Clinical Proof of Concept Trial of Oral Ciclopirox Olamine in Patients with Relapsed/Refractory Hematologic Malignancy
Authors: Minden Mark D. , Hogge Donna E. , Weir Scott , Kasper Jim , Patton Lavonne , Jitkova Yulia , Gronda Marcela , Hurren Rose , Rajewski Lian , Schorno Kevin , Chang Hong , Brandwein Joseph M. , Gupta Vikas , Schuh Andre C. , Trudel Suzanne , Yee Karen W.L. , Reed Greg , Schimmer Aaron D 
Published: October 2019

Abstract
Abstract 1372
Ciclopirox olamine (CPX) is a topical antifungal agent used for the treatment of mild to moderate nail infection. Recently, we and others demonstrated both in vitro and in vivo that CPX chelates intracellular iron and is preferentially cytotoxic to malignant cells including AML cells and stem cells over normal hematopoietic stem cells. To evaluate the clinical activity of this drug in patients with hematologic malignancy, we formulated CPX as an oral suspension in Ora-Sweet® and confirmed stability and purity. With this formulation, 97% bioavailabilty was demonstrated in male C57BL6 mice. Prior pharmacology and toxicology data for CPX related to its use as an anti-fungal was leveraged to receive regulatory approval for a first-in-patient phase I trial of escalating doses and frequencies of oral CPX in patients with relapsed and refractory hematologic malignancy (NCT00990587). 23 patients (AML = 20, myelodysplasia = 2, myeloma = 1) were treated with oral CPX once daily – 5 days. In a 3+3 design, patients received escalating doses of CPX (5–80 mg/m2) over 5 dose levels. Cycles could be repeated every 21 days for patients who were stable or improving and 7 patients received more than one cycle (range 2–4). Pharmacokinetics-guided dose and dose frequency escalation was employed. Upon completion of the 80mg/m2 dose, the frequency was escalated to q.i.d according to predefined criteria to increase dosing frequency based on the half-life and Cmax.
Once daily dosing of CPX was generally well tolerated except for one case of reversible Grade 3 knee pain possibly related to study drug that occurred in a patient with concomitant febrile neutropenia receiving 80 mg/m2 of CPX. A patient receiving 80 mg/m2 daily experienced an adverse event unrelated to study drug (febrile neutropenia) and did not complete all of the follow-up so was replaced with another patient. Dose limiting toxicity was observed at the 80mg/m2 q.i.d dose level with 2 of 5 patients experiencing Grade 3 small bowel enteritis. One patient at this dose level developed Grade 3 typhlitis that was initially classified as unrelated to study drug, but reassessed as possibly related in light of the subsequent cases of small bowel enteritis.
Plasma concentrations of CPX and its glucuronide were measured by LC/MS/MS. Systemic drug exposure increased with increasing dose. At the 80mg/m2 dosage regimen Cmax and AUC(0–6 hrs) up to mean values of 221 ng/ml and 811 h*ng/mL, respectively, were observed. The terminal half- life of CPX at 80mg/m2 was 2.7 hours and the primary route of metabolism was glucuronidation. Cmax and AUC values for CPX glucuronide were 10–20 times higher than were the corresponding values for CPX at all doses.
Pharmacodynamic studies evaluated the ability of CPX to repress survivin expression as we previously demonstrated changes in survivin expression after in vitro treatment of AML cells. Peripheral blood AML blasts from 15 study patients were isolated from the peripheral blood samples by magnetic bead separation before, during (d5), and after (d8) study drug treatment. Total mRNA was isolated and levels of survivin and 18S expression quantified by Q-RTPCR. Mean survivin mRNA expression on d5 of CPX administration was 30 ± 15, 21 ± 13, and 39± 29 percent of pretreatment expression after 20, 40, and 80 mg/m2 once daily dosing, respectively. No reduction in survivin expression was observed at lower doses. However, repression was transient, as levels returned towards baseline by day 8 (3 days off drug).
While no patient had CR or CRp, hematologic improvement was observed in two study patients. A patient with acute panmyelosis receiving 20mg/m2 of CPX had a transient (90 day) decrease in marrow fibrosis and blasts count as well as improvement in the neutrophil and platelet counts. An AML patient with poor risk cytogenetics and progressive disease receiving 40 mg/m2 of CPX had transient (56 day) improvement in platelet count and reduction in leukemic blasts.
In summary, an academic and not-for-profit partnership rapidly translated laboratory-based preclinical and mechanistic studies into a clinical proof of concept trial. Given the transient pharmacodynamic changes and signals of clinical response, further trials should focus on optimizing oral dosage regimens of oral CPX as a novel therapeutic strategy for patients with relapsed/refractory hematologic malignancies.

Disclosures:
Schimmer: Princess Margaret Hospital, University Health Network: Named as an inventor on a patent application claiming the use of ciclopirox olamine in combination with chemotherapy for the treatment of AML Other; Biotheryx: Consultancy.