XL147

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)

• Activation of the PI3K pathway is a frequent event in human tumors, promoting cell proliferation, survival, and resistance to chemotherapy and radiotherapy.

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, 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 proliferation and survival. This survival signal plays a significant role in conferring resistance to chemotherapy and radiotherapy 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 activity in multiple xenograft models over that observed with the corresponding single agents.

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Clinical Data

Interim data from a phase 1 dose-escalation trial of XL147, 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 30 pts available for safety, pharmacokinetic, and tumor response analyses.
  • Pts have been treated with XL147 across seven dose levels, ranging from 30 mg to 900 mg daily, on 28-day cycles with a 21 days on/7 days off schedule.
  • Of 23 evaluable subjects, 8 had achieved prolonged stable disease (> 3 months), 2 of whom are currently on study and 6 of whom subsequently progressed.
• Administration of XL147 at doses up to 600 mg has been generally well tolerated. The maximum tolerated dose (MTD) has not yet been established.
  • One event of Grade 3 study drug-related dose-limiting toxicity (DLT) was reported in 1 of 3 pts at 600 mg. That cohort was expanded and no further DLTs were observed.
  • Two events of Grade 3 study drug-related skin rash occurred in 2 of 3 subjects at 900 mg, which was determined to be the maximum administered dose (MAD).
  • The most common treatment-related adverse events were skin rash and Grade 1 nausea.
  • A total of 5 serious adverse events were reported in 4 pts, but none of these was considered to be related to XL147 treatment.
• Results from pharmacodynamic analyses indicate that XL147 inhibits the PI3K pathway in pts at well-tolerated doses.
  • Reductions of 70-80% in phosphorylation of PI3K pathway components including AKT, PRAS40, and S6 were observed in tumor tissues from 2 pts (leiomyosarcoma and Merkel cell carcinoma) at the 600 mg dose level. Reductions in similar end points were also observed in surrogate tissue (hair and skin) samples from pts, but to a lesser extent than observed in tumor tissue.
  • Inhibition of PI3K pathway signaling was generally exposure-dependent. The pattern of inhibition of protein phosphorylation observed in tissue is consistent with observations from preclinical studies, and suggests that XL147 inhibits PI3K in pts.

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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.