Transcript ABT-526 and ABT-510, Antiangiogenic Thrombospondin-1

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
Thrombospondin-1
RGD
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NH2 - heparin
I
binding
I
binding
EGF-like
1 1 1
Procoll
I
2
_3
3 3 3 3 3
2 2
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cell
binding
(trimer)
COOH
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Large multi-domain protein with multiple receptors
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Anti-angiogenic domain is 2nd type-1 repeat
•Drs. Noel Bouck, Olga Volpert, Jack Henkin
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Series of related TSP-1 peptides: ABT-526
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A-258526
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ABT-526 Inhibits Mouse Corneal Neovascularization
Vehicle
(b-FGF micropellet)
ABT-526 1 mg/kg/day
ABT-526 10 mg/kg/day
Integration of a Comparative Approach
Non-Human Primate
Beagle Dog
Small Animal
Preclinical
Phase I Human
Phase II Human
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Clinical Trials
Clinical Trials
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Phase III Human
Clinical Trials
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New Cancer Drug
Tumor-Bearing
Dog Studies
Tumor-Bearing
Dog Studies
Activity
Toxicity
Pharmacokinetics
Pharmacodynamics
Dose
Regimen
Schedule
Biomarkers
Responding Histologies
Combination therapies
Translational Opportunity
TO PROVIDE OPPORTUNITIES TO
INCLUDE NATURALLY
OCCURRING CANCER MODELS
IN THE STUDY OF CANCER
BIOLOGY AND THERAPY
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
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
Thrombospondin-1 Peptides in Pet Dogs with Measurable Malignant Cancers
Design:
Open label single agent
Eligibility:
Histologically confirmed
Measurable
No concurrent cancer therapy
Washout of 21 days
Endpoints:
Toxicity
Pharmacokinetics (limited)
Tumor Response
Significant disease stabilization
Objective response
Predictions based on past Experience: Thalidomide
Sedation at higher doses
12 cases treated
No objective responses
Disease stabilization 3 cases
All cases measurable and advanced stage of disease
Khanna et al ASCO 2002
TSP-1 Peptide Assignment, Dose, Schedule
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
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
Toxicity
Relevant population (Geriatric Dogs)
No arthritis
No delayed wound healing
No keratitis
Some dogs continue on therapy over 3 years
Results: Pharmacokinetics / In Vitro Activity
In Vitro Activity
Serum Pharmacokinetics
Detection limit 10 ng/ml
VEGF induced Endothelial
Cell chemotaxis
100nM = 0.1 µg/mL
ABT-526 inhibited canine
EC chemotaxis by greater
than 60% at 100 nM
concentrations.
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
RESULTS: RESPONSES
Significant
Objective
Head
stable disease seen in 23/180 (13%) evaluable cases
responses: 19/180 (11%) evaluable cases
and Neck Carcinoma
Mammary
NH
Carcinoma
lymphoma
Cutaneous
Sarcoma
lymphoma
(Objective responses seen in 9/68 (13%) dogs
Synovial
Sarcoma
Hemangiosarcoma
Soft Tissue Sarcoma
Response: Maxillary squamous cell carcinoma (T3N0M0)
Day 0
Day 90
Day 30
Day 270
Day 60
Metastatic Synovial Sarcoma (Agent: TSP-1)
Day 0
Day 30
Day 60
Predictors of Response??
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Response to therapy could not be predicted based on:
 Initial tumor burden
 Stage of disease
 Primary versus metastatic lesions
 Past treatments
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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
Assessment of Biomarkers of Drug Exposure/Response
Canine Patients > 120 Days
Stable Disease
N=22
Canine Patients > 120 Days
N=22
CEC/μl
or %orPositive
CEC/ul
% Positive
60
Initial
50
30.0
40
25.0
30
20.0
#
Day 30
15.0
20
10.0
10
5.0
0
0.0
*
*
*
CEC/ul CEC/μl CD106
*
Baseline
Day 30
Circulating endothelial cells
(CEC’s) and CEC subsets may
predict exposure and response
to TSP-1
CD133
CD133Annexin V
CEC/μl or % Positive
CEC/ul or % Positive
Canine
PatientsDisease
< 30 Days
Progressive
N=17 < 30 Days
Canine Patients
N=17
60
50
30.0
4025.0
Initial
Day 30
3020.0
Baseline
2015.0
10.0
10 5.0
0 0.0
Final
CEC/ul
CEC/μlCD106
CD133CD133 Annexin V
Thrombospondin-1 Peptides
Ask appropriate questions…Listen to the Answers
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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 dogs
Open Label Single Agent
Any Measurable Malignant Cancer
>500 dogs
Biomarker Validation
-Circulating Endothelial Cells
-Other
Adult Phase I
Trial
Adult Phase II
Trial
Adult Phase II
Trial
Adult Phase III
Trial
Pediatric
Trials
Soft tissue sarcoma (biomarker)
Pet dogs
Pet dogs
Relapsed NH-Lymphoma
Randomized Placebo Blinded
Completed 105 cases
Activity supported + CCNU
Hemangiosarcoma
Single agent adjuvant therapy
Completed 30 case pilot
No activity demonstrated
Combination with Chemotherapy
Biology Trials
Pet dogs
High Grade NH-Lymphoma
Newly diagnosed
TSP-1 + Radiation therapy
-Head and Neck Carcinoma
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, LLC
Jennifer Turner
Kate Cadorette
Tony Rusk
Abbott Laboratories Inc
Jack Henkin
Evelyn McKeegan
Rick Lesniewski