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.
Abstract:
Purpose: Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and proinflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABC294640, a first-in-class orally available inhibitor of SK2.Experimental Design: Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid, and 750 mg bid, continuously in cycles of 28 days. Serial blood samples were obtained to measure ABC294640 concentrations and sphingolipid profiles.Results: Twenty-two patients were enrolled, and 21 received ABC294640. The most common drug-related toxicities were nausea, vomiting, and fatigue. Among the 4 patients at 750 mg bid, one had dose-limiting grade 3 nausea and vomiting, and 2 were unable to complete cycle 1 due to diverse drug-related toxicities. The 500 mg bid dose level was established as the recommended phase II dose. ABC294640 administration resulted in decreases in S1P levels over the first 12 hours, with return to baseline at 24 hours. The best response was a partial response in a patient with cholangiocarcinoma at 250 mg qd, and stable disease was observed in 6 patients with various solid tumors across dose levels.Conclusions: At 500 mg bid, ABC294640 is well tolerated and achieves biologically relevant plasma concentrations. Changes in plasma sphingolipid levels may provide a useful pharmacodynamic biomarker for ABC294640. Clin Cancer Res; 23(16); 4642-50. ©2017 AACR.
Insights
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.