Clinical Trial of ABC in Patients with Refractory Multiple Myeloma

DESCRIPTION provided by applicant Multiple myeloma MM is the second most common hematological malignancy in the United States and remains an incurable disease since nearly all MM patients will eventually relapse and develop resistance to currently available drugs Sphingolipid metabolism is being increasingly recognized as a key pathway in tumor biology In particular sphingosine kinases SK and SK provide a potential site for manipulation of the ceramide sphingosine phosphate S P rheostat that regulates the balance between tumor cell proliferation and apoptosis as well as tumor sensitivity to drugs and radiation We have recently demonstrated that SK is overexpressed in MM and that inhibition of SK in MM cell lines by ABC down regulates c Myc expression and promotes apoptosis in MM cells Importantly ABC also effectively inhibits tumor growth in vivo in myeloma xenograft models ABC has recently completed phase I testing in patients with advanced solid tumors and we hypothesize that this drug will be useful for the treatment of MM patients In this phase SBIR project we will conduct the following Specific Aims Perform a phase Ib clinical trial to determine the safety pharmacokinetics and pharmacodynamics of ABC when combined with dexamethasone in relapsed refractory MM patients We will perform a phase b trial with up to patients to determine the safety maximal tolerated dose MTD pharmacokinetics and pharmacodynamics of ABC combined with dexamethasone in relapsed and or refractory MM patients who have previously been treated with both a proteasome inhibitor and an immunomodulatory agent and Perform a phase II clinical trial to determine the preliminary efficacy of ABC combined with dexamethasone in relapsed refractory MM patients Once the MTD has been established up to additional patients with refractory relapsed MM will be enrolled at the MTD to confirm safety and to investigate preliminary efficacy in this population We expect that this clinical trial will have important implications in the treatment of MM We believe that the proposed studies constitute a focused approach for developing a novel treatment for patients with MM a disease with a high unmet clinical need If positive these data will provide justification for a larger multi center phase III study PUBLIC HEALTH RELEVANCE Multiple myeloma MM is a common but incurable disease that requires new therapies Sphingolipid metabolism is being increasingly recognized as a key pathway in cancer biology and is changed in MM cells We have developed the first clinical drug that inhibits a key enzyme SK and have extensive preclinical data that suggest it will be active against MM This project will extend the clinical testing of this drug into MM patients to assess its safety and to provide a preliminary estimation of its therapeutic potential Successful completion of these studies could have important implications for the treatment of MM