This proposal describes our understanding, expertise, and specific ideas for conducting carefully controlled Phase I clinical trials of new agents for solid tumors at Wayne State University in a population having substantial numbers of women and minorities. During our past UO1 period, we have found that clinical assessment combined with traditional laboratory studies of in vitro and in vivo efficacy, human toxicology, human pharmacokinetics and drug metabolism provide crucial information for clinical drug development. However, these studies alone may be sufficient for answering important scientific questions in the Phase I setting. Maximum tolerated doses (MTD) defined by traditional endpoints of toxicity can be well above biologically effective doses, so additional assessment tools may be required in Phase I to define recommended Phase II doses. Assessment of molecular markers in normal tissues and tumor imaging are new tools that we have already used successfully to study drug effect on targets in surrogate tissues as well as tumor efficacy, respectively. For example, the recommended Phase II dose of ZD1839 was well below its MTD and was based on inhibition of a surrogate marker (autophosphorylation of EGFR in skin biopsies) as well as tumor response. We continue to use normal tissues to assess drug effect on molecular targets (XK469; CI-1040). However, there is a need for direct, non-invasive methods to assess tumor response, because there is no guarantee that affecting a molecular target will cause a tumor response and there are not any surrogate tissues to assess the effects of vascular-targeted agents and angiogenesis inhibitors. We have developed DCE-MRI as a tool to quantify small changes in tumor perfusion and visualize drug-effects on tumor. Our Phase I trial of ZD6126 incorporates this tool, and we will explore its use with the alpha-v/beta-3 integrin antagonist MEDI-522. During the past 5 years of this U01, the concept of accelerated titration design (ATD) was published by CTEP, and we have proven its value in three completed phase I trials - KRN5500, 5FP, and BMS247440 - proving the success of ATD in terms of fewer patients, fewer patients treated at ineffective doses, and more rapid completion. It is the design for our current trial of XK469. However, our experience with ATD points to several important issues regarding the design and analysis of correlative studies. It is more difficult to demonstrate that clearance is independent of dose because of small cohort size at lower dose levels. Furthermore, when toxicities occur in a poly-medicated patient, it is more difficult to know if they are related to the study drug and its dose, to drug-drug interactions with co-medications, or to a rare phenotype. We have developed ways to incorporate drug-interaction studies into accelerated titration designs (fenretinide and XK469) and we are identifying patients with single nucleotide polymorphisms (SNPs) in pharmacologically relevant genes in collaboration with Dr. Mark Ratain. Thus, we feel that integrating these newer assessment tools, clinical assessment and pharmacology studies will provide a multi-disciplinary approach to more fully characterize investigational agents and recommend Phase II doses with a strong rationale.
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