XL019
Stage
Phase 1
Status
A phase 1 trial in patients with myeloproliferative disorders is ongoing.
Studies
Myeloproliferative disorders
Principal Targets
Proliferation, differentiation, cell migration and survival: JAK2
- Activating mutations of JAK2 occur frequently in a variety of myeloproliferative disorders including:
- polycythemia vera
- essential thrombocytosis
- idiopathic myelofibrosis
- JAK2 signaling is upregulated in several types of lymphoma and a number of solid tumors.
Preclinical Data
XL019 is a selective inhibitor of the cytoplasmic tyrosine kinase JAK2. JAK2 is activated by cytokine and growth factor receptors and phosphorylates members of the STAT family of inducible transcription factors. Activation of the JAK/STAT pathway promotes cell growth and survival, and is a common feature of human tumors. JAK2 is activated by mutation in the majority of patients with polycythemia vera and essential thrombocytosis and appears to drive the inappropriate growth of blood cells in these conditions. XL019 is a potent and selective JAK2 inhibitor with favorable pharmacodynamic properties and safety profile.
Clinical Data
Preliminary data from an ongoing Phase 1 dose-escalation trial of XL019 in patients with myelofibrosis, a myeloproliferative disorder, were presented at the American Society of Hematology (ASH) 49th Annual Meeting and Exposition in December 2007.
Unaudited data from cohort 1 (100mg), cohort 2 (200mg) and cohort 3 (300mg) were presented and the key findings by investigators include:
- Preliminary clinical activity observed in most subjects, including:
- Reduction in spleen size of 33 to 100% in five of six patients evaluated
- Reduction in erythropoietin-independent colony formation of up to 39% and up to 100% in two patients evaluated
- Relief of constitutional symptoms, including pruritus, fatigue, back pain and abdominal fullness
- Reduction in the number of cells with the JAK2 V617F mutation (allele burden)
- Correlation between XL019 exposure and decreased phosphorylation of STAT, a marker for JAK activity
- XL019 was generally well tolerated
- Adverse events included Grade 1 nausea, headaches, equilibrium imbalance, dizziness, chest discomfort, visual disturbances, fatigue and hypertension.
- Grade 2 AEs of lightheadedness and decreased sensation in soles and one serious adverse event of confusion in a patient with baseline history of dementia were also observed.
- No evidence of myelosuppression
The maximum tolerated dose has not been reached. The phase 1 dose escalating clinical trial continues.
About Myeloproliferative Disorders
Myeloproliferative disorders (MPDs) comprise a group of chronic hematologic malignancies including myelofibrosis, polycythemia vera and essential throbocythemia. These disorders are characterized by abnormally high or low red blood cell, white blood cell and platelet counts, enlarged sleen, and fibrotic changes in the bone marrow. Hydroxyurea and interferon alpha are frequently used in the treatment of MPDs, but both drugs are associated with significant side effects and have limited activity; thus patients with these disorders have few treatment options.
Mutations in the JAK2 kinase, a target of XL019, are common in MPDs, including polycythemia vera, essential thrombosis and idiopathic myelofibrosis.
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.
