Predictive Models of CancerPredictive Models of Cancer

Xenograft Models Of Childhood Xenograft Models Of Childhood Solid TumorsSolid Tumors

Solid Malignancies GroupSolid Malignancies Group

St. Jude Children’s Research HospitalSt. Jude Children’s Research Hospital

Drug Development For ChildrenDrug Development For Children Has To Be Different Has To Be Different

Drug acquired Drug acquired NCI/Industry/AcademiaNCI/Industry/Academia

Phase IPhase I

UnacceptableUnacceptableToxicityToxicity

ActiveActive

InactiveInactive

Phase IIIPhase III

Virtually no drugs are developed specifically Virtually no drugs are developed specifically to treat childhood solid tumors.to treat childhood solid tumors.Aim: Develop and validate tumor models to Aim: Develop and validate tumor models to identify potentially important new drugs.identify potentially important new drugs.

Phase IIPhase IIDiscardDiscard

DiscardDiscard

Does phase II testing reveal any insight as to why this Does phase II testing reveal any insight as to why this drug succeeds or fails? drug succeeds or fails? Aim: Develop predictive models.Aim: Develop predictive models.

How do phase I trials help to prioritize drugs for phase II How do phase I trials help to prioritize drugs for phase II evaluation?evaluation?

Aim:Develop a process allowing more rational prioritization.Aim:Develop a process allowing more rational prioritization.

Human Tumor XenograftsHuman Tumor Xenografts

• Human cancers grown in immune-Human cancers grown in immune-incompetent mice/rats.incompetent mice/rats.

• Models of most childhood solid tumors.Models of most childhood solid tumors.

• Models of childhood ALL established.Models of childhood ALL established.

Xenograft Model ValidationXenograft Model Validation(Rhabdomyosarcoma)(Rhabdomyosarcoma)

• Model tumors respond qualitatively and Model tumors respond qualitatively and quantitatively to drugs known to be quantitatively to drugs known to be active in the respective clinical disease:active in the respective clinical disease:

• Diagnosis models: highly sensitive.Diagnosis models: highly sensitive.• Relapse models: significantly less Relapse models: significantly less

responsiveresponsive• Models prospectively identify effective Models prospectively identify effective

agents.agents.

√√

√√

√√

Retrospective and Prospective Retrospective and Prospective Use of Rhabdomyosarcoma XenograftsUse of Rhabdomyosarcoma Xenografts

DRUG XENOGRAFT (%) CLINICAL (%)VINCRISTINE 78 59CYTOXAN 44 54DACTINOMYCIN 11 24ADRIAMYCIN 19 31

PROSPECTIVEDRUG XENOGRAFT (%) CLINICAL (%)MELPHALAN 83 81TOPOTECAN ~70 46 (65 ARMS/28 ERMS)

SENSITIVITY OF WILMS SENSITIVITY OF WILMS TUMOR XENOGRAFTSTUMOR XENOGRAFTS

TUMOR VINCRISTINE CYTOXANWT1 (fh) ++++++ ++WT7 (fh) ++++++ ++++++WT8 (fh) ++++++ ++++WT9 (fh) ++++++ +++WT10 (fh) ++++++ ++++++SKNEP (ah) ++ +++++

TOPOTECAN++++++++++++++++++++++++++++++++

++ PROGRESSIVE DISEASE+++ STABLE DISEASE++++ PARTIAL REGRESSION+++++ COMPLETE REGRESSION WITH REGROWTH++++++ COMPLETE REGRESSION W/O REGROWTH

Entering into a collaboration with GSK who identified a potential Entering into a collaboration with GSK who identified a potential Wilms target through a genomics/proteomics screenWilms target through a genomics/proteomics screen

Where do Xenograft Models Fit?Where do Xenograft Models Fit?

Drug acquired Drug acquired NCI/Industry/AcademiaNCI/Industry/Academia

Phase IPhase I

•Identification of novel agentsIdentification of novel agents•Mechanisms- molecular targetsMechanisms- molecular targets•Broad spectrum activityBroad spectrum activity•Lack of cross-resistanceLack of cross-resistance

•Optimizing schedules of administrationOptimizing schedules of administration

•Developing relationships betweenDeveloping relationships betweenresponse and systemic exposuresresponse and systemic exposures

Phase IIPhase II

0.1

1

10

0 2 4 6 8 10 12

TU

MO

R V

OLU

ME

(C

M3 )

WEEKS

CONTROL

0.1

1

10

0 2 4 6 8 10 12

TU

MO

R V

OLU

ME

(C

M3 )

WEEKS

CPT-11 5mg/kg i.v.DAILY X 5 Q 21D

0.1

1

10

0 2 4 6 8 10 12

TU

MO

R V

OLU

ME

(C

M3 )

WEEKS

CPT-11 2.5mg/kg i.v.DAILY X 5 X 2 Q21 D

Optimizing schedules of administration Schedule-Dependency of Camptothecins that Target Schedule-Dependency of Camptothecins that Target

Topoisomerase I Topoisomerase I

Importance of SchedulingImportance of SchedulingEmerging Clinical DataEmerging Clinical Data

TopotecanTopotecan Response Response RateRate

Solid Solid TumorsTumors

ScheduleSchedule Sample SizeSample Size InvestigatorInvestigator

qdx5qdx5

(qdx5)2(qdx5)2

8%8%

25%25%

4040

2020

Tubergen et al.Tubergen et al.

Santana et al.Santana et al.

LeukemiaLeukemia qdx5qdx5

(qdx5)2(qdx5)2

5%5%

50%50%

2121

1414

Furman et al.Furman et al.

IrinotecanIrinotecan

Solid Solid TumorsTumors

ScheduleSchedule Sample SizeSample Size InvestigatorInvestigator

qdx5qdx5

(qdx5)2(qdx5)2

6%6%

25%25%

3535

2323

Blaney et al.Blaney et al.

Furman et al.Furman et al.

(qdx5)2(qdx5)2 28%28% 2525 Cosetti et al.Cosetti et al.

Response Response RateRate

Furman et Furman et al.al.

QuickTime™ and aPhoto - JPEG decompressor

are needed to see this picture.

Developing Relationships BetweenDeveloping Relationships BetweenResponse and Drug Systemic ExposuresResponse and Drug Systemic Exposures

•Allows comparison of AUC @MTD (patients) with AUC Allows comparison of AUC @MTD (patients) with AUC causing model tumor regressionscausing model tumor regressions

Developing Relationships BetweenDeveloping Relationships BetweenResponse and Drug Systemic Response and Drug Systemic

ExposuresExposures

DRUG AUC @ MTD MOUSEAUC @ MTD HUMAN

EFFECTIVE DOSERANGE (FOLD FROMMTD)

DMP-840 15-20 ~ 2-3CARZELESIN ~ 80 <2SULOFENUR ~ 8 ~ 3MELPHALAN 1 ~ 3-4TOPOTECAN 3 > 10IRINOTECAN (SN-38) 16 > 100

Evaluation of MGI-114Evaluation of MGI-114(Phase II in COG?)(Phase II in COG?)

Tumor Dose level (mg/kg)7.0 4.6 3.0 2.0 1.3

DAOY ++++++ ++++++ ++++++ +++++ ++D283 ++++++ ++++++ ++++++ +++ +SJ-BT27 ND ++++++ ++++++ +++ +SJ-BT29 ++++++ +++ +++ ND NDSJ-BT33 - - - - -SJ-BT34 ++++++ ++++++ ++++++ ND NDSJ-BT36 ++++++ ++++++ ++++ +++ +++SJ-BT37 ++++++ +++++ +++ + -SJ-BT40 ++++ ++++ ++ + -SJ-BT12 ND ++++ +/- - -SJ-BT16 +++ ++++ +++ ++ +SJ-GBM2 ++++++ ++++++ + ND NDNB-1771 ND ND + - -NB-1382 ++++ ++++ +++ ND NDNB-1643 ++++++ ++++++ ++++ ND NDNB-1691 +++++ +++ ++ + NDRh18 ++++++ ++++ ++++ +++ ++Rh28 ++++++ ++++++ ++++++ +++++ +++Rh30 ND ND ND ++++++ ++++++Rh36 ++++ +++ ++ + -CR+PR/N 14/16 14 /18 8/18 3 /15 1/14

Systemic exposure is still > 10-fold higher than in children @MTDSystemic exposure is still > 10-fold higher than in children @MTD

Neuroblastoma: Preclinical Neuroblastoma: Preclinical PredictionPrediction

• Topotecan: daily x 5 x 2Topotecan: daily x 5 x 2• Preclinical: 4 of 6 objective responses @ Preclinical: 4 of 6 objective responses @

100 ng.hr/ml.100 ng.hr/ml.• Phase II targeted systemic exposure (AUC) Phase II targeted systemic exposure (AUC)

100 ng.hr/ml:100 ng.hr/ml:Clinical: Clinical: Stage IV Stage IV

NeuroblastomaNeuroblastoma 16/28 16/28 responses (57%)responses (57%)

Where Do Xenograft Models Fit in Drug Where Do Xenograft Models Fit in Drug Development for Childhood Cancer?Development for Childhood Cancer?

Drug acquired Drug acquired NCI/Industry/AcademiaNCI/Industry/Academia

Phase IPhase I

Phase IIPhase II

•Prospective identification of active agents

•Optimization of administration schedules•Prioritization of agents for phase I

•Rational decisions to advance/stop development•Potential to focus phase II trials

•Include pediatric tumor models

ConclusionsConclusions

• Valid models of childhood cancers exist.Valid models of childhood cancers exist.• Models reflect clinical drug sensitivity.Models reflect clinical drug sensitivity.• Species differences in drug disposition, Species differences in drug disposition,

metabolism and tolerance are the major metabolism and tolerance are the major problems in accurately translating results.problems in accurately translating results.

• Models accurately identify clinically active Models accurately identify clinically active agents when systemic exposure is agents when systemic exposure is normalized.normalized.

Practical ConsiderationsPractical Considerations

• Access to drugs at an early stageAccess to drugs at an early stage• Establishment of national consortium to Establishment of national consortium to

encompass most childhood tumorsencompass most childhood tumors• Develop predictive pharmacokinetic modelsDevelop predictive pharmacokinetic models• Characterize available models Characterize available models

(genomic/proteomic screens)(genomic/proteomic screens)• Develop a funding mechanism to support Develop a funding mechanism to support

experimentalists involved in preclinical to clinical experimentalists involved in preclinical to clinical transitional science.transitional science.

Drug XTarget

Defined?

Testing @MTD

Tumor A Tumor B Tumor C Tumor D Tumor E

Yes

No

Active in Model(s)?Full Dose

Response/PK

Other Tumor Models Available?

OrthotopicModels

Additional Transgenic

Models

Results to Steering Committee

No

Yes

Yes

Yes

No

TransgenicModel?

Transgenic Model

Yes

No

Testing @MTD

Drug XTarget

Defined?

Testing @MTD

Tumor A Tumor B Tumor C Tumor D Tumor E

Yes

No

Active in Model(s)?Full Dose

Response/PK

Other Tumor Models Available?

OrthotopicModels

Additional Transgenic

Models

Results to Steering Committee

No

Yes

Yes

Yes

No

TransgenicModel?

Transgenic Model

Yes

No

Testing @MTD