XL765

Stage

Phase 1

Status

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

Indications

Advanced Solid Tumors

Principal Targets

Cell proliferation 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 proliferation, survival, and resistance to chemotherapy and radiotherapy.
mTOR is frequently activated in human tumors and plays a central role in tumor cell proliferation.
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 proliferation. 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 anti-tumor activity 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 durable activity 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.

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Clinical Data

Interim data from a phase 1 dose-escalation trial of XL765 is being carried out in patients (pts) with metastatic or unresectable solid tumors for which known effective measures do not exist or are no longer effective were reported at the EORTC-NCI-AACR International Conference on Molecular Targets and Cancer Therapeutics, in October 2008 in Geneva, Switzerland.

As of October 1, 2008 there were 29 pts available for safety, pharmacokinetic, and tumor response analyses.
- Five of 28 evaluable pts with various cancers had achieved stable disease (>3 months), including 2 pts (appendiceal carcinoma and mesothelioma) with stable disease lasting 7 months or longer.
XL765 is orally administered on 28-day cycles at dose levels of 15, 30, 50, 60, and 120 mg twice a day (BID) and 100 mg once a day (QD). The maximum tolerated dose (MTD) has not yet been established and dose ranging is ongoing to establish the MTD for both BID and QD dosing regimens.
- XL765 was generally well tolerated at 30 mg BID, with the most common adverse events (AEs) being gastrointestinal-related toxicities.
- Four dose-limiting toxicities have occurred at higher doses: one event of hypophoshatemia and anorexia at the maximum administered dose (MAD) of 120 mg BID, and one event each of Grade 2 nausea/vomiting, Grade 2 diffuse rash, and Grade 2 ALT increase at 60 mg BID. At 100 mg QD, one event of non-specific neurologic complaints occurred.
- Serious adverse events (SAEs) have been reported for 5 subjects, with one Grade 4 increase in hepatic transaminases being considered study-related. Two study drug-related events of Grade 3 elevated hepatic transaminases have been reported at 120 mg BID.
- The most common study drug-related AEs were Grade 1 or 2 nausea, diarrhea, and increase in ALT/AST.

Pharmacodynamic analyses indicate that XL765 inhibits the PI3K/mTOR pathway in pts at well-tolerated doses.
- Reductions of 80-90% in the phosphorylation of pathway components including AKT, 4EBP1, and S6, and a reduction of 54% in cell proliferation (as assessed by Ki67 staining) were observed in tumor tissue from a patient with chondrosarcoma at the 60 mg BID dose level.
- Reductions in the phosphorylation of these pathway components in surrogate tissues, including hair, skin, and peripheral blood mononuclear cells, were observed at doses as low as 15 mg BID.
- The pattern of inhibition of protein phosphorylation observed in these tissues is consistent with observations from preclinical studies, and suggests that XL765 inhibits PI3K and both mTOR/raptor and mTOR/rictor in pts. Some of the pharmacodynamic effects occurred in an exposure-dependent fashion, and comparable PI3K pathway inhibition was observed in both the 100 mg QD and 60 mg BID cohorts.

XL765 administration also resulted in the augmentation of food-induced changes in plasma insulin in an exposure-dependent fashion, but generally had no effect on plasma glucose levels. PI3K is known to play a key role in insulin signaling, and PI3K inhibition has been shown to increase insulin levels in preclinical models.

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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.