Transcript NCI Initiatives to Develop Non-Clinical Models for Pediatric Oncology

NCI Initiatives to Develop
Non-Clinical Models for
Pediatric Oncology
Malcolm A. Smith, MD, PhD
17 March 2004
Drug Development Pyramid
 Many more agents are
evaluated in phase I trials for
adults than can be
systematically evaluated in
phase I trials in children
 Even fewer new agents can be
evaluated in phase II trials in
children
 For most solid tumors of
children, only 1 phase III study
can be conducted every 4-5
years
 The challenge: How to pick
the right agents??
Phase III
Phase II
Phase I Studies
in Children
Phase I Studies
in Adults
Neuroblastoma Example –
 Drugs under evaluation with potential applicability to
neuroblastoma
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Decitabine
Fenretinide
Interleukin-12
Trk tyrosine kinase inhibitor
Oxaliplatin
HDAC inhibitors (e.g., depsipeptide)
BSO
 Potential for multiple combinations of the above with
standard chemotherapy and with other novel agents
 Which for phase 3 evaluation???
The need for non-clinical testing?
 Predictive non-clinical methods may
contribute to prioritizing agents for evaluation
against specific types of childhood cancer
 A systematic approach to non-clinical testing
is required to assess the predictive value of
pediatric non-clinical models
 NCI Board of Scientific Advisors approved
committing $10 million to this effort over the
next 5 years through Pediatric Preclinical
Testing Program
Role of xenografts in drug
development – Adult experience
 Overall activity across range of tumor xenografts
predicts for eventual clinical success in at least one
tumor type
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Johnson, et al. Br J Cancer 2001; 84(10):1424-1431
 Using panels of xenografts for a given tumor type
increases the likelihood for correct prediction.
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Voskoglou-Nomikos, et al. Clin Cancer Res 2003;
9(11):4227-4239
 Human Tumor Xenografts as Predictive Preclinical
Models for Anticancer Drug Activity in Humans: Better
than Commonly Perceived —But They Can Be
Improved
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Kerbel, Cancer Biol Ther. 2003 Jul-Aug;2(4 Suppl 1):S134-9
Panels of Xenograft Lines Enhance
Predictive Value
Voskoglou-Nomikos, et al. Clin Cancer Res 2003; 9(11):4227-4239
Contribution of Pharmacology to Enhancing
Predictive Ability of Preclinical Models
 Predictive ability of xenografts can likely be
enhanced by comparisons of mouse
pharmacology to human pharmacology.
 Pharmacology can rule out the trivial
explanation for activity in xenograft models:
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Mice tolerate much more of the agent than
humans, and human cancers implanted in
mice are exposed to much higher levels than
would ever occur in the clinical setting.
Why Pediatric Preclinical Models May
Be More Useful than Adult Models
 Pediatric drug development decision-making can
utilize both:
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Pediatric non-clinical testing results
Comparison of mouse PK of agent with PK of agent in
initial adult clinical trials
 Most promising agents are those with activity in
pediatric models at serum levels achievable in
humans
 Example incorporating PK of positive prediction from
pediatric literature : irinotecan
 Example incorporating PK of correctly predicting
inactivity: sulofenur
Pediatric Preclinical TestingThe Potential for Prediction
 The activity of agents in rhabdomyosarcoma
xenografts mirrors the clinical activity of these
agents
 Topoisomerase I inhibitors prospectively
identified in xenograft models as active
agents against rhabdomyosarcoma and
neuroblastoma
 Preclinical in vivo models available for many
childhood cancers
Patient and NOD/SCID peripheral blood
smears
Patient
NOD/SCID
Patient #10
c-ALL
Patient #11
c-ALL
Lock, et al. Blood. 2002;99: 4100, 2002
In vivo responses of childhood ALL to
vincristine in NOD/SCID mice
B. Saline
A. Vincristine
100
100
17
7
80
19
% Human
CD45+ Cells
in Peripheral
Blood
8
60
80
3
60
40
40
2
20
20
0
0
-2
0
2
4
6
Weeks Post Treatment
8
10
-2
0
2
Weeks Post Treatment
Lock, et al. Blood. 2002;99: 4100, 2002
4
In vivo sensitivity to vincristine
correlates with length of CR1
Lock, et al. Blood. 2002;99: 4100, 2002
Molecularly Targeted Agents:
Preclinical PK/PD comparisons
 Especially important in era of molecular targets.
 Can identify degree of target modulation that is
associated with antitumor activity.
 Can identify the duration of target modulation that is
associated with antitumor activity.
 Identify serum levels (systemic exposure) of agent
associated with requisite levels of target modulation.
 Opportunity to correlate antitumor activity with gene
expression profiles and with protein expression
profiles.
Pediatric Oncology Preclinical Protein
and Tissue Array Project (POPP-TAP)
 Collaboration between NCI & COG
researchers
 To develop tissue and cell arrays and protein
lysate arrays of pediatric preclinical cancer
models
 To determine gene expression profiles for
pediatric preclinical cancer models
 To facilitate conduct & interpretation of
preclinical testing of “targeted” agents in
childhood cancer models
Complicating factors in testing
molecularly targeted agents:
 Promiscuity of agent: a targeted agent hits multiple
targets (some recognized, some not)
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Bay 43-9006 (Raf kinase inhibitor)
 Multiple biological effects of modulating target (one
target affects multiple downstream pathways)
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Farnesyltransferase inhibitors (e.g., R115777)
Proteasome inhibitors (e.g., PS-341)
Hsp90 inhibitors (e.g., 17-AAG)
 Potential applicability of agents with broadly
expressed targets is difficult to assess prospectively
 Preclinical testing may allow identification of
previously unrecognized activities or interactions
and may allow identification of unanticipated activity
What are the alternatives?
 Mouse genetic models have made important
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contributions to our understanding of cancer
pathogenesis.
Genetically engineered models must have specific
properties in order to be suitable for drug testing:
short latency and high penetration.
Some genetically engineered models for pediatric
cancers that are suitable for drug testing (e.g.,
MYCN)
A mouse is a mouse, and mouse biology is not the
same as human biology (Rangarajan and Weinberg,
Nature Cancer Reviews 3:952, 2003)
Models based upon more “humanized” mice may
more faithfully replicate human cancers.
NCI Pediatric Preclinical Testing
Program
 Based on panels of xenograft lines for most
common childhood cancers
 Incorporates in vitro testing component
 Systematic testing of 10-15 agents per year
 Seek to obtain agents near time that
commitment to initial clinical evaluation in
adults is made
 Implemented via contract mechanism with
primary contractor and with potential for
subcontracts for testing specific cancer types
Target
Defined?
Drug X
Yes
Transgenic
Model?
No
Yes
No
Testing
@MTD
Tumor A
Tumor B
Tumor C
Active in Model(s)?
Testing
@MTD
Tumor D
Yes
Tumor E
Transgenic
Model
Full Dose
Response/PK
No
Yes
Orthotopic
Models
Other Tum or Models
Available?
Yes
No
Clin Cancer Res 2002; 8(12):3646-3657
Results to Steering
Committee
Additional
Transgenic
Models
Addressing Intellectual Property Issues
 NCI efforts over past 2 years to develop a
Model MTA that will be used (with only minor
modifications) for all transfers by companies
of their proprietary compounds to NCIsupported investigators for preclinical testing
 Acceptance of Model MTA is requirement for
participation in Pediatric Preclinical Testing
Program
 Dr. Sherry Ansher is CTEP contact for
inquiries about Model MTA
Summary
 Appropriate prioritization is key to future
treatment advances for childhood cancer
 NCI’s Pediatric Preclinical Testing Program
may contribute to successful prioritization
 Systematic preclinical testing of all agents
entering clinical evaluation in children should
become the “standard of care”
 Systematic preclinical testing will allow
validation and optimization of pediatric
preclinical tumor panels