Related Experiment Videos
A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors
Carolyn D Britten1, Elizabeth Garrett-Mayer2, Steven H Chin1
1Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina.
Summary
This study found that ABC294640, an inhibitor of sphingosine kinase 2 (SK2), is well-tolerated at 500 mg bid in patients with advanced solid tumors. Plasma sphingolipid changes may serve as a biomarker for this novel cancer therapy.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Sphingosine kinases (SK1 and SK2) are key regulators of tumor growth through the production of sphingosine 1-phosphate (S1P).
- Targeting SK2 offers a potential therapeutic strategy for various cancers.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABC294640, an oral SK2 inhibitor.
- To determine the recommended Phase II dose for ABC294640.
Main Methods:
- Phase I clinical trial with escalating oral doses of ABC294640 (250 mg qd, 250 mg bid, 500 mg bid, 750 mg bid) in patients with advanced solid tumors.
- Serial blood sampling for drug concentration and sphingolipid profiling.
- Assessment of adverse events and objective tumor responses.
Main Results:
- The recommended Phase II dose was determined to be 500 mg bid.
- Common toxicities included nausea, vomiting, and fatigue, with dose-limiting toxicity observed at 750 mg bid.
- ABC294640 administration led to transient decreases in plasma S1P levels.
- One partial response and stable disease in six patients were observed.
Conclusions:
- ABC294640 at 500 mg bid is well-tolerated and achieves pharmacologically relevant concentrations.
- Plasma sphingolipid level changes show potential as a pharmacodynamic biomarker for ABC294640.
- Further investigation in Phase II trials is warranted.