The overall goal of this UO1 phase I application is to efficiently and safely conduct dose finding, pharmacological, and bio-marker evaluation clinical trials of novel anti-cancer agents from the NCI. Information from phase I studies will guide selection of optimal dose and schedule for further study. Most new anti-cancer agents are mechanism-based, have limited toxicities, limited single agent activity, and may be most effective in combination with other therapies, or in populations expressing a specific molecular target or targets. For successful development of such agents, it is essential to provide evidence that these agents hit the intended molecular targets in patients before moving these agents into full scale clinical development. It is also critical to better understand the physiological consequences of this effect in relation to the new agent's activity and toxicity early in clinical development. We propose the following specific aims: 1.To define and describe agents' dose limiting and non-dose limiting toxicities, and provide evidence of clinical activity. 2. To define the pharmacokinetic properties of novel agents, including absorption, distribution, metabolism, and elimination. We will evaluate the pharmacodynamic effect of these parameters on toxicity, efficacy, and target inhibition or stimulation. 3. To evaluate novel biomarker and/or imaging studies that will provide proof of principle for an agent's activity at the target level, and to correlate these with other clinical and pharmaco- kinetic /pharmacodynamic endpoints. 4. To define a phase II dose based upon all available toxicity, efficacy, PK, PD, imaging, and biomarker data. Since the novel agents that will become available in the NCI pipeline are not completely known at this time, we will focus our approaches on classes of agents for which we have both scientific expertise and a track record of productive translational clinical investigation, including, 1) agents targeting tumor angiogenesis; 2) agents targeting tumor or tumor-stromal growth factor inhibition; and 3) novel vaccine and other immunomodulatory agents. We are also expert in studying agents targeted to brain tumor patients for phase I agents. We anticipate 2-3 studies per year. We will emphasize single agent studies but can evaluate combinations of novel agents or with standard chemotherapeutics or radiation therapy. We will emphasize the development and use of correlative biomarker and imaging approaches. Our ex- pertise in phase I clinical trial, large patient base, clinical infrastructure, and depth in basic and translational cancer biology and pharmacology will allow us to efficiently accomplish the goals of this proposal.
| Gollob, Jared A; Rathmell, W Kimryn; Richmond, Tina M et al. (2007) Phase II trial of sorafenib plus interferon alfa-2b as first- or second-line therapy in patients with metastatic renal cell cancer. J Clin Oncol 25:3288-95 |
| Petros, William P; Evans, William E (2004) Pharmacogenomics in cancer therapy: is host genome variability important? Trends Pharmacol Sci 25:457-64 |
