XL820

Stage

Phase 2

Status

A phase 2 trial of XL820 in patients with gastrointestinal stromal tumor (GIST) is ongoing.

Indications

GIST

Principal Targets

Cell proliferation: KIT, PDGFR
Angiogenesis: VEGFR2, PDGFR

KIT is activated by mutation in many patients with GIST, and as a result, GIST patients are highly responsive to KIT inhibitors. KIT is also frequently activated by mutation in some subtypes of melanoma.
VEGFR2 is a potent stimulator of tumor angiogenesis.
PDGFR contributes to the development or stabilization of new tumor vasculature and also plays a role in cancer cell proliferation. Furthermore, activating mutations in PDGFR have been associated with GIST in some patients.

Preclinical Data

XL820 inhibits KIT as well as VEGFR2 and PDGFR, clinically validated targets implicated in a variety of human cancers. In tumor models of breast carcinoma, glioma, and leukemia, the compound exhibited dose-dependent growth inhibition and has been shown to cause tumor regression. XL820 demonstrated excellent activity in target-specific cellular functional assays. In biochemical and cellular assays, XL820 potently inhibits mutant forms of KIT that confer resistance to approved KIT inhibitors. XL820 has good oral bioavailability and has shown sustained inhibition of target RTKs in vivo following a single oral dose.

Clinical Data

Interim data from an ongoing phase 1 clinical trial of XL820 in patients with advanced solid tumors were reported most recently at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2007.

The study evaluated five dosing regimens: 200 mg, 400 mg, 800 mg, or 1,600 mg dosed once daily (QD), and 300 mg dosed twice daily (BID). Twenty-two patients had enrolled in the study as of August 15, 2007.

Three patients (bladder cancer, sarcoma, parotid gland cancer) had stable disease for 16 weeks. In addition, modulation of biomarkers in hair and plasma after administration of XL820 is consistent with targeting of KIT and VEGFR2 in some patients.

Safety data from 15 patients demonstrate that the compound is generally well tolerated. The most common treatment-related adverse events were nausea, fatigue, diarrhea, and vomiting.
Dose-limiting toxicities of Grade 3 nausea and Grade 3 fatigue in one patient at 1600 mg QD and in one patient at 300 mg BID, respectively, were observed.
The maximum tolerated dose has not been reached in the BID regimen. There is no evidence that the 300 mg BID cohort (i.e., 600 mg/day) yields a significant difference in cumulative exposure compared to the 400 mg and 800 mg QQD cohorts (based on limited data).

View the abstract and poster

Data from in vitro analyses also were presented at AACR-NCI-EORTC. These data demonstrate that XL820 is an effective inhibitor of KIT proteins that contain mutations associated with melanoma or with acquired resistance to imatinib and sunitinib in patients with GIST. These data support the phase 2 exploration of XL820 in metastatic melanoma and recurrent GIST, cancers that are associated with KIT activation.

View the abstract and poster

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.