Phase I/II, Randomized, MultiCenter, Dose-Ascension Study of the p38MAPK Inhibitor Scio-469 in Patients with Myelodysplastic Syndrome (MDS).

Pro-apoptotic cytokines generated in the medullary microenvironment potentiate ineffective hematopoiesis in MDS. Preclinical investigations indicate that inhibition of p38α mitogen-activated protein kinase (MAPK) suppresses inflammatory, angiogenic and pro-apoptotic cytokine induction from marrow stromal cells. SCIO-469, is a novel highly selective p38αMAPK inhibitor. SCIO-469 was studied in a phase I/II, multicenter trial in patients (pts) with IPSS low and intermediate-1 risk MDS. The primary objective was to determine the safety and tolerability (NCI CTCAE) of the agent; secondary objectives were to evaluate erythroid response rate, hematologic improvement, bone marrow and cytogenetic response according to IWG MDS response criteria and the relation to biological correlates. Between 2005–2006, 62 pts were enrolled. At the time of abstract submission, 29 pts had preliminary response assessment. Demographic features include IPSS Low (45%) or Int-1 (55%) risk MDS, median age 71.5 years (range 48–88); WHO phenotype: RA 9%, 5q- syndrome 8%, RCMD 32%, RARS 13%, RCDM-RS 13%, RAEB-I 11%, MDS-u 9%, MDS/MPD 4%. Among these, 91% failed erythropoietin treatment (tx) and 11% had prior chemotherapy; 79% received RBC transfusions within 8 wks prior to study tx. Pts were randomly assigned to one of two lower dose levels: 30 mg TID (15 pts) and 60 mg TID (15 pts) and later to a 3^rd dose level of 90 mg TID (15 pts) after initial confirmation of drug tolerance. Since maximal tolerated dose (MTD) was not achieved, a 4^th dose level (120mg TID) was added with 17 pts accrued, none of whom are included in the response data. Responses were evaluated after 16 weeks of tx, with responders continuing SCIO-469 for up to 78 weeks. Fifteen grade 3 or 4 adverse events were observed in 10 pts: 1 jaundice, 1 hyperamylasemia, 1 hyponatremia, 1 atrial FIB, 1 hypotension, 2 cancer (melanoma, colon), 2 pneumonia, 3 neutropenia, 1 lower extremity edema, 1 pyrexia, and 1 abdominal pain. Other than three grade 3 or 4 neutropenia, no significant hematologic toxicities were observed. The MTD for SCIO-469 was not reached. Preliminary response was analyzed in pts completing >16 weeks of treatment [N=29]: Erythroid: major 1, minor 2; Platelet: major 1, minor 0; Neutrophils: major 3, minor 0, with no relation to dose. BM responses evaluated in 25 pts yielded only 1 partial response. Progression occurred in 4 pts. Tx is ongoing with pending analysis of correlative biological studies. Our preliminary analysis indicates that SCIO-469 is generally well tolerated and modestly active as monotherapy in low/int-1 risk MDS at dose levels 30–90 mg po TID.