Tarassoff, Peter G.

Abstract Abstract 3801 Purpose: Decitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases indicated for treatment of myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes. The aim of this study was to determine the absolute bioavailability and safety of a single oral dose of decitabine. Methods: This is an open-label, Phase 1, dose-escalation absolute bioavailability trial in which decitabine was administered orally on Cycle 1 Day 1, and followed by a 1-hour IV infusion of the currently approved regimen (20 mg/m2) on Cycle 1 Days 2–5. Serial blood samples for decitabine pharmacokinetic (PK) assessment were collected up to 6 h post-dosing during Cycle 1 on Days 1 and 2. Three subjects were recruited at each oral dose level of 30, 60, 120 and 240 mg. Subjects were evaluated for adverse events (AEs). Results: Study results are summarized in Table 1. Sixteen subjects were screened and 12 were enrolled. Nine subjects had de novo MDS and 3 had secondary MDS (IPSS score Int-2 = 6, Int-1 = 5, Low = 1). Following oral dose, Cmax was reached within 0.50 h (tmax) and after Cmax the plasma profile showed biphasic decline with terminal half-life ranging between 0.36 to 0.93 hr. Increase in oral dose did not result in proportional increase in Cmax and AUC. The PK parameters following oral doses showed very high variability. Based on comparison of dose normalized exposure, the absolute bioavailability ranged between 3.9 to 14.1% and increased proportionally with dose. The non-dose normalized bioavailabilities were calculated to find a dose at which mean oral bioavailability reaches ≥80% of the current IV regimen of 20 mg/m2. The non-dose normalized bioavailability ranged between 11.7 and 80.5% with highest oral bioavailability observed at 240 mg dose. The most common SAEs were pneumonia (n=4) and neutropenic fever (n=4). Five patients (41.7%) experienced diarrhea and nausea (all grades). Conclusion: The study demonstrates that the absolute bioavailability ranged between 3.9 and 14.1%. Oral decitabine was generally well tolerated at doses between 30–240 mg in MDS subjects and exhibited a safety profile similar to the profile following intravenous administration. The bioavailability and safety data may allow for further testing in the phase 2 setting. Disclosures: Mistry: Eisai Inc.: Employment. Jones:Eisai Inc.: Employment. Kubiak:Eisai Inc.: Employment. Garcia-Manero:Eisai Inc.: Research Funding. Litzow:Eisai Inc.: Research Funding. Mesa:Eisai Inc.: Research Funding. Tarassoff:Eisai Inc.: Employment. Cortes:Eisai Inc.: Research Funding.

Abstract Abstract 1517 Purpose: Decitabine, a deoxycytidine nucleoside derivative, is an inhibitor of DNA-methyltransferases indicated for treatment of myelodysplastic syndrome (MDS) including previously treated and untreated, de novo or secondary MDS of all French-American-British (FAB) subtypes, Intermediate-1, Intermediate-2, and High-Risk International Prognostic Scoring System (IPSS) groups. Laboratory evidence shows that pretreatment of AML cell lines can sensitize leukemia cells to chemotherapy as well as inhibit clonogenic potential. The purpose of this study is to evaluate the safety, pharmacokinetics, and efficacy of decitabine when used as priming before induction therapy in children with newly diagnosed AML. Exploratory analyses of genomic methylation and RNA expression patterns and minimal residual disease (MRD) are embedded correlative studies. Methods: This multicenter, randomized, two-arm, open-label study enrolls pediatric pts ages 1–16 with newly diagnosed AML to either Arm A: daunorubicin, cytarabine, etoposide (D-ADE) preceded by a 5-day course of decitabine (experimental arm) or Arm B: daunorubicin, cytarabine, etoposide (ADE; control arm). Following completion of induction on study, post-induction therapy is at the treating physician's discretion. To date, 20 pts, 10 in each arm (1–16 yrs, median 9.4 yrs in both arms) have been enrolled. Results: At the protocol-specified bone marrow sampling time 3 weeks post-induction, there were 2 CRs, 6 CRi (CR with incomplete hematopoietic recovery), 1 leukemia not in remission and 1 pt who discontinued due to an AE in Arm A. In Arm B, 6 CRs, 2CRi, 1 PR and 1 pt with marrow aplasia have been confirmed. Decitabine PK in all arm A pts (100%) were characterized by mean+SD Cmax, 297+109 ng/mL, AUC0-t, 216+73.7 ng*h/mL, CL, 136+93.9L/h, Vdss 93.1+70.7 L, t1/2 0.456+0.073 h, and median tmax0.925 h. All pts had at least one AE. Grade 3 and 4 non-hematologic AEs in Arm A that were not seen in Arm B were caecitis in 2 (20%), anorexia in 3 (30%), and hypophosphatemia in 2 (20%) of pts. All pts experienced neutropenia and thrombocytopenia as expected. One pt in Arm A had appendicitis and colon perforation on Day 6 that led to study discontinuation, later determined to have been leukemic infiltrate. Two pts have died to date (both in Arm A), one of necrotic bowel, Pseudomonas sepsis and multisystem organ failure 6 months after completing study induction therapy. One pt died 5 months following study treatment from multisystem organ failure after stem cell transplant. Epigenetic changes associated with decitabine pretreatment were analyzed and will be presented. Conclusions: Decitabine in combination with ADE chemotherapy is well tolerated in children with newly diagnosed AML. There were no AEs that had not been previously identified in adults with MDS or AML. No differences have been observed between treatment arms in hematologic toxicities based on the current sample size. To date, the decitabine-treated pts in this study may have more gastrointestinal toxicity and hypophosphatemia. Decitabine-treated pts achieved PK exposures that were similar to those observed in adults treated with decitabine. Preliminary responses by CR/CRi were similar between treatment arms; expected adverse events of neutropenia and thrombocytopenia were similar between both Arms. Molecular changes associated with decitabine pretreatment may be important in the sensitization of clonogenic AML cells. Total accrual of 40 subjects is planned. Disclosures: Off Label Use: AC220 in relapsed/refractory pediatric acute leukemia. Tarassoff:Eisai, Inc.: Employment. Jones:Eisai Inc: Employment.