Page 115 - Haematologica - Vol. 105 n. 6 - June 2020

Oral arsenic trioxide pharmacokinetics and safety
clinical trials with ORH-2014. The most common drug- related AE (observed in ≥3 [25%] patients) were nausea, diarrhea, and headache, which were grade I-II (mild and moderate). ORH-2014 did not induce any clinically signif- icant hepatic toxicities which are reported with IV ATO at a great frequency (16-23% and 44%, respectively).9 Many of the adverse reactions observed with IV ATO are serious (grade ≥III): in a phase 2 study with IV ATO, 25% of patients had QTc interval ≥500 msec (grade III-IV), and the rates of grade III-IV differentiation syndrome, hyperleuko- cytosis, atrial dysrhythmias, and hyperglycemia were 5% to 7.5% with ORH-2014, only one drug-related AE (grade III) of QT prolongation was observed in one (8.3%) patient who was taking both ORH-2014 5 mg and fluo- rofloxacine, an antibiotic known to induce QT prolonga- tion. The event was transient and reversible upon inter- ruption of both drugs, and the patient was able to resume treatment with ORH-2014, at a 5 mg dose alone with no further cardiac conduction issues, for a total duration of 187 days on study. The fewer side effects observed with ORH-2014 could be attributed to its lower Cmax and stead- ier exposure profile3 prior to steady state (~day 15). Altogether, the findings of this phase 1 study indicate that ORH-2014 oral formulation may be safer than the approved IV ATO formulation. The convenient oral dos- ing could make it suitable for the treatment of APL and other hematologic malignancies at home without the need of daily hospital visits for IV administration.
Of note ORH-2014 also resulted in a lower incidence of AE, especially lower liver toxicity, compared to the other two oral arsenic formulations. Indeed, liver toxicity was observed in 48% of the patients (26% of whom had grade III-IV toxicities) with the liquid formulation,22 and 45% (all grade I-II) with the Realgar-Indigo naturalis Formula (RIF) formulation,26 while only one (8.3%) transient grade I liver toxicity occurred with ORH-2014, albeit this was observed in a smaller sample population (n=12).
Although this phase 1 study was not formally intended to demonstrate ORH-2014 efficacy, disease improvement was observed in one patient and another patient became eligible for bone marrow transplant with MDS. Additional studies will need to be conducted in MDS and other hematologic malignancies.
This first-in-human phase 1 study in patients with advanced hematological malignancies was intended to determine the safety profile, PK profile, and dose of ORH- 2014. Therefore, in this study we did not conduct a side- by-side comparison of ORH-2014 and IV ATO, and used IV ATO historical data for comparison. A parallel compar- ison with IV ATO may be performed in the next planned study in patients with APL in whom IV ATO is approved. While data from a crossover design may add value to the study, it requires the drug to be held for over one week for an adequate washout of ATO, which is not acceptable in patients with advanced hematological malignancies who require ongoing treatment.
Oral formulations of ATO, including ORH-2014, could represent safer and similarly active alternatives to IV ATO and could have great utility for the treatment of patients with APL by improving the patients’ quality of life and treatment compliance, while reducing the patient burden and treatment costs. Based on the findings of the present study, a flat dose of 15 mg daily ORH-2014, administered daily (like IV ATO), appears to be adequate for the induc- tion and consolidation therapy in adult patients with hematologic malignancies in future trials. Additional stud- ies may be conducted with alternate treatment regimen if deemed necessary. In pediatric patients, however, a per- weight dose is recommended.
Acknowledgments
The authors thank Florence Paillard for her editorial assis- tance, and Stuart Hossack and Mary Sherman for the expert analysis in pharmacokinetics.
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