, DL 4

γH2AX %NAP

LMP744

0

0

1.08

1

1

0

1.06

0

1.72

1.15

1.57

1.83

1.71

1.19

0

1

4.69

1.05

3.65

1.5

4.82

0

3.16

1.89

1.43

4.8

1.31

2.77

0

3.82

2.04

0

5.32

10.33

2.37

0

4.53

1

0

3.72

1.98

4.42

1

1.87

2.88

1.68

1

1.72

1.4

0

1.48

1

0

0

2.28

1.69

Pre vs D1-6h

Pre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dosePre-dose

D1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2hD1-2h

D1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6hD1-6h

D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6D6

0209* - Indeno 776, DL 2

0211 - Indeno 776, DL 3

1603 - Indeno 776, DL 3

1604 - Indeno 776, DL 3

0213 - Indeno 776, DL 4

0504 - Indeno 776, DL 4

1606 - Indeno 776, DL 4

0215 - Indeno 776, DL 4.5

0216 - Indeno 776, DL 4.5

0217 - Indeno 776, DL 4.5

0509 - Indeno 776, DL 4.5

0613 - Indeno 776, DL 4.5

0614 - Indeno 776, DL 4.5

0507 - Indeno 776, DL 5

0609 - Indeno 776, DL 5

0611 - Indeno 776, DL 5

γH2AX %NAP

LMP776

0

2.14

1.03

2.66

3.58

2.36

2.38

1

0

2.43

1.25

1

1.36

1.42

1

4.81

1

0

1.22

2.64

3.76

0

5.12

1

8.41

4.87

7.28

1.22

0

7.12

2.72

2.31

1.62

0

1.51

0

13.18

0

16.3

1.96

27.23

0

10.97

1.3

0

7.27

3.25

4.82

1

1

1

1.83

0

0

0

1.73

1

1.19

1

1

1.33

2.72

1

0

Pre vs D6

Tumor BiopsiesStock plot:HighLowNC - not collected#N/A (TQ, QC)ULQSTADARDIZED ANNOTATION - Assign to Patient#: *No pre-dose sample. +No post-dose sample, ^Pre-dose

1. Can indenoisoquinolines be safely administered to tumor-bearing animals?• Yes

2. What are the comparable toxicity profiles of the three indenoisoquinolines in tumor-bearing animals?• Toxicity profiles are similar across all 3 agents• No unexpected adverse events

3. What are comparative PK profiles and correlative PD marker(s) for response?• 744 exhibits 10x higher tumor drug accumulation than 766 and 400• γH2AX signal does not correlate for biologic response for 744• TOPO-1 inhibition may not be 744’s main mechanism of action

4. Are indenoisoquinolines active in a naturally occurring model of non-Hodgkin’s lymphoma?• 744 overall response rate is 2x that of 776 and 400

Study Summary

25

What lies ahead for comparative oncology’s role in cancer research and drug development?

Emphasis on continuing the scientific dialogue on applicability and validity of the dog model of cancer for strategic advancement of novel agents

Maintain the highest standards for clinical trial design, execution and reporting

Continue developing portfolio of canine-specific reagents and correlative assays to support trial efforts and enhance human translation

26

Acknowledgements

NIH-NCI Center for Cancer Research-Molecular Imaging Program (Dr. Peter Choyke, Elaine Jagoda, Baris Turkbey, Dagane Daar, Tieu Hoa, Alicia Forest, Phil Eclarinal, Karen Wong)-Genetics Branch (Dr. Paul Meltzer)-Pediatric Oncology Branch (Drs. Javed Khan, Kathy Warren, Rosandra Kaplan, Fernanda Arnaldez)-Radiation Oncology and Biology Branches (Drs. Murali Cherukuri, Kazu Yamamoto)-NeuroOncology Branch (Dr. Mark Gilbert, Dr. Mioara Larion, Victor Ruiz)

NIH-NCI Comparative Oncology Program-Christina Mazcko; Dr. Ling Ren; Dr. Shan Huang; Aswini Cherukuri-Dr. Hongsheng Wang-Christine Tran Hoang-Anusha Kambala

NCI Division for Cancer Treatment & Diagnosis (DCTD)NIH Divisions of Veterinary Resources (DVR) and Radiation Safety (DRS)NIH Imaging Probe Development Center (IPDC)

Dr. Chand KhannaCOTC member institutions, investigators, and support staff: past, present and future

Thanks for your attentionQuestions?

www.cancer.gov www.cancer.gov/espanol

��The NCI Comparative Oncology Program: Clinical Trials in Pet Dogs with Cancer and Insight for Humans��Amy LeBlanc, DVM DACVIM (Oncology)�Director, Comparative Oncology Program�NIH/NCI/CCRThe State of Comparative Oncology in North AmericaSlide Number 3Slide Number 4Slide Number 5A Comparative and Integrated Approach to Cancer Drug DevelopmentSlide Number 7Comparative oncology’s challenge: to move past observations and into actionSlide Number 9Slide Number 10A Comparative Approach to Osteosarcoma Drug Development:�Translational studies of agents designed to improve outcomes for dogs and humansSlide Number 12Slide Number 13Slide Number 14Indenoisoquinolines: novel inhibitors of topoisomerase 1 (TOP1)Why develop the indenoisoquinoline class?Indenoisoquinolines: �γH2AX as pharmacodynamic (PD) readoutCOTC007b: A multicenter trial, open-label prospective preclinical trial of indenoisoquinolines in pet dogs with lymphomaSlide Number 19Slide Number 20Slide Number 21Slide Number 22gH2AX at pre-dose, 2 hr, 6 hr, Day 6Slide Number 24�What lies ahead for comparative oncology’s role in cancer research and drug development?AcknowledgementsSlide Number 27Slide Number 28