1. Clinical Trial Design, Biostatistics, Ethics, and Recruitment Clinical Trial Design  Anthony J. Murgo, MD.,MS; NCI/DCTD Biostatistics  Larry Rubinstein, PhD; NCI/DCTD/BRB Ethical Considerations  Holly Taylor, PhD,MPH; JHU Berman Bioethics Instit.  David Wendler, PhD; NIH Clinical Center Phase 0 and patients  Deborah Collyar; Pres. Patient Advocates In Research Recruitment  Martin Gutierrez, MD; NCI/CCR

2. Phase 0 Trial Designs How do They Differ From First-in-Human Phase 1 Trials Anthony J. Murgo, MD, MS Division of Cancer Treatment and Diagnosis National Cancer Institute Sept. 5, 2007 Mark O. Hatfield Clinical Research Center Building 10, Warren Grant Magnuson Clinical Center

3. Differences Between Phase 0 & Phase 1 Trials Phase 1 TrialPhase 0 Trial Primary Endpoint Establish dose- limiting toxicities and maximum tolerated dose Establish a safe dose-range that modulates (or images) target for use in subsequent definitive trials Patient Population Advanced incurable malignancy, after failure of standard therapy May include patients with indolent disease not requiring treatment Washout Period Usually at least 4 weeks May be 2 weeks or less Number of patients Usually >2010-15

4. Differences Between Phase 0 & Phase 1 Trials Phase 1 TrialPhase 0 Trial Dose Escalation Guided primarily by toxicity Intended to achieve desired drug exposure and/or target modulation Duration of Dosing Multiple cycles until disease progression or unacceptable toxicity Limited dosing (1-7 days) (one cycle only) Evaluation for Therapeutic benefit YesNo

5. Differences Between Phase 0 & Phase 1 Trials Phase 1 TrialPhase 0 Trial Biomarker Assays Not consistently performed. Most Phase 1 trials do not emphasize PD markers Biomarker assays and/or imaging studies are integrated to establish MOA in patient samples Tumor BiopsiesUsually optional Serial tumor biopsies required to evaluate drug effect on target Pharmacokinetic/ Pharmacodynamic analysis Samples are usually batched and analyzed at a later time point Real time

6. The Next Speaker is: Dr. Larry Rubinstein