Small Molecule PD and Imaging

1
Small Molecule PD and Imaging Models and Assay
Development

• DCTD Phase 0 Primer, September 5, 2007
• Ralph E Parchment, PhD
• SAIC-Frederick, Inc., NCI-Frederick,
• Frederick, Maryland 21702
• Funded by Contract N01-CO-12400

2
Session Speakers and Topics

• Dr. Robert Kinders, Principal Scientist, PD Assay
  Development Implementation Section,
  SAIC-Frederick
• Assay Development/Validation
• Phase 0 Clinical Trial Modeling Using Preclinical
  Models
• Dr. Melinda Hollingshead, Chief, BTB/DTP/DCTD/NCI
• Implementing Clinical Biopsy Procedures in Small
  Animal Models
• Dr. Susan Galbraith, VP of Clinical Discovery
  Research at BMS
• Phase 0 Trials-Why Arent They More Widely Used
  by Industry?
• Dr. David Mankoff, University of Washington
• PET Imaging Assessment of Therapeutics

3
Building Blocks of the DCTD Program in Clinical
Pharmacodynamics
Phase I dose escalation with PD to establish surrogate tissue for tumor Phase I dose escalation with PD to establish surrogate tissue for tumor Phase I dose escalation with PD to establish surrogate tissue for tumor Phase I dose escalation with PD to establish surrogate tissue for tumor
Establish reliable supply of key materials with QC and batch equivalency Establish reliable supply of key materials with QC and batch equivalency Establish reliable supply of key materials with QC and batch equivalency Establish reliable supply of key materials with QC and batch equivalency
Phase 0 clinical trial PD assay gives 1o endpoint surrogate tissues also evaluated Phase 0 clinical trial PD assay gives 1o endpoint surrogate tissues also evaluated Preclinical modeling of tumor-surrogate relationship Preclinical modeling of tumor-surrogate relationship
eIND filing Transfer validation to clinical lab Transfer validation to clinical lab Create real-time reporting
Preclinical modeling of Phase 0 design to prove suitability of drug-target pair Preclinical modeling of Phase 0 design to prove suitability of drug-target pair Preclinical modeling of Phase 0 design to prove suitability of drug-target pair Preclinical modeling of Phase 0 design to prove suitability of drug-target pair
Validate specimen handling SOPs Validate specimen handling SOPs Validate specimen handling SOPs Validate specimen handling SOPs
Validate an SOP-driven PD assay Validate an SOP-driven PD assay Validate an SOP-driven PD assay Validate an SOP-driven PD assay
Select clinical procedures specimen collection, processing, storage, extraction and dilution Select clinical procedures specimen collection, processing, storage, extraction and dilution Select clinical procedures specimen collection, processing, storage, extraction and dilution Select clinical procedures specimen collection, processing, storage, extraction and dilution
Test candidate PD assay for dose effect and specificity (inactive control) Test candidate PD assay for dose effect and specificity (inactive control) Test candidate PD assay for dose effect and specificity (inactive control) Test candidate PD assay for dose effect and specificity (inactive control)
Identify 1o/2o assay endpoints Identify technology platform(s)/assay Identify surrogate tissue candidate(s) Schedule supply of specimens
Scientific knowledge base mechanism of action, target(s), signal transduction pathways Scientific knowledge base mechanism of action, target(s), signal transduction pathways Scientific knowledge base mechanism of action, target(s), signal transduction pathways Scientific knowledge base mechanism of action, target(s), signal transduction pathways
4
Clinical scientists
Veterinarians
Lab scientists
Phase II trials using surrogate tissue for PD assessments Phase II trials using surrogate tissue for PD assessments Phase II trials using surrogate tissue for PD assessments Phase II trials using surrogate tissue for PD assessments
Phase I dose escalation with PD to establish surrogate tissue for tumor Phase I dose escalation with PD to establish surrogate tissue for tumor Phase I dose escalation with PD to establish surrogate tissue for tumor Phase I dose escalation with PD to establish surrogate tissue for tumor
Establish reliable supply of key materials with QC and batch equivalency Establish reliable supply of key materials with QC and batch equivalency Establish reliable supply of key materials with QC and batch equivalency Establish reliable supply of key materials with QC and batch equivalency
Phase 0 clinical trial PD assay gives 1o endpoint surrogate tissues also evaluated Phase 0 clinical trial PD assay gives 1o endpoint surrogate tissues also evaluated Preclinical modeling of tumor-surrogate relationship Preclinical modeling of tumor-surrogate relationship
eIND filing Transfer validation to clinical lab Transfer validation to clinical lab Create real-time reporting
Preclinical modeling of Phase 0 design to prove suitability of drug-target pair Preclinical modeling of Phase 0 design to prove suitability of drug-target pair Preclinical modeling of Phase 0 design to prove suitability of drug-target pair Preclinical modeling of Phase 0 design to prove suitability of drug-target pair
Validate specimen handling SOPs Validate specimen handling SOPs Validate specimen handling SOPs Validate specimen handling SOPs
Validate an SOP-driven PD assay Validate an SOP-driven PD assay Validate an SOP-driven PD assay Validate an SOP-driven PD assay
Select clinical procedures specimen collection, processing, storage, extraction and dilution Select clinical procedures specimen collection, processing, storage, extraction and dilution Select clinical procedures specimen collection, processing, storage, extraction and dilution Select clinical procedures specimen collection, processing, storage, extraction and dilution
Test candidate PD assay for dose effect and specificity (inactive control) Test candidate PD assay for dose effect and specificity (inactive control) Test candidate PD assay for dose effect and specificity (inactive control) Test candidate PD assay for dose effect and specificity (inactive control)
Identify 1o/2o assay endpoints Identify technology platform(s)/assay Identify surrogate tissue candidate(s) Schedule supply of specimens
Scientific knowledge base mechanism of action, target(s), signal transduction pathways Scientific knowledge base mechanism of action, target(s), signal transduction pathways Scientific knowledge base mechanism of action, target(s), signal transduction pathways Scientific knowledge base mechanism of action, target(s), signal transduction pathways
5
Select Clinical Procedures Specimen Collection,
Processing, Storage, Extraction and Dilution

• Current limitations in PD
• Replicating human medicine procedures in the
  animal models
• Implementing PD measurements within clinical
  constraints of tissue yield, procedure time,
  logistics of specimen handling, anesthesia
  effects, etc., because method can affect PD
  measurement
• Processing strategy is hurrying to stabilize the
  signal after tissue is removed from the body
• Limited to a very static measurement of PD via
  biopsy at 1-2 time points
• This area will be addressed in detail by Dr.
  Hollingshead

6
Select Clinical Procedures Specimen Collection,
Processing, Storage, Extraction and Dilution

• Future improvements in PD.
• Change philosophy of specimen handling to create
  procedures and devices that stabilize molecular
  profile prior to tissue removal (FY2008 SBIR
  Contract Solicitation, Topic 250)
• Create methods for repeat sampling to achieve
  more dynamic pharmacodynamics, such a
  circulating tumor cells, permanent placement of
  biopsy access port, etc
• If we all use inhibitors of enzymes that degrade
  the product of the molecular target during tissue
  extraction, why dont we also use inhibitors of
  the enzymes that produce them?
• Develop methods to directly assess target enzyme
  activity in biopsies

7
Preclinical Modeling of Phase 0 Design to Prove
Suitability of Drug-Target Pairs Validate
Specimen-Handling SOPs

• 120 rule for dynamic range
• assumes 33-50 yield
• assumes that a 80-90 inhibition level will need
  to be measured
• achievable with 3 of 3 platforms (immunosandwich
  assays, immunofluorescent assays on tissue
  sections, and qRT-PCR)
• Assess influence of
• biomatrix on assay signal (dilution
  non-linearity)
• tumor heterogeneity on PD variability and
  required drug effect
• effect of prior Bx on subsequent Bx, including
  drug effect
• time required after dosing to find PD effect in
  tumor Bx
• This area will be addressed in detail by Dr.
  Kinders

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Preclinical Modeling of Phase 0 Design to Prove
Suitability of Drug-Target Pairs
Candidate Phase 0 Pairs Candidate Phase 1 Pairs
Non-toxic dose range
Non-toxic dose range
Target Function
Target Function
Dose or Exposure
Dose or Exposure
Non-toxic dose range
Non-toxic dose range
Target Function
Target Function
Dose or Exposure
Dose or Exposure
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The Next Speaker isDr. Melinda Hollingshead