Comparative Oncology - American College of Laboratory Animal Medicine

Report
Amy K. LeBlanc, DVM Diplomate ACVIM (Oncology)

What is comparative oncology?

What resources are available to those employing a
comparative approach for drug development,
biomarker discovery, other endeavors?

How are such studies designed and executed?

How can comparative oncology be an example for
other One Health initiatives?
Coming in July.....
Amy K. LeBlanc DVM, Diplomate ACVIM (Oncology)
Staff Scientist - Comparative Oncology Program
Oral cavity/mucosal
malignant melanoma
Biologically aggressive,
responsive to immune-based
therapies
Canine: BRAF(-); c-kit (-);
N-ras (-)
Image courtesy of Eric Carlson, DMD, MD, FACS
A Comparative and Integrated Approach to
Cancer Drug Development
Nature Reviews Cancer 2008
Comparative Oncology
TO PROVIDE OPPORTUNITIES TO
INCLUDE NATURALLY
OCCURRING CANCER MODELS
IN THE STUDY OF CANCER
BIOLOGY AND THERAPY
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 chemotherapy
No “Gold Standards”
Compressed progression times
Tumor heterogeneity
Recurrence/Resistance
Metastasis biology
Expression Profiles for Canine and Human Osteosarcoma
are Indistinguishable
Normal Tissues
BMC Genomics 2009
Osteosarcoma
Tumor vaccines administered for
canine lymphoma 13,14
Regulatory
Guidance 2009
Comparative Oncology
Program and Comparative
Oncology Trials ConsortiumNCI founded 2003
Canine Genome
Release 2005
Cytokine and chemotherapeutic
inhalation strategies first assessed
in dogs with cancer 76-79
Defined toxicity, activity, PK
and tumoral PD with tyrosine
kinase inhibition 44, 84
Development of bone marrow
transplantation regimes in dogs 11,12
Evaluation of BCG immunotherapy
in canine melanoma 9
Measurable and minimal residual disease
Descriptive design: size focused
1960
1980
1990
Hyperthermia (thermoradiotherapy)
techniques correlated with clinical
efficacy in a canine model 69
2000
2012
DNA vaccine
L-MTP-PE evaluated
approved for use in
in MRD osteosarcoma guided
canine melanoma 37,99COG studies 94
100
Limb sparing optimized
in canine osteosarcoma 71,72
Paoloni and Khanna Nature Reviews Cancer 2008
Integrated
Canine Comparative
Oncology and Genomics
Consortium founded 2006
Projected “Value” of an Integrated Drug Development Path
# of Cancer Drugs Reaching This Phase in Development
100
90
40
30
20
Cost
(Conventional
development
pathway)
# of Drugs
in CONVENTIONAL
DRUG
PATH
10
# of Drugs
in INTEGRATED
DRUG
PATH
Cost
(Integrated
development
pathway)
Preclinical
Phase I
Phase II
Phase III
Approval
Gordon, I et al. PLoS Med 6(10): e1000161. doi:10.1371/journal.pmed.1000161
Projected “Value” of an Integrated Drug Develpment Path
$3b
90
$2b
40
30
$1b
20
Cumulative Cost of Cancer Clinical Trials
# of Cancer Drugs Reaching This Phase in Development
100
Cost
(Conventional
development
pathway)
# of Drugs
in CONVENTIONAL
DRUG
PATH
Cost
(Integrated
development
pathway)
# of Drugs
in INTEGRATED
DRUG
PATH
#Cost
of drugs
(Integrated development
pathway)
of CONVENTIONAL
DRUG PATH
#Cost
of drugs
(CoventionalDRUG
development
of INTEGRATED
PATH pathway)
10
Preclinical
Phase I
Phase II
Phase III
$0b
Approval
Gordon, I et al. PLoS Med 6(10): e1000161. doi:10.1371/journal.pmed.1000161
Comparative Oncology Program – Center for Cancer Research
Comparative Oncology Trials Consortium (COTC)
Reagent/Resources
to conduct studies in
Comparative Oncology
Advocacy for the Appropriate
Integration of Comparative
Oncology Trials
Genomics
Proteomics
Antibodies
Biospecimen Repository
PD Core
Academia
Pharma
NCI
Regulatory Bodies
Canine Comparative Oncology
and Genomics Consortium
Progress by the Comparative Oncology Trials Consortium (COTC)
Initiated of Letters of Intent
Initiated study protocols
Studies completed
Studies published
Studies in progress/in press
19
11
9
3
7
Studies of COTC are published under a “Collection” in PLoS One
Canine Comparative Oncology & Genomics Consortium (CCOGC)
•Pfizer-CCOGC Biospecimen Repository is now open for tissue release
•Currently houses over 2,000 patient samples
• osteosarcoma, lymphoma, melanoma, pulmonary tumors, mast
cell tumor, soft tissue sarcomas and hemangiosarcoma.
• tumor and normal tissues (formalin fixed, snap frozen and OCT), frozen serum,
plasma, urine and whole blood.
Requests for samples/data from fixed sample resource
Pfizer
CCOGC Repository
MTA
Frederick MD
CCOGC
Pathology Review
CCOGC
BioBank
Review
MTA/MOU
Government
Pharma
Biotech
Academia
CCOGC
Sample Collection
Sites
Ownership of
tissue and IP is held
but may be transferred
by CCOGC
Repository business model
Pfizer CCOGC Biospecimen Repository: Total Number of Canine
Patients Collected
600
Tumor and Normal Tissues
Blood
500
520
Frozen
RNAlater
Formalin fixed
400
441
332
300
200
182
100
102
0
92
180
CCOGC Sample Distribution Progress
Nearly 1000 canine patient samples have been distributed world-wide since October 2012.
Lymphoma Frozen Tumor
40
32 63
Lymphoma Frozen Normal
40
270
48
Melanoma Frozen Tumor
50
Osteosarcoma Frozen
Tumor
52
Melanoma Whole Blood
98
227
108
Osteosarcoma Whole
Blood
Osteosarcoma Frozen
Normal Tissues
COTC Pharmacodynamic (PD) Core
Purpose: To develop an efficient virtual lab that can
be responsive to the service and scientific needs of
the COTC
COTC studies biologically intensive
 PD “heavy”
 Previously done internally or contracted out
 Time consuming
 Did not engage the quality or expertise in the veterinary
academic community
COTC PD Core
Provide assay services and scientific expertise
• Scientific guidance and trial review
• Preclinical studies prior to trial initiation
• Trial pharmacodynamic and biologic endpoint support
Multiple members from COTC member institutions
• Prospectively identified via solicitation of
collaboration
• Development of a “catalog” to streamline process
COTC PD Core - areas of interest/expertise

Cell Culture/ Proliferation/
Migration/Invasion
 Cell lines
 Clinical Pathology*
 Pathology
 PARR for clonality
 IHC / ICC
 Pathology

Flow cytometry
 Gene Expression
 Proteomics
 Western Blot
 Pharmacology
 Bone Metabolism
 qRT-PCR
* Majority of clinical pathology performed at GLP veterinary laboratory
Clinical Data Collection
• GCP-compliant
• GLP clinical pathology
COTC Study Development:
1. Discuss questions not answered fully through
conventional models or human trials.
1. Determine if the dog can be used to answer
questions.
• Validation of target/drug biology in the dog
• CCOGC Biospecimen Repository
• PD Core
3. Iterative collaboration to define study
overview/endpoints
Patient
Eligibility
checklist
Biopsy
Tumor/Normal
Biopsy
Tumor/Normal
Patient
Enrollment
checklist
Day 0 Agent
administration
Day 7 Agent
administration
Imaging
Imaging
4. Develop study protocol and data base
Day 14 Agent
administration
5. Selection of COTC sites to manage clinical study
• Based on study completion goals and
protocol intensity
6. Conduct study
•
Amend protocol with data input
7. Complete study
Day 21 Agent
administration
Biopsy
Tumor/Normal
Imaging
Day 28: patient
reassessment
Advanced imaging with pathologic correlates is
possible and increasing among COTC sites
Lawrence J et al: Vet Radiol Ultrasound 50(6): 660, 2009
Comparative Oncology Trials Consortium: Study Examples
Antitumor activity and immunomodulatory effects
“Evaluation of IL-12 and IL-2 Immunocytokines in Tumor
Bearing Dogs”
Modeling Personalized Medicine Delivery in Dogs
Molecuiarly informed therapy
Tumor Specific Targeting – Tolerability
“Evaluation of RGD Targeted Delivery of Phage
Expressing TNF-a to Tumor Bearing Dogs”
Pick the Winner – Biological and Antitumor activity
“Preclinical Comparison of Three TOPO-1 inhibitors in
Dogs with Lymphoma”
Protocol Development
Study Implementation and Contract Process
COTC007: Novel Topoisomerase I Inhibitors:
Integrated Comparative Approach to Identify Lead Agent
Toxicity
Pharmacokinetics
Pharmacodynamics
Therapeutic Index
Low throughput selection of “lead”
Lead Candidate Discrimination/Selection Study: COTC007b
Biological Endpoints
Serum Pharmacokinetics
Tumoral drug Levels
Drug Target/Modulation
Biological Activity
Circulating Tumor Cell
Numbers
Target Modulation
Biological Activity
Normal tissue (Bone marrow)
Target Modulation
Biological Activity
Agent X-1 Enrollment
Agent X-2 Enrollment
50
20
17.5 mg/m2
15
40
30
10
20
Patient Entry
5
Patienty Entry
10
0
6/13/09
5/13/09
4/13/09
3/13/09
2/13/09
1/13/09
12/13/08
11/13/08
10/13/08
9/13/08
8/13/08
7/13/08
6/13/08
5/13/08
0
Grade 5 event. Not attributable to IND. Expanded cohort 1 (3mg/m2).
Grade 4 Neutropenia & Thrombocytopenia (DLT). Cohort 5 expanded.
Grade 5 event. Not attributable to IND. Cohort 3 expanded. Currently in
cohort 5.
Grade 4 Neutropenia & Thrombocytopenia (DLT). Cohort closed.
Agent X-3 Enrollment
Grade 3 Allergic reaction. Cohort 4 (125mg/m2) expanded.
125
100
75
50
25
0
100 mg/m2
Patient Entry
Grade 2 Hypersensitivity reaction.
Grade 4 Neutropenia, Thrombocytopenia, AST, ALT (DLT)
Grade 4 Neutropenia (DLT). Cohort Closed.
Biological Activity: H2AX Cytospin Images
Agent X-3 Cohort 3 (75mg/m2/day)
Tumor Aspirate
Pre-dose
Pre-dose
D1 2h
D1 6h
Bone Marrow
D6
D6
JI/NCTVL
Comparison of Tumoral Drug Exposure:
Tumor Levels
Across Compounds
Compound
and Cohort& Cohorts
X-1
X-2
X-2 (ng/g)
3
6
9
15
1000
100
1000
100
10
0
24
48
72
96
100000
X-3 (ng/g)
X-1 (ng/g)
8
16
24
10000
10000
10
120
0
X-3
24
48
25
50
75
10000
1000
100
0
24
48
72
96
120
72
96
120
Best Overall Response
100
90
Agent
Agent 1X-1
Agent
Agent 2X-2
Agent
Agent3X-3
3mg/m2
8mg/m2
25mg/m2
6mg/m2
16mg/m2
50mg/m2
9mg/m2
24mg/m2
75mg/m2
15mg/m2
40mg/m2
125mg/m2
80
70
50
40
30
20
20mg/m2
0610
**0208
0203
0402
1606
0404
1607
1601
0611
0206
0407
0504
0604
0213
0605
0507
0608
0406
0506
0602
0607
1604
0209
0607
1602
1603
0212
0601
0207
0609
0503
0211
0502
0405
0205
0204
0501
0403
0210
0401
**1605
-10
0902
0
0202
10
0901
Response Assessment (%)
60
Pa ents
-20
-30
-40
-50
-60
-70
-80
-90
-100
PR
PR
COTC007: Novel Topoisomerase I Inhibitors:
Integrated Comparative Approach to Identify Lead Agent
Toxicity
Pharmacokinetics
Pharmacodynamics
Therapeutic Index
COTC007: Novel Topoisomerase I Inhibitors:
Integrated Comparative Approach to Identify Lead Agent
Opportunities to Answer Questions
to Inform Phase III Designs:
Toxicity
No “Gold Standards” soPharmacokinetics
ability to treat in
naïve disease
Pharmacodynamics
Index
Compressed progressionTherapeutic
times
Assess activity of drugs that uniquely target
metastatic progression
Minimal Residual Disease
Combinational Therapies
Novel Biomarkers
Integrated Approach to Osteosarcoma Drug Development
Translational studies of agents that target “vulnerable” metastatic cells.
Localized Primary
Canine OS Trials
Minimal Residual
Disease
Distant Gross
Metastasis
Minimal residual disease studies
• Comparative Oncology Trials
Consortium
•5 new agents in 5 yrs
• Prioritize agents for human
MRD/adjuvant based studies of
metastatic progression
12 Months
Early Phase Trials
Therapeutic Approach:
Later Phase Trials
Aminobisphosphonates
Rapalog inhibition of mTOR
Ezrin small molecule inhibitors
Measurable
Disease
Minimal Residual
Disease
Perceived Risks and Concerns with the Integration of a Comparative Approach
Study Duration
• Timelines are longer than those in rodent models
• Strategic inclusion of pet dogs should allow timely integration of data into human trials
Patient to Patient Variability
• Tumor-bearing dogs represent a different clinical population compared to research dogs
• SNP frequency amongst dogs is similar to that of patients in early phase cancer studies
Cancer Prevalence by Histology
• Most common: sarcomas and lymphoid neoplasms
• Less common: Breast, prostate, gastrointestinal, lung carcinomas
• Studies in the less common histologies require more time for completion and more clinical
trial centers
• Histology is increasingly replaced with biology and not often a primary question for trial
design
Target biology may be unique and must be defined (“credentialed”)
• Canine Comparative Oncology and Genomics Consortium
• Pfizer - Canine Oncology and Genomics Consortium Biospecimen Repository
• Comparative Oncology Program Tissue Array Resource
Perceived Risks and Concerns with Integration of a Comparative Approach
Drug and Budget Requirements
• Greater drug supply needed
• GMP not required
• Study costs include: clinical management, serial biopsy of tumors,
imaging and other correlative endpoints
Control and reporting of data
• Good Clinical Practice guidelines
• Adverse Event reporting: Assign severity, duration, and attribution
• Compliance by pet owners and study investigators is very high
Regulatory oversight/reporting
• Pre-IND agents - guidance has been proposed and used
•(Khanna et al Clin Cancer Res 2009)
• Post-IND agents - guidance exists
Biotech and aversion to “rocking” the development boat

What is comparative oncology?

What resources are available to those employing a
comparative approach for drug development,
biomarker discovery, other endeavors?

How are such studies designed and executed?

How can comparative oncology be an example for
other One Health initiatives?
Acknowledgements
Tumor and Metastasis Biology Section, Pediatric Oncology
Branch, National Cancer Institute
Comparative Oncology Program
CCR, National Cancer Institute
Melissa Paoloni
Christina Mazcko
Ira Gordon
Katherine Hansen
Monika Jankowski
Ling Ren
Arnulfo Mendoza
Michael Lizardo
James Morrow
Allyson Koyen
Tanasa Osborne
Rhadika Gharpure
Martin Mendoza
Molecular Oncology Section, Pediatric Oncology Branch,
National Cancer Institute
Sung Hyeok Hong
Choh Yeung
Manpreet Alhuwalia
Lee Helman
Jessica Cassavaugh
Joseph Briggs
Georgetown
C3D,- NCI
COTC
CCOGC
Jun Wei
Javed Khan
Aykut Uren
CGB CCR - NCI
LCB - NCI
Paul Meltzer
Liang Cao
Sean Davis
Yien Cha Tsai
Alan Weismann
Caryn Steakley
Allison Wise
Jeffrey Shilling
Sawsan Sahin
Deven Shah
Rohit Paul
Amy LeBlanc
Jeffrey Phillips
Shelley Newman
Doug Thamm
Susan Plaza
Christie Anderson
Carolyn Henry
Kimberly Selting
David Vail
Ilene Kurzman
Karin Sorenmo
Amy LaBlanc
Timothy Fan
William Kisseberth
Barb Kitchell
Heather Wilson
David Vail
Matthew Breen
Sue Lana
Jaime Modiano
Kerstin Linblad-Toh
Elizabeth McNeil
Phil Bergman
Steve Withrow
Mark Simpson
Cheryl London
Bill Kissebirth
POB-OGS - NCI
Pathology - NCI
U. Chicago
Hue Luu
Stephen Hewitt
Frederick - NCI
Nancy Colburn
Tim Veenstra
CSU
Dan Gustafson
Hansen
Last Slide

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