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Pharmacodynamic Evaluation of CCI-779, an Inhibitor of mTOR, in Cancer Patients¹

The University of Texas Health Science Center at San Antonio [J. M. P., L. d., W. F., L. F., V. G., G. W., M. H.], and Institute for Drug Development, Cancer Therapy and Research Center [M. H.], San Antonio, Texas

CCI-779 is an ester of rapamycin and inhibitor of mammalian target of rapamycin (mTOR) currently in Phase II clinical development for the treatment of patients with cancer. CCI-779 interacts with mTOR and inhibits its kinase activity, resulting in inhibition of the mTOR-regulated translational controllers p70^s6 kinase and 4E-BP1. Ultimately, CCI-779 decreases the translation of mRNAs involved in the control of the cell cycle, resulting in cell cycle arrest. The objective of this study was to develop a method to determine the pharmacodynamic effects of CCI-779 suitable for use in clinical trials. Exposure of Raji lymphoblastoid cells to increasing concentrations of rapamycin resulted in a linear concentration-dependent inhibition of p70^s6 kinase activity, suggesting that p70^s6 kinase activity could be an appropriate marker for mTOR-interacting agents. In subsequent experiments, treatment of nude mice bearing the CCI-779 susceptible breast cancer cell line MDA-468 with a single dose of 10 mg/kg CCI-779 resulted in a >80% inhibition of p70^s6 kinase activity in peripheral blood mononuclear cells (PBMCs) 72 h after treatment. Importantly, the degree of p70^s6 kinase inhibition was identical in PBMCs and simultaneously collected tumor tissue, suggesting that the PBMCs are an adequate surrogate tissue for p70^s6 kinase activity in vivo. The intrasubject coefficient of variation of p70^s6 kinase activity measured in PBMCs collected from five healthy volunteers on days 1, 4, and 8 was 14%, indicating that p70^s6 kinase activity in PBMCs remains relatively stable over time. Finally, p70^s6 kinase activity was measured in PBMCs from nine patients with renal cell cancer treated with a single dose of 25, 75, or 250 mg of CCI-779 i.v. (three patients each). PBMCs were collected on days 2, 4, and 8 after CCI-779 treatment. In this small data set, eight of the nine patients had evidence of p70^s6 kinase activity inhibition after treatment that was independent of the administered dose. There was a significant linear association between time to disease progression and inhibition of p70^s6 kinase activity 24 h after treatment. In conclusion, these results indicate that the pharmacodynamic effects of CCI-779 can be determined using a p70^s6 kinase assay in PBMCs. This assay is currently being incorporated in Phase I and II studies with CCI-779 to determine its relationship with dose and plasma concentration of the agent and its value as a predictor of treatment efficacy.

Commentary

Immunophilins, mTOR, and Pharmacodynamic Strategies for a Targeted Cancer Therapy: Commentary re: J. M. Peralba et al., Pharmacodynamic Evaluation of CCI-779, an Inhibitor of mTOR, in Cancer Patients. Clin. Cancer Res., 9: 2887–2892, 2003.

Matthew W. Harding
Clin. Cancer Res. 2003 9: 2882-2886. [Full Text] [PDF]

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