PS1037 FINAL REPORT: CLINICAL STUDY OF ORAL ARSENIC TRIOXIDE CAPSULE FORMULATION, ORH‐2014, DEMONSTRATING HIGH BIOAVAILABILITY, GOOD SAFETY AND TOLERABILITY IN PATIENTS WITH ADVANCED HEMATOLOGIC DISORDERS
Authors: Ravandi F. , Tallman M. , Roboz G. , Strickland S. , Garcia‐Manero G. , Borthakur G. , Naqvi K. , Meyer M.‐A. , Koumenis I. , Johri A. , Pudipeddi M. , Nidarmarthy S. , Vaddi K. , Kantarjian H. 
Published: June 2019

Background:Daily administration of intravenous arsenic trioxide (ATO) in acute promyelocytic leukemia (APL) presents challenges related to administration costs as well as patients’ quality of life. Oral arsenic derivatives may offer significant advantages by improving quality of life, drug compliance and by decreasing administration costs. The latest guidelines for the management of patients with standard risk APL (WBC< 10∗109/L) recommend the concurrent use of all trans‐retinoic acid (ATRA) and ATO for induction with superiority over ATRA plus chemotherapy as demonstrated in large randomized trials (LoCoco F 2013, Burnett AK 2015). Oral arsenic formulations in China have reported similar efficacy and safety in studies with long term follow‐up (Au WY 2011, Zhu HH 2018).Aims:To identify the optimal and safe dose of oral ORH‐2014 for future studiesMethods:This is a multicenter Phase 1 dose‐escalating study of oral Arsenic Trioxide (ORH‐2014) in patients with relapsed and/or refractory hematologic disorders. ORH‐2014 is a novel formulation of arsenic trioxide, developed using a patented process to produce micron‐sized drug particles with high surface area and rapid dissolution profile. ORH‐2014 was administered orally, once a day, in the fasted state. The study has completed enrollment with a total of 12 patients across three cohorts: 3 patients at 5 mg, 6 patients at 10 mg and 3 patients at 15 mg (cohorts 1, 2 and 3, respectively). The primary endpoints were to assess safety and tolerability of ORH‐2014 and to identify the recommended dose for future trials. Secondary endpoints were pharmacokinetics (PK), effect on QTc interval, and efficacy. Dose Limiting Toxicities (DLT) were monitored on Days 1–29 of dosing, and plasma samples were collected for PK analysis between Days 1–22 of dosing. Total arsenic concentrations in plasma were measured by a validated method using inductively coupled plasma mass spectrometry (ICP‐MS).Results:The trial enrolled 12 patients with advanced hematologic malignancies including 7 with advanced myelodysplastic syndrome and 5 with refractory acute myeloid leukemia with NPM1 mutation. The median age of patients was 77 (range 45–81) years with a median of 2 (range 1–5) prior therapies. There were no DLTs, no significant safety issues and no drug related severe adverse events including no significant QT prolongation. Three patients were replaced due to progression of AML, patient decision and adverse event, respectively, with all patients included in the safety analysis set. Following QD dosing of 15 mg ORH–2014, on day 15, geometric mean Cmax was 114 ng/mL which is similar to the Cmax of approved dose of IV ATO (124 ng/mL) and AUC(0–24) was 2140 h∗ng/mL which is approximately 64% higher that the IV ATO AUC(0–24) (1302h∗ng/mL). AUC and Cmax remained similar on Days 15 and 22 indicating steady state was reached on Day 15. These results indicate that ORH‐2014 is highly bioavailable when administered once daily. Disease improvements as reported by investigators were observed in two patients with MDS.Summary/Conclusion:The 15 mg QD ORH‐2014 is highly bioavailable and provides the desirable exposure in total arsenic as compared to the approved dose of IV ATO (0.15 mg/kg). This safe and well tolerated dose of ORH‐2014 is recommended for a future randomized trial in standard risk APL patients, as frontline therapy and in exploratory studies in MDS and other hematologic diseases.