Background: Fosciclopirox (CPX-POM) is a broad-spectrum anticancer agent being developed through a public-private partnership between CicloMed LLC and KU Cancer Center (KUCC). Following intravenous administration, fosciclopirox is rapidly and completely metabolized to its active metabolite ciclopirox (CPX). Given fosciclopirox is a prodrug lacking pharmacologic activity, in vitro mechanistic studies were conducted utilizing CPX as the test article. In collaboration with Notable Labs (Foster City CA), we characterized ex vivo sensitivity to CPX in bone marrow and peripheral blood samples from ten newly diagnosed and relapsed acute myeloid leukemia (AML) patients. Reductions in blast counts were seen in each of the 10 patients studied at clinically relevant concentrations. In vitro experiments in AML cell lines (HL-60 and MV4-11) characterized the mechanism(s) of the anti-leukemia activity of CPX. CPX inhibited proliferation of AML cell lines in a dose- and time-dependent manner with IC50 values ranging from 2.5-4 µM. CPX induced cell cycle arrest in the subG0 phase and CPX-treated cells lost their ability to enter to G0-G1 phase. Moreover, CPX induced early and late phase apoptosis. CPX also activated Caspase 3/7 activity. This preclinical data led to the development of a multi-center Phase 1B/2A clinical proof of concept trial (NCT04956042) in AML patients. Methods: Eligible AML patients are adults with primary refractory (two prior regimens) or relapsed AML; ECOG PS 0-2; adequate end organ function. Prior allogeneic stem cell transplant is allowed if patient is more than 100 days post-transplant with no active graft-versus-host disease. CPX-POM is administered as 900 mg/m2 once daily as an IV infusion on Days 1 to 5 of each 21-day cycle. Day 8 bone marrow sample is collected for correlative studies. Ex vivo Drug Sensitivity Screening (DSS) will be performed on samples obtained prior to treatment and C1 Days 8 and 21. 14 evaluable patients will be enrolled in Cohort 1a. If disease response is observed in at least 4 of 14 patients, an additional 14 patients will be enrolled in Cohort 1b. During Cohort 1a, patients who do not respond to CPX-POM alone may be switched to the combination of CPX-POM + cytarabine. Patients who respond to the combination treatment may continue until evidence of disease progression. If disease response to CPX-POM alone is not observed in at least 4 of 14 patients in Cohort 1a, the study may be terminated or a Cohort 2a may be initiated using the combination of CPX-POM and cytarabine. The trial is currently open at two sites with 14 patients enrolled and 8 evaluable for the primary endpoint. Clinical trial information: NCT04956042.