XL147

Co-developed with sanofi-aventis.

Development Status

A phase 1b/2 trial of XL147 in combination with erlotinib in non-small cell lung cancer (NSCLC) patients is ongoing.

A phase 1b/2 trial of XL147 in combination with paclitaxel/carboplatin in patients with solid tumors is ongoing.

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

Indications

NSCLC+erlotinib
Solid tumors+paclitaxel/carboplatin
Solid Tumors

Principal Targets

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

PI3K plays an important role 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..

XL147 Targets

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 PI3Ka 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 most recently at the American Society of Clinical Oncology Annual Meeting, in June 2009.

The study is evaluating a 28-day dosing cycle with either an intermittent dosing schedule (21 days on/7 days off; doses from 30 mg to 900 mg) or a continuous daily dosing (CDD, doses of 100 mg and 400 mg) schedule. Most patients’ cancer had progressed following treatment with multiple regimens. Sixteen of 43 (37%) evaluable patients including 5 of 13 (38%) patients with non-small cell lung cancer (NSCLC) had remained on study for 12 or more weeks.
Three of the patients with NSCLC were progression-free for more than 6 months. One of these NSCLC patients had a partial response with a 33% reduction in the size of their target lesion. This patient had previously received four prior treatment regimens and has remained on study with XL147 for more than 70 weeks.
Adverse events have generally been of Grade 1 or 2 severity and manageable.
- Skin rash was reported in 12 patients and was Grade 1 or 2 in eight patients. Four patients in the 21 days on/7 days off dosing schedule experienced dose-limiting Grade 3 rash (1 patient each in the 400 and 600 mg cohorts, and 2 patients in the 900 mg cohorts).
- Other frequent adverse events reported included fatigue (25%) and cough (22%).
  
  The maximum tolerated dose (MTD) for the 21 days on/7 days off dosing schedule is 600 mg. No dose-limiting toxicities have been reported for the 100 and 400 mg cohorts on the CDD schedule, and additional patients are being enrolled.
Pharmacodynamic analyses demonstrated substantial reductions in biomarkers of PI3K pathway signaling in multiple tumor types across a range of well-tolerated doses. These analyses also demonstrated 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 and skin, with robust pathway inhibition noted in samples at the lowest doses administered in the study (30-60 mg 21 days on/7 days off). Target inhibition appeared to be exposure-dependent, and was progressive with time in cases where serial samples were obtained.
Pharmacokinetic analyses demonstrate that XL147 exposure increased dose-proportionally over 24 hours from 30 to 400 mg on the 21 days on/7 days off dosing schedule. Exposures were similar at the 400, 600 and 900 mg doses. Repeated dosing of XL147 resulted in a 5- to 13-fold accumulation, and steady-state levels were reached 15 to 21 days after initiation of dosing.

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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.