Oral arsenic trioxide ORH-2014 pharmacokinetic and safety profile in patients with advanced hematologic disorders

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 trioxide formulation, consisting of micron-size drug particles with rapid dissolution and high bioavailability. We conducted a multicenter phase 1 doseescalating 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 C max 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.clinicaltrials.gov).

Resurrection of Oral Arsenic Trioxide for Treating Acute Promyelocytic Leukaemia: A Historical Account From Bedside to Bench to Bedside

“…Since then, the main finding of this study, namely that orally administered (though differently formulated) As 2 O 3 attains virtually the same systemic bioavailability as i.v. dosing was confirmed by others (18,19). The latter researchers also pointed out that compared to i.v.…”

“…dosing (21,22), differences in arsenic absorption capacity from the gut is unlikely to be the main explanation. with these types of therapeutic doses are safe (18,19,23). The optimal dose of oral-As 2 O 3 we suggest is 10 mg (0.15-0.2 mg/kg) per day in adult patients (≥50 kg) with normal renal function.…”

“…For instance, ORH-2014 was recently shown to be safe in patients with leukaemia and had comparable bioavailability to i.v. As 2 O 3 (19).…”

The Role of Reactive Oxygen Species in Arsenic Toxicity

“…Arsenic can be found in soil, water, and air from natural and anthropogenic sources. Over time, arsenic has accumulated a variety of uses, for example in cosmetics, wood preservatives, cotton desiccants, pesticides, and even in the treatment of acute promyelocytic leukemia (APL) [2][3][4]. however, evidence of arsenic poisoning has occurred from oral ingestion of arsenic, when found as a contaminant in food or potable water and when used as a therapeutic.…”

The History of the Chemo-Free Model in the Treatment of Acute Promyelocytic Leukemia

“…Early death (ED) is commonly defined as death from any cause within 30 days of diagnosis 12 or at any time during induction (10,11). Details about this definition have been systematically reviewed in recent years (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). As a result of selection bias, clinical trial data have underestimated the impact of ED, but a series of epidemiologic studies revealed that a significant proportion of patients continue to suffer early death (27)(28)(29).…”