An Early-Phase Clinical Trial Evaluating ABC294640 in Patients with Refractory/Re

DESCRIPTION provided by applicant Diffuse large B cell lymphoma DLBCL represents one of the most common variants of Non Hodgkinandapos s lymphoma NHL and oncogenic herpesviruses EBV and KSHV are the etiologic agents for the majority of these tumors in patients over or those infected with the human immunodeficiency virus HIV Despite modest improvements in outcomes for patients receiving standard therapy patients with virus associated DLBCLs exhibit more widespread andquot extranodalandquot disease and less favorable outcomes Notably increased treatment failure and mortality have been observed for patients from urban minority predominant cohorts with high rates of virus associated DLBCL and HIV infection who have been largely excluded from clinical trials Apogee Biotechnology Corporation has developed the first non lipid inhibitors of sphingosine kinase SK and has evaluated their biologic and therapeutic activity in a variety of models for cancer and inflammatory diseases The first clinical compound in this series ABC is an orally available selective inhibitor o SK that attenuates signal transduction induces tumor cell death and inhibits host angiogenesis and inflammation in the context of solid tumor formation We have found that ABC induces apoptosis for virus infected DLBCL lines in part through attenuation of virus associated signal transduction Most importantly ABC significantly reduces virus associated DLBCL tumor burden in xenograft models for both EBV and KSHV DLBCLs Therefore we hypothesize that ABC will have significant clinical activity for many DLBCLs refractory to standard therapy especially virus associated DLBCLs To begin development of ABC as a new drug for DLBCL we propose to conduct a Phase I IIa clinical study of this agent enrolling patients with refractory relapsed DLBCL from minority predominant urban populations in Louisiana at high risk for poor outcomes with this disease In this open label dose escalation study ABC will be given orally to HIVneg or HIV patients with primary objectives including determination of the maximum tolerated dose MTD dose limiting toxicities and pharmacokinetics for ABC in these patients Secondary objectives will include determination of the effects of ABC on plasma sphingosine phosphate levels PBMC and tumor associated viral load EBV and KSHV and tumor expression of S P receptors as first steps toward identification of putative biomarkers for drug resistance We will also evaluate antitumor activity for ABC using objective radiographic and clinical assessments Up to patients will be enrolled in the dose escalation phase of the study and once the MTD has been established up to additional patients with DLBCL will be enrolled using this dose in order to obtain additional preliminary efficacy and safety data This study will form the foundation for follow on clinical trials of ABC in patients with DLBCL thereby expanding the commercial market for this agent to include hematologic malignancies and offering a new therapeutic approach for underrepresented patients for whom DLBCL incurs especially high mortality PUBLIC HEALTH RELEVANCE DLBCL incurs high mortality for patients with advanced or refractory disease so new drugs that target critical pathways controlling growth and survival of DLBCL cells are desperately needed Sphingolipid metabolism and sphingosine kinases in particular may play a critical role in DLBCL progression ABC is a novel sphingosine kinase inhibitor that has anti DLBCL activity in mouse models as a single agent and can be used alone or in combination with standard drugs given to DLBCL patients to reduce tumor growth The proposed Phase I IIa clinical trial will establish the maximum tolerated dose safety profile and preliminary efficacy for ABC in patients from an underrepresented minority predominant cohort with treatment refractory DLBCL for whom the disease incurs especially high mortality