XL765

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) and mammalian target of rapamycin (mTOR)

Activation of the PI3K pathway is a frequent event in human tumors, promoting cell growth, survival, and resistance to chemotherapy and radiotherapy.
mTOR is frequently activated in human tumors and plays a central role in tumor cell growth.
mTOR can be activated via upregulation of PI3K, or via PI3K-independent mechanisms.

Preclinical Data

XL765 targets both PI3K and mTOR, key kinases in the PI3K signaling pathway. mTOR is a serine/threonine kinase that controls the protein translation machinery and hence cell growth. mTOR is activated by growth factors via PI3K and AKT, but is also activated in a PI3K-independent fashion in response to nutrient and energy levels. Hence, in some tumors targeting both PI3K and mTOR may provide additional benefit compared with selectively targeting PI3K. XL765 is a potent inhibitor of PI3K and mTOR and has shown attractive pharmacokinetic and pharmacodynamic properties and compelling efficacy in several preclinical xenograft models both as a single agent and in combination with chemotherapy.

Preclinical data presented at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2007 demonstrate that XL765 inhibits PI3K pathway signaling in cellular assays and in xenograft tumor models. In addition, administration of XL765 results in the inhibition of tumor growth and angiogenesis, and of tumor cell survival in xenograft models. XL765 is orally available, exhibits a 24-hour duration of action in pharmacodynamic studies, and is well tolerated at doses that exhibit anti-tumor activity. XL765 also enhances the apoptotic activity of chemotherapeutic agents (paclitaxel or carboplatin) in xenograft tumor models.

View the abstract and poster

Clinical Data

Interim results of an ongoing phase 1 trial of XL765 were presented at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2007. In this trial, XL765 is dosed twice daily in patients with metastatic or unresectable solid tumors for which known effective measures do not exist or are no longer effective. No dose limiting toxicities or adverse events related to XL765 were reported in the first two dose cohorts. Additional dose escalation is ongoing. Pharmacodynamic analyses suggest that there is a correlation between XL765 exposure and changes in plasma insulin levels, consistent with inhibition of PI3K. Additional pharmacodynamic studies in blood and hair samples from patients participating in the phase 1 trial are ongoing.

At AACR-NCI-EORTC, data also were reported from ex vivo studies evaluating potential biomarkers of XL765 activity in blood and hair samples donated from healthy volunteers. These studies indicate that reductions in the phosphorylation of PI3K pathway targets can be measured, and that these reductions may be used as biomarkers to assess XL765 activity. Additional evaluation of these potential biomarkers is ongoing.

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.