XL999 ¹ ² ³

Stage

Phase I

Status

In the third quarter of 2006 we received new data that impacted the Phase II trials for XL999. Although there were encouraging signs that XL999 has the potential to provide benefit to patients with lung cancer and acute myelogenous leukemia our internal safety monitoring board became concerned with the frequency of cardiovascular events experienced in October by patients in the program, and by November 1, we suspended enrollment in all XL999 trials pending collection and analysis of further data.

In April 2007, Exelixis was notified that the U.S. Food and Drug Administration (FDA) has completed its review of a clinical trial protocol for XL999 in patients with non-small cell lung cancer (NSCLC) and has agreed that the trial may be initiated.

This clinical trial will evaluate XL999 in patients with NSCLC who have failed at least one previous therapy. The trial will have a dose-escalation format starting at 0.4 mg/kg dosed weekly, while monitoring patients for potential cardiovascular events. Results from this Phase 1 clinical trial could provide Exelixis with the opportunity to move directly into a late stage clinical trial if XL999 demonstrates anti-tumor activity with an acceptable side-effect profile in this well-defined NSCLC patient population. Exelixis expects to begin enrolling patients in this trial during the summer of 2007.

Studies

Non-Small Cell Lung Cancer

Principal Targets

Angiogenesis: FGFR, VEGFR, PDGFR

Cell growth: FGFR, FLT3, KIT, PDGFR, RET

VEGF/VEGFR is a potent stimulator of tumor angiogenesis and a validated target for cancer therapy.
PDGFR and FGFR contribute to the development or stabilization of new tumor vasculature and also play a role in cancer cell proliferation.
FGFR3 is highly expressed in some multiple myeloma patients, and inhibition of FGFR3 suppresses growth and/or survival of multiple myeloma cells grown in culture or in xenograft models.
FLT3 is an important driver of leukemia cell proliferation in patients with acute myelogenous leukemia.
RET is mutationally activated in hereditary forms of medullary thyroid cancer and in sporadic forms of both medullary and papillary thyroid cancer.

Preclinical Data

XL999 is a potent inhibitor of key receptor tyrosine kinases implicated in the development and maintenance of tumor vasculature and in the proliferation of some tumor cells. It inhibits FGFR1, FGFR3, RET, VEGFR2 and PDGFR, and is also a potent inhibitor of FLT3, an important driver of leukemia cell proliferation in some patients with acute myelogenous leukemia (AML). XL999 exhibited excellent activity in target-specific cellular functional assays.

Clinical Data

Data from a Phase I trial of XL999 in patients with advanced solid tumors dosed every two weeks or weekly were reported at the 18th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in November 2006.

As of October 1, 2006, 45 patients had been enrolled and reported on in the Phase I trial and were evaluable for safety and tumor response assessments. Three dosing regimens were studied: weight based bi-weekly, weight based weekly, and fixed dose weekly dosing. Of these patients, 23 received weight-based dosing of XL999 administered every 2 weeks, with a maximum tolerated dose (MTD) established at 3.2 mg/kg; 15 patients received weekly weight-based dosing of XL999 (seven patients at 3.2 mg/kg and eight at 2.4 mg/kg); and seven patients received a weekly fixed dose of 200 mg XL999.

Three patients had partial responses (one each squamous cell cancer in the liver, renal cell cancer and thyroid cancer [unconfirmed]). Ten other patients have had stable disease for 3 to 25.5+ months (thyroid cancer [2], renal cell carcinoma [2], and one each cystoid adenoma, esophageal cancer, gastrointestinal stromal tumor, colorectal cancer, carcinoid and hepatocellular carcinoma).

The weekly weight-based and fixed dose safety characteristics of XL999 have been similar in nature but less severe at lower doses than previously reported for the bi-weekly dosing regimen (Papadopoulos et al, 2005, Proceedings of the 17th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics). The reported dose-limiting toxicity at 6.4 mg/kg for the bi-weekly dosing regimen was fatal cardiac failure and elevated transaminases. In the weekly weight-based dosing cohorts at 3.2 mg/kg, one patient developed a reversible decrease in left ventricular ejection fraction, elevated troponins, and ECG changes on day 1, and another patient treated at 2.4 mg/kg had asymptomatic grade 1 hypotension with nonspecific ECG changes. At weekly 200 mg fixed dosing, serious adverse events considered related to study drug include one patient with grade 3 hypotension, grade 3 ECG changes, and grade 3 increased troponin, and one patient with grade 2 cardiac failure, grade 2 ECG changes, grade 3 dyspnea, and grade 3 increased troponin. All cardiac events occurred with the first dose of XL999.

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 XL880, XL820, XL184, XL844, XL999, XL281, XL418 and XL228.
2 Out-licensed to Symphony Evolution, Inc. and subject to a repurchase option.
3 Received U.S. Food and Drug Administration approval to initiate a Phase I clinical trial with non-small cell lung cancer.