XL184 ¹

Stage

Phase 1

Status

A phase 1 trial of XL184 in patients with solid tumors for whom there are no available therapies known to prolong survival is ongoing.

Studies

Solid Tumors

Principal Targets

Cell growth and migration: MET, RET
Angiogenesis: MET and VEGFR

MET is mutationally activated in hereditary papillary renal cell carcinoma and in some non-small cell lung cancer tumors; activated or over-expressed in head and neck cancer, glioma, and other solid tumors; and amplified in a subset of gastric and lung cancers.
VEGF and HGF (the ligand for MET) act synergistically 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.
RET is mutationally activated in hereditary forms of medullary thyroid cancer and in sporadic forms of both medullary and papillary thyroid cancer.

Preclinical Data

XL184 inhibits VEGFR2, MET and RET, key drivers for tumor formation, growth and migration. The compelling preclinical efficacy of XL880, our first VEGFR2/MET inhibitor, increased our interest in inhibitors of these receptor tyrosine kinases and resulted in the discovery and development of XL184 as an additional compound with potent MET/VEGFR2 inhibitory activity. XL184 has demonstrated dose-dependent tumor growth inhibition and tumor regression in a variety of tumor models including breast, colon, small cell lung cancer and glioblastoma.

Clinical Data

Interim data from an ongoing phase 1 clinical trial of XL184 in patients with solid tumors for whom there are no available therapies were reported at the 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO) in June 2007 and most recently at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2007. For the EORTC presentation, there were 33 patients available for safety, pharmacokinetic and tumor response analyses as of the June 22, 2007 cutoff; further data were also provided for six additional patients after the cutoff. As reported by the investigators:

Anti-tumor activity has been observed in a variety of cancers at doses that are not associated with significant toxicity.
Of seven patients with medullary thyroid cancer (MTC), three have had partial responses (2 confirmed and 1 unconfirmed).
- Six of the seven patients had tumor shrinkage and one had non-measurable disease.
- All seven assessable patients with MTC experienced a rapid decrease in plasma levels of calcitonin, a marker frequently elevated in MTC.
- Six of the seven patients had a decrease in the tumor marker carcinoembryonic antigen.
- All seven MTC patients remain on study.
One patient with a neuroendocrine tumor has an unconfirmed partial response.
In total, 15 patients with various malignancies have had stable disease lasting from 3 to 20 months, including nine patients with stable disease for more than six months.
To date, five dose-limiting toxicities (DLTs) have been reported:
- Grade 3 palmar/plantar erythema (hand-foot syndrome)
- Grade 3 AST elevation
- Grade 3 ALT elevation
- Grade 3 lipase elevation in patients dosed at 11.52 mg/kg (intermittent dosing schedule)
- Grade 2 mucositis in a patient dosed at 265 mg (daily dosing schedule)
Serious adverse events (AEs) considered possibly or probably related to XL184 include one report each of Grade 3 fatigue and Grade 3 pulmonary embolism.
Preliminary analyses of pharmacodynamic samples show changes in VEGF-A, sVEGFR2 and PIGF consistent with effects observed with other antiangiogenic agents.
Preliminary pharmacokinetic analyses of nine dose levels (0.08-11.52 mg/kg) indicate a long half-life of XL184 of 59 to 136 hours.

View the poster

Dose escalation continues in order to determine a maximum tolerated dose (MTD).

About Non-Small Cell Lung Cancer

According to the American Cancer Society, lung cancer is the leading cause of cancer death in both men and women. More than 213,000 new cases of lung cancer are anticipated in 2007. The American Association of Cancer Research estimates that 80-90% of lung cancers are non-small cell lung cancer (NSCLC). Localized cancers are treated with surgery. In patients with early-stage NSCLC, chemotherapy following surgery appears to improve survival. Chemotherapy, radiation therapy and targeted therapies such as erlotinib or gefitinib are typically used to treat later-stage disease. Current data indicate that the 1-year survival rate for all lung cancers is 42%; 5-year survival is only 16%.

Inhibition of signaling through the VEGF pathway, a target of XL184, is a validated approach to treating NSCLC. Amplification of MET, another target of XL184, has been shown to play an important role in the development of resistance to EGFR inhibitors in NSCLC. Dual inhibition of both MET and VEGFR may block two pathways known to contribute to the pathogenesis of NSCLC, and may result in enhanced therapeutic benefit over currently approved targeted therapies for the disease.

About Medullary Thyroid Cancer

The American Cancer Society estimates that medullary thyroid cancer (MTC) accounts for 5% of all thyroid cancers. MTC occurs in sporadic and inherited forms (approximately 80% and 20% of MTC, respectively). The inherited form usually appears at a younger age, while dietary iodine deficiency and radiation exposure are risk factors for the sporadic form. MTC may metastasize to lymph nodes or other organs before it is ever diagnosed. Additionally, MTC does not take up radioactive iodine, which is commonly used to treat other types of thyroid cancers and diagnose metastases. As a result, MTC is more difficult to treat than other thyroid cancers. Common treatments for MTC include surgery to remove malignant tissue, radiation therapy and chemotherapy, all of which are associated with potential side effects, some of which may be long-term.

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 Pursuant to a product development and commercialization agreement between Exelixis and GlaxoSmithKline, GlaxoSmithKline has the option, after completion of proof-of-concept by Exelixis, to elect to develop up to three compounds in the Exelixis pipeline including XL820, XL184, XL844, XL281 and XL228.