ABT-526 and ABT-510, Antiangiogenic Thrombospondin-1 Peptides, Are Active in Dogs With Naturally Occurring Canine Cancers Including Soft

Tissue Sarcomas

Anthony Rusk1, Jack Henkin2, Evelyn McKeegan2, Fortuna Haviv2, Sandra Majest2, and Chand Khanna

Animal Clinical Investigation, LLC1 and Abbott Laboratories2

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• Large multi-domain protein with multiple receptors

• Anti-angiogenic domain is 2nd type-1 repeat•Drs. Noel Bouck, Olga Volpert, Jack Henkin

• Series of related TSP-1 peptides: ABT-526

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ABT-526 Inhibits Mouse Corneal Neovascularization

Vehicle ABT-526 1 mg/kg/day ABT-526 10 mg/kg/day

(b-FGF micropellet)

Integration of a Comparative Approach

ActivityToxicity

PharmacokineticsPharmacodynamics

DoseRegimenScheduleBiomarkers

Responding HistologiesCombination therapies

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Small AnimalPreclinical Phase III Human

Clinical TrialsQuickTime™ and a

TIFF (LZW) decompressorare needed to see this picture.

Tumor-BearingDog Studies

Phase II HumanClinical Trials

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are needed to see this picture.

Phase I HumanClinical Trials

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are needed to see this picture.

Tumor-BearingDog Studies

Non-Human PrimateBeagle Dog

New Cancer Drug

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Companion Animal Cancer Models Large outbred Animals Strong Genetic similarities to Humans

Naturally Occurring cancers Immune competant and syngeneic Relevant Tumor Histology/Genetics

Relevant Response Profiles to Conventional Chemotherapy

Tumor Heterogeneity Metastasis Biology Recurrence/Resistance

Cancer IN Companion Animals 75 Million Companion Animals in the US

6 million pet dogs diagnosed with cancer each year

Pet owners seek advanced care for their pets

Translational Opportunity

TO PROVIDE OPPORTUNITIES TO INCLUDE NATURALLY OCCURRING CANCER MODELS IN THE STUDY OF CANCER BIOLOGY AND THERAPY

Thrombospondin-1 Peptides in Pet Dogs with Measurable Malignant Cancers

Design: Open label single agent

Eligibility: Histologically confirmedMeasurableNo concurrent cancer therapyWashout of 21 days

Endpoints: ToxicityPharmacokinetics (limited)Tumor ResponseSignificant disease stabilizationObjective response

Khanna et al ASCO 2002

Predictions based on past Experience: Thalidomide

Sedation at higher doses

12 cases treatedNo objective responsesDisease stabilization 3 cases

All cases measurable and advanced stage of disease

Dog #1-26: ABT-526 12.5 mg BID, SC

Dog #27-72: ABT-526 0.5 mg/kg BID, SC

Dog# 1-30: ABT-510 12.5-17.5 mg BID, SC

Dog# 31-170: ABT-510 1.0 mg/kg QD or divided BID, SC

TSP-1 Peptide Assignment, Dose, Schedule

Results: Accrual and Toxicity

Animal Clinical Investigation, LLC: Cancer Network

Accrual Total: 242 Cases (2 years)Evaluable: 180 (68 sarcomas) *on therapy > 30 days

No ToxicityRelevant population (Geriatric Dogs)

No arthritisNo delayed wound healingNo keratitisSome dogs continue on therapy over 3 years

VEGF induced Endothelial Cell chemotaxis

ABT-526 inhibited canine EC chemotaxis by greater than 60% at 100 nM concentrations.

Serum Pharmacokinetics

In Vitro Activity

100nM = 0.1 µg/mL

Results: Pharmacokinetics / In Vitro Activity

ABT-526 half-life = 48 min (range 33 to 60 min) ABT-510 half-life = 44 minutes (range 36 to 44 min) Pharmacokinetic profile stable after 1 month

Detection limit 10 ng/ml

RESULTS: RESPONSES

Significant stable disease seen in 23/180 (13%) evaluable cases

Objective responses: 19/180 (11%) evaluable cases

Head and Neck Carcinoma

Mammary Carcinoma

NH lymphoma

Cutaneous lymphoma

Sarcoma (Objective responses seen in 9/68 (13%) dogsSynovial Sarcoma HemangiosarcomaSoft Tissue Sarcoma

Day 30Day 30 Day 60Day 60

Day 90Day 90

Response: Maxillary squamous cell carcinoma (T3N0M0)

Day 270Day 270

Day 0Day 0

Metastatic Synovial Sarcoma (Agent: TSP-1)

Day 0 Day 30

Day 60

Predictors of Response??

Response to therapy could not be predicted based on: Initial tumor burden Stage of disease Primary versus metastatic lesions Past treatments

Notable responses: Slow Progression: Progression rate that would allow > 30 days of treatment Soft tissue sarcoma (No responses in 10 dogs with osteosarcoma) Lymphoma Radiation “field’ failures

Canine Patients < 30 DaysN=17

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Initial

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Canine Patients > 120 Day sN=22

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Assessment of Biomarkers of Drug Exposure/Response

Circulating endothelial cells (CEC’s) and CEC subsets may predict exposure and response to TSP-1

Stable Disease Canine Patients > 120 Days

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Final

Thrombospondin-1 Peptides

Ask appropriate questions…Listen to the Answers

• Antiangiogenic TSP-1 peptides are active against bulky and

metastatic disease • Antiangiogenic TSP-1 peptides require extended time on therapy• Antiangiogenic TSP-1 peptides are active against NH-Lymphoma• Most dogs do not respond to therapy

•Determinants of the responsive “patient” not known • Resistance has been seen in 80% of dogs responding to

antiangiogenic therapy• The biology of antiangiogenic responses seen in measurable

tumors may not predict responses against micrometastatic

disease• Combination of TSP-1 peptides with cytotoxic chemotherapy are

complimentary• Circulating endothelial cells may be a valuable predictor of

response

Translational Trials with Antiangiogenic Thrombospondin-1 Peptides

Pet dogsOpen Label Single AgentAny Measurable Malignant Cancer>500 dogs

Adult Phase ITrial

Adult Phase IITrial

PediatricTrials

Relapsed NH-LymphomaRandomized Placebo BlindedCompleted 105 casesActivity supported + CCNU

Pet dogs

HemangiosarcomaSingle agent adjuvant therapyCompleted 30 case pilotNo activity demonstrated

Pet dogs

Biomarker Validation-Circulating Endothelial Cells-Other

Adult Phase IITrial

Adult Phase IIITrial

High Grade NH-LymphomaNewly diagnosed

Soft tissue sarcoma (biomarker)

Biology Trials Pet dogs

TSP-1 + Radiation therapy -Head and Neck Carcinoma

Combination with Chemotherapy

Ongoing Studies

DOGS Prospective study of antiangiogenic peptides of TSP-1 in dogs with measurable soft tissue sarcoma

Endpoints Response (MRI confirmation) Biomarkers of exposure and response (tumor, circulating cells, plasma)Goal: To define determinants of the response “patient”

HUMAN Over 400 cancer patients have been treated in Phase 1 and 2 trials with ABT-510

Signals of efficacy is seen in soft tissue sarcoma

Characteristics of responding patient are unknow

Acknowledgements

Animal Clinical Investigation, LLCJennifer TurnerKate CadoretteTony Rusk

Abbott Laboratories IncJack HenkinEvelyn McKeeganRick Lesniewski