XL228 ¹
Stage
Phase 1
Status
A phase 1 trial of XL228 is ongoing in patients with chronic myelogenous leukemia (CML) and Philadelphia-positive acute lymphocytic leukemia (ALL).
Studies
Chronic Myelogenous Leukemia, Philadelphia-positive Acute Lymphocytic Leukemia and Advanced Malignancies
Principal Targets
Drug resistance: T315I mutant form of BCR-ABL
Cell growth and survival: BCR-ABL, IGF1R, SRC
- The BCR-ABL translocation (also known as the Philadelphia chromosome) results in constitutive activation of ABL kinase, which drives cell proliferation.
- The T315I BCR-ABL mutation is resistant to approved BCR-ABL inhibitors.
- SRC is a proto-oncogene that plays an important role in tumor angiogenesis, progression and metastasis.
- SRC kinases are activated and/or overexpressed in many tumors. Deregulation of SRC contributes to cell growth, survival and migration.
- IGF1R enhances cell growth and survival and is overexpressed in many solid tumors and hematological malignancies.
- Colon, breast, prostate, ovarian and hepatocellular tumors and multiple myeloma may be sensitive to IGF1R/SRC/FAK inhibition.
Preclinical Data
XL228 potently inhibits the T315I mutant form of ABL, which is resistant to inhibition by other targeted therapies approved for chronic myelogenous leukemia. 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 showed efficacy in a variety of solid tumor xenograft models.
About Chronic Myelogenous Leukemia
Chronic myelogenous leukemia (CML) is a form of leukemia characterized by unregulated growth of predominantly myeloid cells in the bone marrow and accumulation in the peripheral blood. CML typically results from a genetic abnormality known as the Philadelphia chromosome, which causes constitutive activation of the ABL tyrosine kinase. This causes malignant cells to proliferate and survive. CML cells initiate the process of maturation within the bone marrow but fail to complete it. As they accumulate, they crowd out other normal hematopoietic cells. This can lead to bleeding disorders, anemia and a reduced capacity to fight infection.
Because CML develops over a long period of time, the 5-year survival is close to 100%. Targeted therapies (imatinib and dasatinib) have radically changed the management of CML, resulting in high rates of proloned hematologic and cytogenetic remission. However, the long-term efficacy of currently approved BCR-ABL inhibitors is not yet known. Some mutant forms of BCR-ABL are associated with drug resistance, and the T315I mutation causes resistance to all approved BCR-ABL inhibitors. Patients with resistant disease have few treatment options. Preclinical data show that XL228 retains its activity against the T315I mutant form of BCR-ABL.
About Philadelphia-Positive Acute Lymphocytic Leukemia
Philadelphia-Positive Acute Lymphocytic Leukemia (Ph+-ALL) is a cancer of lymphoid cells ( a subset of white blood cells) within the bone marrow, and accounts for 20-30% of all adult ALL cases. ALL cells do not mature and differentiate, leading to rapid accumulation of malignant cells in the bone marrow and subsequent spread throughout the body. According to the American Cancer Society, untreated ALL can be lethal within a few months. While the BCR-ABL inhibitors imatinib and dasatinib have shown clinical benefit in the treatment of Ph+ALL, some mutant forms of BCR-ABL are resistant to these drugs. XL228 retains activity against a variety of mutant forms of BCR-ABL, including the T135I mutation, which confers resistance to imatinib and dasatinib.
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.
