Nci initiatives to develop non clinical models for pediatric oncology
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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

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Nci initiatives to develop non clinical models for pediatric oncology l.jpg

NCI Initiatives to Develop Non-Clinical Models for Pediatric Oncology

Malcolm A. Smith, MD, PhD

17 March 2004


Drug development pyramid l.jpg
Drug Development Pyramid Oncology

  • 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


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Neuroblastoma Example – Oncology

  • Drugs under evaluation with potential applicability to neuroblastoma

    • 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???


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The need for non-clinical testing? Oncology

  • 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


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Role of xenografts in drug development – Adult experience Oncology

  • Overall activity across range of tumor xenografts predicts for eventual clinical success in at least one tumor type

    • 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.

    • 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

    • Kerbel, Cancer Biol Ther. 2003 Jul-Aug;2(4 Suppl 1):S134-9


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Panels of Xenograft Lines Enhance Predictive Value Oncology

Voskoglou-Nomikos, et al. Clin Cancer Res 2003; 9(11):4227-4239


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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:

    • 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.


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Why Pediatric Preclinical Models May Be More Useful than Adult Models

  • Pediatric drug development decision-making can utilize both:

    • 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


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Pediatric Preclinical Testing- Adult ModelsThe 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


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Patient Adult Models

NOD/SCID

Patient #10

c-ALL

Patient #11

c-ALL

Patient and NOD/SCID peripheral blood smears

Lock, et al. Blood. 2002;99: 4100, 2002


In vivo responses of childhood all to vincristine in nod scid mice l.jpg

B. Saline Adult Models

A. Vincristine

100

100

17

7

80

80

19

8

3

% Human

CD45+ Cells

in Peripheral

Blood

60

60

40

40

2

20

20

0

0

-2

0

2

4

-2

0

2

4

6

8

10

Weeks Post Treatment

Weeks Post Treatment

In vivo responses of childhood ALL to vincristine in NOD/SCID mice

Lock, et al. Blood. 2002;99: 4100, 2002


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In vivo Adult Models sensitivity to vincristine correlates with length of CR1

Lock, et al. Blood. 2002;99: 4100, 2002


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Molecularly Targeted Agents: Adult ModelsPreclinical 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.


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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


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Complicating factors in testing molecularly targeted agents: Project (POPP-TAP)

  • Promiscuity of agent: a targeted agent hits multiple targets (some recognized, some not)

    • Bay 43-9006 (Raf kinase inhibitor)

  • Multiple biological effects of modulating target (one target affects multiple downstream pathways)

    • 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 interactionsand may allow identification of unanticipated activity


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What are the alternatives? Project (POPP-TAP)

  • Mouse genetic models have made important 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.


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NCI Pediatric Preclinical Testing Program Project (POPP-TAP)

  • 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



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Addressing Intellectual Property Issues Project (POPP-TAP)

  • 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 NCI-supported 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


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Summary Project (POPP-TAP)

  • 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


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