XL228

Development Status

Phase 1 trials of XL228 are ongoing in patients with resistant chronic myelogenous leukemia (CML), and in patients with advanced malignancies.

Indications

Resistant CML
Advanced Malignancies

Principal Targets

Drug resistance: T315I mutant form of BCR-ABL
Cell proliferation and survival: BCR-ABL, IGF1R, SRC

• The T315I mutant form of BCR-ABL, which is resistant to approved BCR-ABL inhibitors, and BCR-ABL, IGF1R and SRC, are important for cell proliferation and survival.
• Tumors including colon, breast, prostate, ovarian, lung and hepatocellular tumors, as well as multiple myeloma, may be sensitive to inhibition of IGF1R and SRC.

Preclinical Data

XL228 potently inhibits the T315I mutant form of BCR-ABL, which is resistant to inhibition by other targeted therapies approved for CML. XL228 also targets IGF1R, which is a receptor tyrosine kinase that is highly expressed and activated in a broad range of human tumors and is thought to promote tumor growth, survival, and resistance to chemotherapeutic agents. XL228 exhibited activity in a variety of solid tumor xenograft models.

Clinical Data

Preliminary phase 1 data from a dose-escalation trial of XL228 in patients with advanced malignancies (solid tumors, lymphoma, or multiple myeloma) for which standard therapies are no longer effective were reported most recently at the American Society of Clinical Oncology Annual Meeting, in May 2009 in Orlando, Florida.

• The dose-escalation trial evaluated eight dose levels of XL228 (ranging from 0.45-8.0 mg/kg) administered once or twice weekly. Most of these patients had received multiple prior treatment regimens.
  • 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.
• 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. The study is now enrolling additional patients to the once weekly MTD cohorts, which includes subjects with colorectal cancer, multiple myeloma, and lung cancer.
  • 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).
• 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.

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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.