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
COOH
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Thrombospondin-1
• 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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OH3C CH3
H3C
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A-258526
OHH3C CH3
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NH2
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H3C N
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H N
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OH3C CH3
H3C
H3C
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OHH3C CH3
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NH2
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H3C N
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H N
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CH3 O
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OH3C CH3
H3C
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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
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
Small AnimalPreclinical Phase III Human
Clinical TrialsQuickTime™ and a
TIFF (LZW) decompressorare needed to see this picture.
Tumor-BearingDog Studies
Phase II HumanClinical Trials
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
Phase I HumanClinical Trials
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
Tumor-BearingDog Studies
Non-Human PrimateBeagle Dog
New Cancer Drug
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
QuickTime™ and aTIFF (LZW) decompressor
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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
0
10
20
30
40
50
60
CEC/ul CD106 CD133 Annexin V
CEC/ul or % Positive
Initial
Day 30
Canine Patients > 120 Day sN=22
0
10
20
30
40
50
60
CEC/ul CD106 CD133 Annexin V
CEC/ul or % Positive
Initial
Day 30 #
* *
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
N=22
0.0
5.0
10.0
15.0
20.0
25.0
30.0
CEC/_l CD133CEC/_l or % Positive
Baseline
Day 30*
*
Progressive Disease Canine Patients < 30 Days
N=17
0.0
5.0
10.0
15.0
20.0
25.0
30.0
CEC/_l CD133CEC/_l or % Positive
Baseline
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
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