Background: LY2510924 is a peptide antagonist of CXCR4, a key component of the CXCR4/SDF-1 signaling axis that is critical for homing of stem cells in the bone marrow and activation of downstream pathways involved in cell proliferation and survival. In a preclinical AML model, LY2510924 showed significant activity as a single agent and in combination with chemotherapy (Cho et al. Blood 2015). Methods: A phase I study was designed to determine the safety and toxicity profile of combination therapy of LY2510924 with IA in patients (pts) with R/R AML. Pts aged 18 to 70 years who failed prior therapy (≤ salvage 3) were eligible. LY2510924 is administered from days 1-7 followed by IA starting day 8. In responders, 4-6 consolidation cycles were administered. Two dose escalation levels (10 and 20 mg) were planned, according to a 3+3 design; up to 12 pts to be enrolled in phase I portion. Results: Eleven pts have been enrolled with a median age of 55 (range, 19-70) years. Of 10 pts tested, 2 (20%) had complex cytogenetics. Median prior therapies were 1 (1-3). Six pts were treated at dose level ‘0’ (10 mg) and 5 at dose level ‘1’ (20 mg); 3 of 5 treated at dose level ‘1’ were evaluable for response. Most non-hematologic toxicities were grade 1-2 in severity. At dose level ‘0’, 1 pt experienced dose limiting toxicity (DLT) (2 grade 3 DLTs: rash and hypo-cellular marrow). No major toxicities occurred at dose level ‘1’. At ‘0’ dose level, 1 pt had a CR and 2 had CRi; at dose level ‘1’, 1 achieved CR; the overall response rate was 44%. By flow cytometry, 4 of 9 had ≥ 50% decrease in CXCR4 mean fluorescence intensity. Conclusions: Combination of LY2510924 with IA is safe in R/R AML pts. Dose-escalation to 40 mg of LY2510924 is planned to achieve > 90% blockade of CXCR4 receptor occupancy, followed at the expansion phase of the study at recommended phase 2 dose level. Clinical trial information: NCT02652871