Page 109 - Haematologica - Vol. 105 n. 6 - June 2020

Myeloid Neoplasms
Oral arsenic trioxide ORH-2014 pharmacokinetic and safety profile in patients with advanced hematologic disorders
Farhad Ravandi,1 Iphigenia Koumenis,2 Anandhi Johri,2 Martin Tallman,3 Gail J. Roboz,4 Stephen Strickland,5 Guillermo Garcia-Manero,1
Gautam Borthakur,1 Kiran Naqvi,1 Meghan Meyer,1 Madhu Pudipeddi,2 Sirish Nidarmarthy,2 Kris Vaddi2 and Hagop Kantarjian1
1M.D. Anderson Cancer Center, Houston, TX; 2Orsenix, Wilmington, DE; 3Memorial Sloan Kettering Cancer Center, New York, NY; 4Weill Cornell Medicine, New York, NY and 5Vanderbilt University Medical Center, Nashville, TN, USA
ABSTRACT
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 tri- oxide formulation, consisting of micron-size drug particles with rapid disso- lution 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 recom- mendation 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 ther- apies. 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 inter- ruption. 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 com- pared 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).
Introduction
As a rare subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) accounts for 10 to 15% of approximately 21,450 new cases of adults with AML per year in the USA.1 APL leukemic cells typically harbor a t (15:17) chromosomal translocation resulting in the expression of the promyelocyt- ic leukemia-retinoic acid receptor (PML-RARα) gene fusion, which blocks the nor- mal cell differentiation processes. Clinically, the disease often presents with coagu- lopathy that can lead to catastrophic hemorrhage. Until recently, the standard-of- care for patients with newly diagnosed with APL involved the combination of all- trans-retinoic acid (ATRA) plus anthracycline-based chemotherapy for induction and consolidation.2 In general, patients receive two to three cycles until complete molecular remission is achieved. After consolidation, patients receive ATRA with or without low-dose chemotherapy for 1 to 2 years for maintenance.
Arsenic has been used to treat a variety of diseases such as the plague and malaria for more than 2 millennia.3 In the late 1900s arsenic was found to have anti- leukemic activity and was used for ~70 years to treat various leukemias. In the 1990s, three teams of Chinese researchers found that intravenous (IV) arsenic tri- oxide (ATO) was effective in patients with APL, with complete responses (CR)
Ferrata Storti Foundation
Haematologica 2020 Volume 105(6):1567-1574
Correspondence:
FARHAD RAVANDI
fravandi@mdanderson.org
Received: June 13, 2019.
Accepted: September 24, 2019. Pre-published: September 26, 2019.
doi:10.3324/haematol.2019.229583
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/106/6/1567
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