XL147

Stage

Phase 1

Status

A Phase 1 trial in patients with solid tumors is ongoing.

Studies

Solid Tumors

Principal Targets

Cell growth and survival: phosphoinositide-3-kinase (PI3K)

Activation of the PI3K pathway is a frequent event in human tumors, promoting cell growth, survival, and resistance to chemo- and radio-therapy.

Preclinical Data

XL147 selectively targets PI3K. Upregulation of PI3K activity is one of the most common characteristics of human tumor cells and can result from activation of growth factor receptors, mutational activation or amplification of the PI3K gene, activating mutations in the PI3K gene, downregulation of the phosphatase and tensin homolog (PTEN) lipid phosphatase or activating mutations in RAS. Activation of PI3K results in stimulation of AKT and mammalian target of rapamycin (mTOR) kinases, resulting in promotion of tumor cell growth and survival. This survival signal plays a significant role in conferring resistance to chemo- and radio-therapy by inhibiting apoptotic cell death.

Preclinical data presented at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2007 demonstrate that XL147 is a potent and selective inhibitor of Class I PI3K lipid kinases. In preclinical studies, XL147 blocks PI3K signaling in tumor cells in vitro, and exhibits dose-dependent and sustained inhibition of PI3K signaling in multiple human tumor xenograft models when administered as a single agent. These xenograft models also show a correlation between XL147 pharmacodynamic activity and increased apoptosis, inhibition of tumor cell proliferation, and inhibition of angiogenesis. Administration of XL147 in combination with various targeted and chemotherapeutic agents results in enhanced anti-tumor efficacy in multiple xenograft models over the corresponding single agents.

View the abstract and poster

Clinical Data

Interim results of an ongoing phase 1 trial of XL147 were presented at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2007. In this trial, XL147 is dosed daily for 21 days in a 28-day cycle in patients with metastatic or unresectable solid tumors for which known effective measures do not exist or are no longer effective. As of the time of the presentation, no dose limiting toxicities or adverse events related to XL147 have been reported and dose escalation continues. Plasma insulin is being evaluated as a potential circulating biomarker of PI3K inhibition, and potential biomarkers in other tissues are also under evaluation.

View the abstract and poster

Information on Clinical Trials

Information about ongoing clinical trials of Exelixis' investigational product candidates is available at ClinicalTrials.gov, a service of the U.S. National Institutes of Health. General information about clinical trials and issues related to participating in clinical trials also is available at ClinicalTrials.gov.

Related Publications

For publication information related to this compound, please see the Related Publications page.