amy k. leblanc, dvm diplomate acvim (oncology). what is comparative oncology? what resources are...
TRANSCRIPT
Comparative Oncology: “One Health” in action
American College of Laboratory Animal Medicine ACLAM Forum May 5, 2014
Amy K. LeBlanc, DVM Diplomate ACVIM (Oncology)
An overview
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
Image courtesy of Eric Carlson, DMD, MD, FACS
Oral cavity/mucosal malignant melanoma
Biologically aggressive, responsive to immune-based
therapiesCanine: BRAF(-); c-kit (-);
N-ras (-)
A Comparative and Integrated Approach to Cancer Drug Development
Nature Reviews Cancer 2008
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
Comparative OncologyTO PROVIDE OPPORTUNITIES TO INCLUDE NATURALLY OCCURRING CANCER MODELS IN THE STUDY OF CANCER BIOLOGY AND THERAPY
BMC Genomics 2009
Expression Profiles for Canine and Human Osteosarcoma are Indistinguishable
OsteosarcomaNormal Tissues
1960 20121980 1990 2000
Comparative OncologyProgram and Comparative
Oncology Trials Consortium-NCI founded 2003
Canine ComparativeOncology and GenomicsConsortium founded 2006
Canine GenomeRelease 2005
Limb sparing optimized in canine osteosarcoma 71,72
Hyperthermia (thermoradiotherapy)techniques correlated with clinical
efficacy in a canine model 69
Cytokine and chemotherapeutic inhalation strategies first assessed
in dogs with cancer 76-79
Descriptive design: size focused Measurable and minimal residual disease
L-MTP-PE evaluated in MRD osteosarcoma guided
COG studies 94
Integrated
Defined toxicity, activity, PKand tumoral PD with tyrosine
kinase inhibition 44, 84
DNA vaccine approved for use in
canine melanoma 37,99-100
Development of bone marrow transplantation regimes in dogs 11,12
Tumor vaccines administered forcanine lymphoma 13,14
Evaluation of BCG immunotherapy in canine melanoma 9
Paoloni and Khanna Nature Reviews Cancer 2008
Regulatory Guidance 2009
Cost (Conventional development pathway)
Cost (Integrated development pathway)
Preclinical Phase I Phase II Phase III Approval
100
90
40
30
20
10
# of
Can
cer D
rugs
Rea
chin
g Th
is P
hase
in D
evel
opm
ent
Gordon, I et al. PLoS Med 6(10): e1000161. doi:10.1371/journal.pmed.1000161
Projected “Value” of an Integrated Drug Development Path
# of Drugs in CONVENTIONAL DRUG PATH
# of Drugs in INTEGRATED DRUG PATH
Cost (Conventional development pathway)
Cost (Integrated development pathway)
# of drugs (Integrated development pathway)
# of drugs (Coventional development pathway)
Preclinical Phase I Phase II Phase III Approval
100
90
40
30
20
10
Cumulative Cost of Cancer Clinical Trials
$3b
$2b
$1b
$0b
# of
Can
cer D
rugs
Rea
chin
g Th
is P
hase
in D
evel
opm
ent
Gordon, I et al. PLoS Med 6(10): e1000161. doi:10.1371/journal.pmed.1000161
Projected “Value” of an Integrated Drug Develpment Path
# of Drugs in CONVENTIONAL DRUG PATH# of Drugs in INTEGRATED DRUG PATHCost of CONVENTIONAL DRUG PATHCost of INTEGRATED DRUG PATH
Reagent/Resources to conduct studies in
Comparative Oncology
GenomicsProteomicsAntibodies
Biospecimen RepositoryPD Core
Canine Comparative Oncology and Genomics Consortium
Advocacy for the Appropriate Integration of Comparative
Oncology Trials
AcademiaPharma
NCIRegulatory Bodies
Progress by the Comparative Oncology Trials Consortium (COTC)
Initiated of Letters of Intent 19Initiated study protocols 11Studies completed 9Studies published 3Studies in progress/in press 7
Studies of COTC are published under a “Collection” in PLoS One
Comparative Oncology Trials Consortium (COTC)
Comparative Oncology Program – Center for Cancer Research
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, mastcell tumor, soft tissue sarcomas and hemangiosarcoma.
• tumor and normal tissues (formalin fixed, snap frozen and OCT), frozen serum, plasma, urine and whole blood.
CCOGCSample Collection
Sites
Pfizer CCOGC Repository
Frederick MD
CCOGCPathology Review
GovernmentPharmaBiotech
Academia
CCOGCBioBankReview
Requests for samples/data from fixed sample resource
Repository business modelRepository business model
MTA
MTA/MOUOwnership of
tissue and IP is heldbut may be transferred
by CCOGC
Osteo
sarc
oma
Lym
phom
a
Mel
anom
a
Pulm
onar
y
STS/MH/H
SM
CT
Heman
gios
arco
ma
0
100
200
300
400
500
600
520
441
102 92
332
182 180
Pfizer CCOGC Biospecimen Repository: Total Number of Canine Patients Collected
Tumor and Normal TissuesBlood
FrozenRNAlater
Formalin fixed
CCOGC Sample Distribution Progress
Nearly 1000 canine patient samples have been distributed world-wide since October 2012.
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:
Patient Eligibilitychecklist
Day 0 Agentadministration
Day 7 Agentadministration
Day 21 Agentadministration
Day 14 Agentadministration
Day 28: patientreassessment
BiopsyTumor/Normal
BiopsyTumor/Normal
BiopsyTumor/Normal
Imaging
Imaging
Imaging
Patient Enrollment checklist
1. Discuss questions not answered fully through conventional models or human trials.
2. 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
4. Develop study protocol and data base
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
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
Tumor Specific Targeting – Tolerability“Evaluation of RGD Targeted Delivery of Phage Expressing TNF-a to Tumor Bearing Dogs”
Antitumor activity and immunomodulatory effects“Evaluation of IL-12 and IL-2 Immunocytokines in Tumor Bearing Dogs”
Pick the Winner – Biological and Antitumor activity“Preclinical Comparison of Three TOPO-1 inhibitors in Dogs with Lymphoma”
Modeling Personalized Medicine Delivery in Dogs
Molecuiarly informed therapy
Protocol Development
Study Implementation and Contract Process
COTC007: Novel Topoisomerase I Inhibitors: Integrated Comparative Approach to Identify Lead Agent
ToxicityPharmacokineticsPharmacodynamicsTherapeutic Index
Low throughput selection of “lead”
Lead Candidate Discrimination/Selection Study: COTC007b
Biological Endpoints
Serum Pharmacokinetics
Tumoral drug LevelsDrug Target/ModulationBiological Activity
Circulating Tumor CellNumbersTarget ModulationBiological Activity
Normal tissue (Bone marrow)Target ModulationBiological Activity
Grade 5 event. Not attributable to IND. Expanded cohort 1 (3mg/m2). Grade 5 event. Not attributable to IND. Cohort 3 expanded. Currently in cohort 5.
Grade 3 Allergic reaction. Cohort 4 (125mg/m2) expanded.
Grade 2 Hypersensitivity reaction. Grade 4 Neutropenia, Thrombocytopenia, AST, ALT (DLT)
Grade 4 Neutropenia (DLT). Cohort Closed.
Grade 4 Neutropenia & Thrombocytopenia (DLT). Cohort closed.
8/14
/08
9/2/
08
9/21
/08
10/1
0/08
10/2
9/08
11/1
7/08
12/6
/08
12/2
5/08
1/13
/09
2/1/
09
2/20
/09
3/11
/09
3/30
/09
4/18
/09
5/7/
09
5/26
/09
0
25
50
75
100
125
Agent X-3 Enrollment
Patient Entry
100 mg/m2
5/13
/08
6/12
/08
7/12
/08
8/11
/08
9/10
/08
10/1
0/08
11/9
/08
12/9
/08
1/8/
09
2/7/
09
3/9/
09
4/8/
09
5/8/
09
6/7/
090
5
10
15
20
Agent X-1 Enrollment
Patient Entry
Grade 4 Neutropenia & Thrombocytopenia (DLT). Cohort 5 expanded.
7/15
/08
8/7/
08
8/30
/08
9/22
/08
10/1
5/08
11/7
/08
11/3
0/08
12/2
3/08
1/15
/09
2/7/
09
3/2/
09
3/25
/09
4/17
/09
5/10
/09
6/2/
09
6/25
/09
0
10
20
30
40
50
Agent X-2 Enrollment
Patienty Entry
17.5 mg/m2
Biological Activity: H2AX Cytospin Images Agent X-3 Cohort 3 (75mg/m2/day)
Pre-dose D6Bone Marrow
Pre-dose D1 6h D6D1 2h
Tumor Aspirate
JI/NCTVL
Comparison of Tumoral Drug Exposure: Compound and Cohort
Agent 1 Agent 2 Agent 3
COTC007: Novel Topoisomerase I Inhibitors: Integrated Comparative Approach to Identify Lead Agent
ToxicityPharmacokineticsPharmacodynamicsTherapeutic Index
COTC007: Novel Topoisomerase I Inhibitors: Integrated Comparative Approach to Identify Lead Agent
ToxicityPharmacokineticsPharmacodynamicsTherapeutic Index
Minimal Residual Disease
Combinational Therapies
Novel Biomarkers
Opportunities to Answer Questions to Inform Phase III Designs:
No “Gold Standards” so ability to treat in naïve disease
Compressed progression times Assess activity of drugs that uniquely
target metastatic progression
Integrated Approach to Osteosarcoma Drug DevelopmentTranslational studies of agents that target “vulnerable” metastatic cells.
Early Phase Trials
Canine OS TrialsMinimal residual disease studies• Comparative Oncology Trials
Consortium • 5 new agents in 5 yrs
• 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
MeasurableDisease
Therapeutic Approach:
AminobisphosphonatesRapalog inhibition of mTOR
Ezrin small molecule inhibitors
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
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
Perceived Risks and Concerns with Integration of a Comparative Approach
In conclusion… are you convinced?
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?
The UT Molecular Imaging and Translational Research Program
Acknowledgements
Comparative Oncology ProgramCCR, National Cancer Institute Melissa Paoloni Christina MazckoIra GordonKatherine HansenMonika Jankowski
Tumor and Metastasis Biology Section, Pediatric Oncology Branch, National Cancer Institute
Ling Ren
Arnulfo Mendoza
Michael Lizardo
James Morrow
Allyson Koyen
Tanasa Osborne
Rhadika Gharpure
Martin Mendoza
Sung Hyeok Hong
Manpreet Alhuwalia
Jessica Cassavaugh
Joseph Briggs
Molecular Oncology Section, Pediatric Oncology Branch, National Cancer Institute
Choh Yeung
Lee Helman
C3D,- NCI Caryn SteakleyAllison WiseJeffrey ShillingSawsan SahinDeven ShahRohit Paul
CCOGCDavid VailMatthew BreenSue LanaJaime ModianoKerstin Linblad-TohElizabeth McNeilPhil BergmanSteve WithrowMark SimpsonCheryl LondonBill Kissebirth
COTCAmy LeBlancJeffrey PhillipsShelley NewmanDoug ThammSusan PlazaChristie AndersonCarolyn HenryKimberly SeltingDavid VailIlene KurzmanKarin SorenmoAmy LaBlancTimothy FanWilliam KisseberthBarb KitchellHeather Wilson
GeorgetownAykut Uren
LCB - NCIYien Cha TsaiAlan Weismann
POB-OGS - NCIJun WeiJaved Khan
CGB CCR - NCIPaul MeltzerLiang CaoSean Davis
Pathology - NCIStephen Hewitt
Frederick - NCINancy ColburnTim Veenstra
U. ChicagoHue Luu
CSUDan GustafsonHansen
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