XL228

Stage

Phase 1

Status

Phase 1 trials of XL228 are ongoing.

Indications

Chronic Myelogenous Leukemia (CML), Philadelphia Chromosome-Positive Acute Lymphocytic Leukemia (Ph+ ALL), Advanced Malignancies

Principal Targets

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

The BCR-ABL translocation (also known as the Philadelphia chromosome) results in constitutive activation of the ABL kinase, which drives cell proliferation.
The T315I mutant form of BCR-ABL is resistant to approved BCR-ABL inhibitors.
SRC is a tyrosine kinase that plays an important role in tumor angiogenesis, progression, and metastasis.
SRC is activated and/or overexpressed in many tumors. Deregulation of SRC contributes to cell proliferation, 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, 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 (pts) with advanced malignancies (solid tumors, lymphoma, or multiple myeloma) for which standard therapies are no longer effective were reported at the EORTC-NCI-AACR International Conference on Molecular Targets and Cancer Therapeutics, in October 2008 in Geneva, Switzerland.

XL228 is administered as a one-hour IV infusion once- or twice-weekly in pts with solid tumors, multiple myeloma, or lymphoma, for whom standard therapies are no longer effective.
As of October 10, 2008, thirty pts have received > 1 dose of XL228 in this study, and of these, 23 have completed at least 4 weeks of treatment.
As of October 10, 2008, 7 of 16 evaluable pts have experienced prolonged stable disease (> 3 months), with one metastatic non-small cell lung cancer patient experiencing a 27% reduction in all target lesions by RECIST criteria.
Dose levels tested so far are 0.45, 0.9, 1.8, 3.6, 5.4, and 8.0 mg/kg once-weekly (Cohorts 1-6) and 2.7 mg/kg twice weekly (Cohort 1T). Final determination of the maximum tolerated dose (MTD) is ongoing.
- As of October 10, 2008, no drug-related serious adverse events (SAEs) have been reported.

Asymptomatic XL228-related hyperglycemia (Grade 1 to 3) not requiring medical intervention and lasting up to 4 hours post-infusion has been observed at doses ≥ 3.6 mg/kg weekly and at 2.7 mg/kg twice-weekly.
Other common AEs (Grade 1 to 2) reported as possibly XL228-related include perioral numbness, tongue tingling and numbness, dysgeusia, lightheadedness, euphoria, anxiety, diarrhea, and hypophosphatemia.
Dose-limiting toxicity (DLT) of neutropenia (Grade 3 and 4) has been reported in two subjects receiving XL228 at the 8.0 mg/kg once-weekly dose.
One DLT of neutropenia (Grade 4) has also been reported in a subject receiving XL228 at the 2.7 mg/kg twice-weekly dose.

Results from pharmacodynamic analyses, inhibition of IGF1R and SRC kinase pathway signaling by XL228 was observed in circulating leukocytes, hair follicles, and skin biopsy samples. Transient upregulation of plasma glucose and insulin was also observed, consistent with an impact on insulin and insulin-like growth factor signaling.

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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.