Phase 1B/2A safety, pharmacokinetics, and pharmacodynamics study of fosciclopirox alone and in combination with cytarabine in patients with relapsed/refractory acute myeloid leukemia.
Authors: Lin Tara L. , Wood Robyn , Ham Tammy , Sullivan Taegen , Bhattacharyya Sangita , Dandawate Prasad , Anant Shrikant , Santaguida Marianne T , Zhang Na , Toren Paul , Jensen Roy A. , Taylor John A. , Baltezor Michael Jay , Dalton Michael , McBride John , Umbreit Jay Nicholas , McCulloch William , Vanderlaag Kathryn , Wagner Joseph , Weir Scott James 
Published: June 2022

TPS7069 Background: Fosciclopirox (F) is a γ-secretase inhibitor being developed for the treatment of acute myeloid leukemia (AML). Following intravenous (IV) administration, F is rapidly and completely metabolized to its active metabolite, ciclopirox (CPX). CPX binds to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. In HL60 cells, CPX inhibits Notch 1 and Notch 2 expression, reduces levels of γ-secretase complex proteins Presenilin 1 and Nicastrin, and decreases expression of the downstream Notch target gene Hes-1. Utilizing Notable Labs predictive precision medicine platform, bone marrow (BM) and peripheral blood (PB) samples obtained from 10 AML patients treated with CPX demonstrated significant blast count reductions. Methods: Study CPX-POM-003 (NCT04956042) is an open-label Phase 1B/2A, trial designed to characterize the efficacy, safety, and PK/PD of F alone and in combination with cytarabine (ara-C) in patients with relapsed/refractory AML (R/R AML). Eligible patients must be 18 years of age or older with relapsed AML after complete remission or with primary refractory AML refractory to at least two cycles of induction therapy. There will be up to three cohorts of patients, approximately 42 R/R AML patients, evaluated. If disease response to F alone (Cohort 1a) is observed in at least 4 of 14 patients, an additional 14 patients will be enrolled in Cohort 1b. If disease response is not observed following F alone, the study may be terminated or a second cohort, Cohort 2a, may be initiated to evaluate the combination of F + ara-C. If disease response to F + ara-C is observed in at least 4 of 14 patients, an additional 14 patients will be enrolled in Cohort 2b. If response to F + ara-C is not observed in at least 4 of 14 patients, the study will be stopped for futility. F is being administered as 900 mg/m2 once daily as a 20-minute IV infusion on Days 1 to 5 of each 21-day treatment cycle. Ara-C is administered as 1 gm/m2 once daily on Days 1 to 5 of each cycle. BM and PB samples are collected prior to and during Cycles 1 (C1) and 2 (C2) for disease response assessment and blast count determination. Additional BM and PB samples are obtained after every two cycles beyond C2 for patients continuing treatment. Disease response is determined based on Döhner et al, Blood 2017;129(4)424-447. Next Generation Sequencing (NGS) profiles will be determined prior to and at the end of C1, and thereafter as clinically indicated. Immunohistochemistry will be performed on BM samples to elucidate drug mechanism. Ex vivo Drug Sensitivity Screening (DSS) will be performed on BM and PB samples obtained prior to treatment as well as on C1 Days 8 and 21. The steady-state plasma pharmacokinetics of F are being characterized during C1. Enrollment began in October 2022 with four patients enrolled to date. Clinical trial information: NCT04956042.