XL765

Co-developd with sanofi-aventis.

Development Status

A phase 1b/2 trial of XL765 with temozolomide in glioblastoma patients is ongoing.

A phase 1b/2 trial of XL765 with erlotinib in non-small cell lung cancer (NSCLC) patients is ongoing.

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

Indications

Glioblastoma+temozolomide
NSCLC+ erlotinib
Solid Tumors

Principal Targets

Cell proliferation and survival: phosphoinositide-3-kinase (PI3K) and mammalian target of rapamycin (mTOR)

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

XL765 Targets

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 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.

View poster

Clinical Data

Interim data from a phase 1 dose-escalation trial of XL765 that is being carried out in patients with metastatic or unresectable solid tumors for which known effective measures do not exist or are no longer effective were reported most recently at the American Society of Clinical Oncology Annual Meeting, in June 2009.

The study is evaluating continuous daily dosing of XL765 administered once or twice daily. Six of 50 patients were on study for approximately 16 or more weeks. Four of these 6 patients, including 1 patient each with appendiceal, rectal, and colon cancer with KRAS mutations in their tumors, were on study for 24 weeks or more. Most patients had previously received multiple treatment regimens.
Adverse events have generally been of Grade 1 or 2 severity and manageable.
- The most frequently occurring adverse events were: nausea (all incidences, 36%; Grade3/4, 4%), diarrhea (32%; 0%), fatigue (28%; 6%), anorexia (26%; 4%), vomiting (22%; 2%) and transaminase increase (22%; 6%).
- For the twice-daily dosing schedule, the preliminary maximum tolerated dose (MTD) has been established at 50 mg, and additional patients are being enrolled in this dose cohort.
- The daily dosing schedule is currently evaluating a 90 mg dose and a preliminary MTD has not yet been determined.
Pharmacodynamic analyses demonstrate substantial reductions in biomarkers of PI3K and mTOR activity in multiple tumor types. These analyses also demonstrate inhibition of the ERK signaling pathway in tumors, in contrast to the induction of this pathway observed with inhibitors that selectively target TORC1.
Pharmacodynamic target modulation was also observed in hair, skin, and blood samples, with robust pathway inhibition noted in samples at the lowest dose administered in the study (15 mg twice daily).
Pharmacodynamic effects in peripheral blood cells exhibited an exposure-dependent trend, while data from serial hair samples suggest that inhibition is progressive in a time-dependent manner.
The pharmacodynamic effects observed in blood cell and skin samples were comparable between the daily and twice-daily dosing schedules.
XL765 had a small but significant effect on fasting plasma insulin levels after multiple doses, but had minimal to no effect on glucose levels.
Pharmacokinetic analyses indicate that the maximal concentration and exposure of XL765 increased with dose. Repeated dosing of XL765 resulted in low to moderate accumulation.

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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.