Research Project
8216986
DESCRIPTION (provided by applicant): A large body of research has demonstrated that sphingolipid metabolism plays a key role in the regulation of tumor cell proliferation and apoptosis, as well as host inflammatory and angiogenic processes. In particular, sphingosine kinase (SK) is a critical regulator of the ceramide /sphingosine 1-phosphate rheostat that is thought to control the balance between tumor cell proliferation and apoptosis. Signaling through SK is required for Ras-induced carcinogenesis, as well as host inflammatory responses. Because Ras is frequently mutated in pancreatic cancer, and because inflammation (i.e. chronic pancreatitis) is an established risk factor for pancreatic cancer, sphingolipid signaling may be of particular importance in this disease. Therefore, inhibition of sphingolipid signaling may provide a unique, multifocal mechanism for treating pancreatic cancer. The sponsor has developed the first non-lipid inhibitors of SK, and has conducted extensive studies of their biological and therapeutic activities in multiple models of cancer and inflammatory diseases. The first clinical compound in this series, ABC294640, is an orally-available selective inhibitor of sphingosine kinase-2 (SK2) that attenuates signaling through the Ras-Raf-MEK-ERK pathway, promotes tumor cell killing, and inhibits host angiogenesis and inflammation. Additionally, combinations of ABC294640 with gemcitabine or paclitaxel result in synergistic cytotoxicity in vitro and enhanced antitumor effects in vivo. Therefore, the investigators hypothesize that ABC294640 will have significant activity against pancreatic cancer through its effects on tumor cells and host immunologic processes. As the first step toward the development of ABC294640 as a new drug for pancreatic cancer, the goal of this project is to conduct the first-in-human, Phase 1 clinical study of this agent. This will be an open-label, dose escalation, safety, pharmacokinetic and pharmacodynamic study of ABC294640 given orally twice a day in patients with advanced solid tumors. The primary objectives of the study will be to determine the maximum tolerated dose (MTD) and the dose limiting toxicities of ABC294640; to establish the dose of ABC294640 recommended for future Phase 2 protocols; and to determine the pharmacokinetics of ABC294640. The secondary objectives will be to determine the effects of ABC294640-treatment on the pharmacodynamic marker, plasma sphingosine 1-phosphate (S1P) levels, and to observe patients for any evidence of antitumor activity of ABC294640 by objective radiographic assessment. Up to 33 patients will be enrolled in the dose-escalation phase of the study. In addition, once the MTD has been established, up to 12 additional patients with pancreatic cancer may be enrolled at the MTD dose level to confirm safety in this population.
