Small Molecule PD and Imaging – Models and Assay Development

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 Aren’t 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

4. Lab scientists Clinical scientists Veterinarians

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 don’t 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 • 1:20 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

8. Preclinical Modeling of Phase 0 Design to Prove Suitability of Drug-Target Pairs CandidatePhase 0 PairsCandidate 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

9. The Next Speaker is:Dr. Melinda Hollingshead