TY - JOUR AU - Farhad Ravandi, AU - Iphigenia Koumenis, AU - Anandhi Johri, AU - Martin Tallman, AU - Gail J. Roboz, AU - Stephen Strickland, AU - Guillermo Garcia-Manero, AU - Gautam Borthakur, AU - Kiran Naqvi, AU - Meghan Meyer, AU - Madhu Pudipeddi, AU - Sirish Nidarmarthy, AU - Kris Vaddi, AU - Hagop Kantarjian, PY - 2020/06/01 Y2 - 2024/03/28 TI - Oral arsenic trioxide ORH-2014 pharmacokinetic and safety profile in patients with advanced hematologic disorders JF - Haematologica JA - haematol VL - 105 IS - 6 SE - Articles DO - 10.3324/haematol.2019.229583 UR - https://haematologica.org/article/view/9432 SP - 1567-1574 AB - Daily intravenous arsenic trioxide administered with all-trans retinoid acid, the standard-of-care for acute promyelocytic leukemia, is costly and challenging to administer. ORH-2014 is a novel, oral arsenic trioxide formulation, consisting of micron-size drug particles with rapid dissolution and high bioavailability. We conducted a multicenter phase 1 dose-escalating study in patients with advanced hematologic malignancies. Twelve patients received ORH-2014 at 5 mg (n=3), 10 mg (n=6), or 15 mg (n=3) orally once a day (fasted state). Objectives were to assess the safety, tolerability and pharmacokinetics of ORH-2014 to support a dose recommendation for future trials. The median age of the patients was 77 years (range: 45-81) and they had received a median of two (range: 1-5) prior therapies. There were no dose limiting toxicities and no drug-related severe adverse events, except one grade III QT prolongation occurring beyond the dose limiting toxicity assessment period and resolving after treatment interruption. ORH-2014 steady-state plasma concentration was reached on day 15. ORH-2014, 15 mg Cmax was comparable to the calculated approved dose of intravenous arsenic trioxide (mean [% coefficient of variation]: 114 [21%] vs. 124 [60%] ng/mL) and area under the curve from 0 to 24 hours was 2,140 (36%) versus 1,302 (30%) h*ng/mL. These results indicate that ORH-2014 at 15 mg is safe, bioavailable, and provides the required arsenic exposure compared to intravenous arsenic trioxide at the approved dose (0.15 mg/kg); this ORH-2014 dose is recommended for future trials. (NCT03048344; www.clin-icaltrials.gov). ER -