XL880 (GSK089) ¹

Stage

Phase 2

Indications

Papillary Renal Cell Carcinoma, Gastric Cancer, Head and Neck Cancer

Principal Targets

Cell proliferation and migration: MET
Angiogenesis: VEGFR2, MET

MET is mutationally activated in hereditary papillary renal cell carcinoma and in some non-small cell lung tumors, activated or overexpressed in head and neck cancer, glioma, and other solid tumors, and amplified in a subset of gastric and lung cancers. MET also appears to cooperate with VEGF in the response of tumors to hypoxia.
VEGF and HGF (the ligand for MET) act cooperatively to stimulate angiogenesis.
In response to hypoxia, tumor cells upregulate VEGF to stimulate angiogenesis, and MET to promote survival and stimulate migration to better-oxygenated tissue. Dual targeting of MET and VEGFR2 therefore blocks two of the major mechanisms tumors use to overcome hypoxia.

Preclinical Data

XL880 has attractive pharmaceutical properties with high solubility and oral bioavailability and demonstrates nanomolar potency against its targets, which translates to potent activity in cellular assays. In preclinical studies, XL880 potently inhibited VEGFR2 and MET, including mutant activated forms of MET found in hereditary papillary renal carcinomas. The compound also demonstrated dose-dependent growth inhibition in tumor models of breast cancer, colorectal cancer, non-small cell lung cancer, and glioblastoma, and has been shown to cause substantial tumor regression in all models tested. Importantly, a single dose of XL880 completely inhibited tumor growth in a glioma model for 21 days. In addition, XL880 prolonged survival in an FLT3-driven leukemia model.

Clinical Data

Phase 2
Interim data from an ongoing phase 2 trial of XL880 in patients with papillary renal cell carcinoma (PRC) were reported most recently at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2007. As of October 10, 2007, a total of 21 patients were enrolled in this ongoing study: 5 with activating MET mutations and 16 with wild type MET.

As reported by the investigators:

Of 19 patients with measurable disease evaluable for tumor responses, 15 (79%) had a decrease in tumor size (4-33%), including one patient with a partial response.
All 19 evaluable patients with at least one post-baseline tumor assessment had stable disease for at least three months, including 12 patients with stable disease for 6 months to 15+ months.
Results of preliminary analyses of plasma biomarkers and tumor samples were consistent with inhibition of angiogenesis and proliferation, and an increase in apoptosis.

Sixteen patients were evaluable for safety endpoints:

The majority of adverse events (72%) related to XL880 were Grade 1, 21% were Grade 2, and 5% were Grade 3 or higher. The Grade 3 adverse events were hypertension in three patients.
There were no Grade 4 or 5 adverse events that were judged related to XL880 treatment.
A total of 15 serious adverse events in seven patients were reported, of which three were considered related to XL880 (two events of vomiting in one patient, and hypertension in another patient).

Eleven patients were available for pharmacodynamic analyses:

Statistically significant changes in PIGF, VEGF-A, sVEGFR2, and EPO, markers of anti-angiogenic activity, were observed following administration of XL880.
A potential plasma marker of MET inhibition, sMET, was statistically significantly increased in all 11 patients.
Pre- and post-XL880 tumor biopsies from one patient demonstrated growth inhibition and induction of apoptosis following XL880 administration.

View the abstract and poster

Preliminary pharmacokinetic analyses were consistent with results from the phase 1 trial as detailed below.

Phase 1
Comprehensive phase 1 data for XL880 were presented at the 43rd Annual Meeting of the American Society of Clinical Oncology in June 2007. The data presented were taken from two phase 1 studies of XL880 in patients with advanced solid tumors. One study evaluated an intermittent, weight-based dosing regimen and the other evaluated fixed daily dosing. Both studies included pharmacokinetic, pharmacodynamic, and tumor response analyses.

As reported by investigators:

Five partial responses (>30% tumor regression by RECIST) were observed, including three in papillary renal cell cancer, one in medullary thyroid cancer, and one in Hurthle cell thyroid cancer.
Tumor shrinkage of less than 30% or prolonged stable disease of greater than 3 months was observed in an additional 20 patients.
In a best response evaluation as determined by RECIST criteria, 39 of 45 patients in the combined phase 1 studies had either tumor regression or stable disease.
Histological analyses of tumor samples from four patients showed decreases in the phosphorylation of MET following administration of XL880. These decreases resulted in predicted downstream effects, including reduction of phosphorylated AKT levels and markedly increased tumor cell death. These effects were not observed in control samples of normal tissue obtained from the same patients.
Pharmacokinetic analyses showed that peak and average plasma concentrations of XL880 over 28 days were higher with intermittent dosing compared with daily dosing, reflecting the higher dose administered with the intermittent schedule and the compound's long half life.
XL880 was generally well tolerated, and reported side effects were treatable and reversible.
Dose-limiting toxicities included hypertension, dehydration, hand-foot syndrome, tumor hemorrhage, and elevation of liver enzymes and lipase. Most of the common reported side effects are consistent with previously identified effects associated with inhibition of VEGF signaling, such as hypertension and proteinuria. Elevations in liver function tests also were observed and considered possibly related to XL880.

View the poster

Updated data from the phase 1 daily-dosing trial were presented at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2007. Ten of 22 patients showed stable disease for at least three months. In a preliminary analysis of samples from 21 patients in this clinical trial, statistically significant anti-angiogenic pharmacodynamic marker changes have been detected, consistent with effects observed with other anti-angiogenic agents. This finding is also consistent with observed hypertension in these patients.

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.

Footnotes:
1 In December 2007, GSK exercised its option under a development and commercialization agreement between Exelixis and GSK to further develop and commercialize XL880 (GSK089). The transfer of the XL880 program occurred during the first quarter of 2008.