Public HealthExelixis Reports Encouraging Phase 1 Data To Be Presented At ASCO For XL228, A Multi-Targeted Inhibitor Of Key Cancer Signaling Kinases
Exelixis, Inc. (Nasdaq: EXEL) today reported encouraging data from an ongoing Phase 1 dose-escalation trial of XL228 in patients with advanced malignancies. XL228 is a small molecule inhibitor of insulin-like growth factor type 1 receptor (IGF1R), SRC, Aurora kinases, and fibroblast growth factor receptor types 1, 2, and 3 (FGFR1-3), which are associated with cancer cell proliferation, survival, and metastasis. The compound also inhibits BCR-ABL, including the T315I mutant form which is resistant to currently approved inhibitors. David Smith, MD, Professor of Medicine at the University of Michigan, an investigator on the Phase 1 trial, will present the data in an oral session (Abstract #3512) beginning at 4:15 p.m. local time on Saturday, May 30, 2009, at the American Society of Clinical Oncology Annual Meeting, which is being held May 29-June 2 in Orlando.
"The data from this ongoing Phase 1 study are encouraging with respect to both clinical and pharmacodynamic activity and safety," said Michael M. Morrissey, Ph.D., president of research and development at Exelixis. "A confirmed partial response in a patient with NSCLC and an additional 30% of patients remaining on study for 12 or more weeks suggest that XL228 may provide clinical benefit to cancer patients with no other options. Additionally, the clinical pharmacodynamic data are consistent with preclinical results indicating that XL228 effectively inhibits multiple targets that play key roles in various malignancies."
The dose-escalation trial evaluated eight dose levels of XL228 (ranging from 0.45-8.0 mg/kg) administered once or twice weekly. Of 40 evaluable patients, 1 patient with non-small cell lung cancer, whose cancer had progressed after 5 prior treatment regimens, had a confirmed partial response and was on study for 48 weeks. Twelve additional patients (30%) were on study for 12 or more weeks, including 2 patients (1 with small cell lung cancer and 1 with colorectal cancer) on study for more than 12 months, and 3 patients (1 with pancreatic cancer, 1 with leiomyosarcoma, and 1 with colorectal cancer) on study for more than 6 months. Most of these patients had received multiple prior treatment regimens.
Adverse events have generally been of Grade 1 or 2 severity and manageable. Three serious drug-related adverse events have been reported: 1 patient with Grade 3 vomiting, 1 patient with Grade 2 hypotension and bradycardia, and 1 patient with Grade 3 diarrhea. In the once weekly dosing schedule, dose-limiting toxicities (DLTs) were observed in 2 of 5 patients in the 8.0 mg/kg cohort (Grade 3 and Grade 4 neutropenia), which established 6.5 mg/kg as the maximum tolerated dose (MTD) for weekly dosing. At this MTD, 1 of 6 patients experienced a DLT of Grade 3 hyperglycemia. In the twice weekly dosing schedule, 2 of 6 patients receiving the maximum administered dose (2.7 mg/kg twice weekly) experienced DLTs (1 patient with Grade 4 neutropenia, and 1 patient with Grade 3 neutropenia, Grade 3 anemia, and Grade 2 thrombocytopenia). The study is now enrolling additional patients to the once weekly MTD cohorts, which includes subjects with colorectal cancer, multiple myeloma, and lung cancer.
Pharmacodynamic assessments demonstrated substantial inhibition of IGF1R, SRC, Aurora B, and FGFR1 signaling in tumor samples from patients with small cell and non-small cell lung cancer. Analyses of peripheral blood cells, hair, and skin also revealed consistent pathway inhibition in these tissues after administration of XL228. Transient modulation of glucose and insulin, which can be attributed to inhibition of IGF1R and insulin receptor signaling, was observed and resulted in mild to moderate (Grade 1/2) asymptomatic hyperglycemia, which resolved within a few hours.
Pharmacokinetic analyses indicate that exposure to XL228 increases with dose. Minimal accumulation was observed after repeat dosing.
About XL228
XL228 is a small molecule protein kinase inhibitor with potent activity against IGF1R, SRC, FGFR1-3, and the Aurora kinases. IGF1R is commonly activated in neoplastic growth and contributes to cell proliferation, cell survival, and resistance to cytotoxic agents. SRC is a mediator of cell migration and invasion, key aspects of the metastatic phenotype. FGFR1-3 play important roles in tumor growth and angiogenesis. Aurora kinases control crucial steps in mitotic progression and cytokinesis. XL228 also inhibits BCR-ABL, including the T315I mutant form which is resistant to currently approved BCR-ABL inhibitors. XL228 has exhibited potent pharmacodynamic and anti-tumor activity in a variety of solid tumor xenograft models.
Exelixis