XL281 (BMS-908662)

Out-licensed to Bristol-Myers Squibb Company. Exelixis continues to conduct the ongoing phase 1 trial for XL281.

Development Status

A phase 1 trial of XL281 in patients with cancer is ongoing.

Indications

Cancer

Principal Targets

Cell proliferation: B-RAF, V600E mutant form of B-RAF, C-RAF

• RAF is a cytoplasmic serine/threonine protein kinase that is a direct down-stream effector of the RAS GTPase, and is an important component in the RAS/RAF/MEK/ERK (MAPK) signaling pathway.
• This pathway functions to transmit growth and survival signals from cell surface receptors and cytoplasmic signaling elements to the nucleus. Signal transduction through this pathway plays an important role in the proliferation and survival of tumor cells.

Preclinical Data

XL281 specifically targets RAF, a cytoplasmic serine/threonine kinase that lies immediately downstream of RAS and is a key component of the RAS/RAF/MEK/ERK pathway that is frequently activated in human tumors. Activating mutations in B-RAF occur in approximately 60 percent of melanoma patients indicating a potentially pivotal role for deregulation of this kinase in the progression of melanoma. XL281 is a potent and highly selective inhibitor of RAF kinases, is orally bioavailable, and showed activity in tumor xenograft models.

Clinical Data

Interim phase 1 data from a dose-escalation trial of XL281 in patients with advanced solid malignancies were reported most recently at the American Society of Clinical Oncology Annual Meeting, in May 2009.

• The study is evaluating daily oral dosing of XL281 on a 28-day cycle. Of 55 evaluable patients, one patient with ocular melanoma carrying the KIT M541L mutation had a confirmed PR and 19 patients remained on study for ≥ 12 weeks for a clinical benefit rate of 36%. This included patients with and without mutations in components of the RAS/RAF signaling pathway (including the mutations BRAF V600E, NRAS Q61R and KRAS G12S). 
• The majority of adverse events have been of Grade 1 or 2 severity and manageable.
  • Grade 3 adverse events were reported in 8 patients (3 fatigue, 3 vomiting two diarrhea and one each nausea and arthralgia).
  • There have been 2 cases of Grade 4 vomiting and 2 case of Grade 4 nausea.
  • Cutaneous squamous cell carcinoma or keratoacanthoma were reported in 4 subjects with histological confirmation pending in one subject.
  • Dose-limiting toxicities (DLTs) were reported at the maximum administered dose of 225 mg (Grade 4 nausea, Grade 3 fatigue, Grade 3 diarrhea and Grade 3 vomiting). No DLTs have been reported in any other cohorts, including the maximum tolerated dose of 150 mg.  Expansion of this cohort is currently ongoing.
• Pharmacodynamic analyses demonstrate robust pathway inhibition across diverse tumor types and independent of RAS/RAF genotype status, with decreases in biomarkers for pathway activity ranging from 40 to 85%. The investigators report that increasing pathway inhibition over time was observed in patients for whom serial hair samples were available.
• Pharmacokinetic analyses demonstrate that XL281 exposure increases with dose. Time to maximal plasma concentration was 2 hours and the half-life was approximately 8 hours. There was an approximately 1.5-fold accumulation of XL281 after repeated 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.