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

Farhad Ravandi, Iphigenia Koumenis, Anandhi Johri, Martin Tallman, Gail J Roboz, Stephen Strickland, Guillermo Garcia-Manero, Gautam Borthakur, Kiran Naqvi, Meghan Meyer, Madhu Pudipeddi, Sirish Nidarmarthy, Kris Vaddi, Hagop Kantarjian, Farhad Ravandi, Iphigenia Koumenis, Anandhi Johri, Martin Tallman, Gail J Roboz, Stephen Strickland, Guillermo Garcia-Manero, Gautam Borthakur, Kiran Naqvi, Meghan Meyer, Madhu Pudipeddi, Sirish Nidarmarthy, Kris Vaddi, Hagop Kantarjian

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 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).

Copyright© 2020 Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
Arsenic oxide structural formula. Atoms are represented as spheres, with oxygen in red and arsenic in purple.
Figure 2.
Figure 2.
ORH-2014 particles and dissolution profile. A: ORH-2014 Lyopremix by scanning electron microscopy; bar represents 5 μm. B: ORH-2014 capsule dissolution kinetic. See the Online Supplementary Materials and Methods for ORH-2014 particle size and dissolution assessments.
Figure 3.
Figure 3.
Plasma arsenic concentration-time curves at days 1, 5, 15, and 22. Red curves: 5 mg ORH-2014 QD (n=3); green curves: 10 mg ORH-2014 QD (n=6); blue curves: 15 mg ORH-QD (n=3). Data are arithmetic mean ± standard deviation (SD) total arsenic (ng/mL plasma). See the Online Supplementary Materials and Methods for pharmacokinetic (PK) data analyses. h: hours.

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Source: PubMed

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