Phase I trial of ABC294640, a first-in-class sphingosine kinase-2 inhibitor.

Sphingosine kinases (SK1 and SK2) are new potential targets for anticancer drugs because SK inhibitors elevate ceramide levels thereby promoting apoptosis of tumor cells, and concomitantly reduce sphingosine 1-phosphate (S1P) levels thereby attenuating tumor cell proliferation and migration, as well as reducing host angiogenesis and inflammation. ABC294640 is a first-in-class orally-available inhibitor of SK2 that has activity both as a single-agent and in drug combinations in models of liver, kidney, pancreas, breast, ovary, colon and lung cancer, as well as leukemia and multiple myeloma. ABC294640 is currently in Phase I testing in patients with advanced solid tumors. The primary objectives are to identify the MTD, to determine the dose limiting toxicities (DLTs) and to evaluate the safety of ABC294640. Secondary objectives are to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of ABC294640, and to assess its antitumor activity. The study employs a standard 3+3 dose-escalation design. To date, this Phase I trial has enrolled 16 patients 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 (2 patients). In general, the drug has been well tolerated, with the most common side effects being low-grade fatigue and nausea. One pancreatic cancer patient at 250 mg po qd developed grade 4 DLT of hyperglycemia as disease progressed, which was possibly related to drug. Additionally, a patient at 750 mg po bid with a malignant neoplasm of the ovary experienced a grade 3 DLT of nausea and vomiting that was possibly drug-related. After 2 cycles of treatment (8 weeks), tumor imaging demonstrated that 6 of 10 patients had stable disease. Notably 2 patients have 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 t1/2 for ABC294640 was 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 μM) is sufficient for anticancer efficacy in mouse models. This study includes the first-ever analysis of plasma S1P levels as a potential PD biomarker for activity of a sphingolipid-targeted drug, and will establish the degree of intra-and inter-patient variability needed for assessment of this PD marker in future clinical trials. Overall, this first-in-human study provides key information about the safety, toxicities, PK and PD of ABC294640 that are needed to support future Phase II and III clinical trials. (Supported by: P30 CA138313 from the National Cancer Institute to MUSC; R01 FD004102 from the Food and Drug Administration to Apogee; and SAP#4100061668 from the Pennsylvania Department of Health to Apogee.) Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C62. Citation Format: Melanie B. Thomas, Carolyn D. Britten, Elizabeth Garrett-Mayer, Steve H. Chin, Tricia A. Bentz, Alan Brisendine, Terri L. Matson, Susan Cusack, Lynn W. Maines, Yan Zhuang, Charles D. Smith. Phase I trial of ABC294640, a first-in-class sphingosine kinase-2 inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C62.