Pharmacodynamic-guided Dose-finding Study of Rapamycin

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DESCRIPTION (provided by applicant): mTOR, a serine-threonine kinase involved in the phosphatidyl-inositol kinase (PI3K)/Akt signaling pathway, is a key regulator of cell growth, proliferation, and survival. Aberrant signaling through mTOR is a frequent alteration in cancer and represents a strategic target for anticancer drug development. Currently, there are several mTOR inhibitors in clinical development for cancer treatment with promising results. Rapamycin is the prototypal mTOR inhibitor, which is currently approved for the prevention of graft rejection in recipients of solid organ transplants. In preclinical models, rapamycin exerts antitumor effects including inhibition of cell cycle progression, induction of apoptosis, and inhibition of angiogenesis suggesting that it should be tested as an anticancer drug. The long-term goal of our research team is to develop rapamycin as an anticancer agent. In this research application we propose a phase I study of rapamycin in patients with advanced cancer as the first step towards this goal. The proposed research is based on the hypothesis that rapamycin will only be effective as an anticancer drug if tolerable doses efficiently inhibit its target in tumor tissues. In the application we proposed a pharmacodynamic-guided dose finding study of rapamycin in patients with advanced solid tumors. In Specific Aim # 1 we will estimate a pharmacodynamic active dose of rapamycin in cancer patients. To this end we will measure activation of S6 kinase, a downstream mediator of mTOR function, in peripheral blood mononuclear cells (PBMC) as the pharmacodynamic endpoint based on our prior experience with mTOR inhibitors and will utilize a modified continuous reassessment method (mCRM) adapted for a pharmacodynamic endpoint to optimize dose escalation and dose selection in a phase I dose-finding study. In Specific Aim # 2 we will confirm that the dose selected in Specific Aim # 1 is effective in inhibiting S6K activity in pair tumor biopsies. Overall this study will determine the biologically active dose of rapamycin in cancer patients that can then be explored in disease-oriented studies.