XL281

Stage

Phase 1

Status

A phase 1 trial of XL281 in patients with advanced solid tumors is ongoing.

Indications

Advanced Solid Tumors

Principal Targets

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

RAF kinases act downstream of RAS and are key components of the RAS/RAF/MEK/ERK kinase signaling pathway.
Genetic lesions that activate this pathway are common in human tumors, with activating mutations in K-RAS occurring in approximately 30 percent of tumors, and activating mutations in B-RAF occurring in approximately 60 percent of melanomas.

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

Preliminary phase 1 data from a dose-escalation trial of XL281 in patients (pts) with advanced solid malignancies were reported at the EORTC-NCI-AACR International Conference on Molecular Targets and Cancer Therapeutics, in October 2008 in Geneva, Switzerland.

In the trial, 29 pts have been enrolled in seven cohorts, with XL281 administered orally at doses ranging from 10 to 225 mg daily. Tumor types include colorectal cancer (N=7), papillary thyroid cancer (N=5), ovarian cancer (N=1), prostate cancer (N=1), carcinoid tumor (N=2), and melanoma (N=4).
As of October 3, 2008, one partial response (ocular melanoma) and 12 pts with stable disease (> 3 months) have been observed.
- Five pts with papillary thyroid cancer, two with a confirmed BRAF V600E mutation, have had stable disease (68, 64+, 53+, 26, 20 weeks, respectively).
- Three pts with colorectal cancer have had stable disease for 20 weeks, and two pts with carcinoid tumor have had stable disease (53+ and 22 weeks).
- One patient with Hurthle cell thyroid cancer and one with prostate cancer have had stable disease (31+ and 14 weeks, respectively).
The maximum administered dose (MAD) has been established as 225 mg and the maximum tolerated dose (MTD) as 150 mg.
- Dose-limiting toxicities (DLTs) were reported in 3 of 3 pts receiving an oral daily dose of 225 mg XL281. No DLTs were observed at any of the other dose levels.
- No Grade 4 or 5 adverse events (AEs) considered related to XL281 have been reported.
- Some subjects receiving XL281 at 150 mg (either as a starting dose or following dose escalation from a lower dose) developed fatigue and weight loss after Cycle 1 and required a dose reduction to 100 mg. In the majority of these cases, fatigue was rapidly reversible following dose reduction.

The most frequent treatment-related AEs have been Grade 1 or 2 fatigue, nausea, diarrhea, and vomiting.

Pharmacokinetic analyses indicated that for the 150 mg/day cohort, XL281 accumulated approximately 1.75-fold in plasma with repeated daily dosing, with steady state reached by approximately Day 8. XL281 plasma exposure increased with increasing dose, and exceeded levels associated with anti-tumor activity in preclinical models.
In pharmacodynamic analyses, substantial modulation of the BRAF signaling pathway was observed in tumor tissue, skin, and hair as indicated by decreases in the phosphorylation of MEK and ERK following treatment with XL281. A reduction in proliferation and an increase in apoptosis were observed in tumor tissue following treatment with XL281.

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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.