ABC294640 is a first-in-class orally-available, small molecule inhibitor of the enzyme sphingosine kinase-2, which is essential for tumor growth and aberrant inflammation. Sphingosine kinases (SK1 and SK2) are new targets for anticancer drugs because SK inhibitors elevate ceramide levels which promotes apoptosis of tumor cells, reduces sphingosine 1-phosphate (S1P) levels thereby attenuating tumor cell proliferation and migration, and reduces host angiogenesis and inflammation. Preclinical studies with ABC294640 demonstrated its activity in many cancer models, as well as in models of inflammatory diseases such as Inflammatory Bowel Disease, Rheumatoid Arthritis and Radiation Poisoning. Specific to cancer, ABC294640 has significant activity both as a single-agent and in combination with several standard of care drugs in models of liver, kidney, pancreas, breast, ovary, colon and lung cancer, as well as leukemia and multiple myeloma.
Key data to be discussed derive from 17 patients treated at the following dose levels: 250 mg po qd (6 patients), 250 mg po bid (4 patients), 500 mg po bid (4 patients) and 750 mg po bid (3 patients). In general, the drug has been well tolerated, with the most common side effects being low-grade fatigue and nausea. After 2 cycles of treatment (8 weeks), tumor imaging demonstrated that 6 of 10 patients had stable disease. Notably 2 patients had prolonged stabilization of disease: 1 patient with metastatic cholangiocarcinoma (16 months), and 1 patient with metastatic/recurrent bladder cancer (11 months). The MTD has not yet been reached, and dose escalation is continuing.
The half-time for clearance of ABC294640 from plasma is approximately 4 hours, and through at least the first 3 cohorts, PK parameters (Cmax and AUC) were proportional to the dose of ABC294640 received. Importantly, the average Cmax for patients receiving 500 mg ABC294640 (16.4 micromolar) is sufficient for anticancer efficacy in preclinical models.
This study also includes the first-ever analysis of plasma S1P levels as a potential pharmacodynamics (PD) biomarker for activity of a sphingolipid-targeted drug, and will establish the degree of intra- and inter-patient variability of this bioactive lipid.
Overall, this first-in-human study provides key data about the safety, toxicities, PK and PD of ABC294640 needed to support future phase 2 and 3 clinical trials.
Keywords for this news article include: Glycols, Oncology, Sphingosine, Therapeutics, Amino Alcohols,
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