Page 112 - Haematologica - Vol. 105 n. 6 - June 2020

F. Ravandi et al.
Table 3. Common drug-related adverse events (observed in ≥2 subjects). 5 mg
10 mg n=6
4 (66.7%)
2 1 1 1 1
15 mg n=3
4 (66.7%)
1 2 1 1 1
All subjects n=12
8 (66.7%)
5 (41.6%) 4 (33.3%) 3 (25.0%) 2 (16.6%) 2 (16.6%)
Number of subjects with ≥1 drug-related AE Nausea
Diarrhea
Headache
Dizziness Anorexia
Data are n (%) of subjects.
n=3
2 (66.7%)
2 1 1 0 0
mutation, and two with CMML (Table 2). The median patient age was 76.5 years (range: 45-81), (83.3%) were white, the median weight was 81.5 kg (range: 56.0-104.1) and patients had a median of two prior therapies (range: 1-5).
ORH-2014 safety profile
All 12 patients were included in the safety analysis set. No DLT was reported during the four-week DLT observa- tion period. Eight subjects (66.7%) had drug-related AE; the incidence of AE was identical in the three dose groups (66.3%) (Table 3). The most common drug-related AE were nausea (n=5), diarrhea (n=4), and headache (n=3). All but one drug-related AE were mild or moderate (grade I- II). Grade III AE of QTcF prolongation occurred in one subject (8.3%) outside of the DLT observation period (on day 68), and was attributed to ORH-2014 and concomi- tant levofloxacine (Levaquin®; a fluoroquinolone antibiot- ic). Since both levofloxacin and ATO are known to induce QT prolongation,9,30 both were stopped. The AE resolved, and treatment with ORH-2014 alone was resumed at the same dose (5 mg), without any further occurrence of QT prolongation. The patient was able to receive ORH-2014 at 5 mg QD for a total of 171 days. There were very few renal, hepatic, and hematologic AE related to the underly- ing disease state, with the exception of grade I transamini- tis attributed to ORH-2014; this event resolved on its own without treatment interruption or any medications. Two deaths occurred (on days 35 and 40 post dose) due to pro- gression of the disease, both unrelated to ORH-2014.
ORH-2014 pharmacokinetic profile Total plasma arsenic
Following single and repeated oral administration of 5, 10 or 15 mg of ORH-2014 QD, the median Tmax for total plasma arsenic occurred between 1 and 12 hours (Table 4). On day 15, Cmax and AUC0-24 geometric means increased by 3.4- and 2.9-fold, respectively, over the 3-fold dose increase (5-15 mg), indicating that systemic exposure was nearly dose-proportional (Figure 3). There was a low cor- relation (below 0.2) between total the arsenic exposure and patients’ BMI, suggesting that a flat dose of ORH- 2014 (rather than mg/kg dose) is adequate.
On days 15 and 22, between-subject variability (geo- metric % CV) was generally moderate with % CV ranging from 17% to 37% for Cmax, and from 34% to 41% for AUC0-24 (Table 4)
The mean extent of accumulation (AR, which is based on AUC0-24) was approximately 3- to 4-fold on Day 5, 4- to 5-fold (excluding a patient receiving 5 mg ORH-2014 who had a 7-fold accumulation) on Day 15, and 4- to 5-
fold on Day 22 (Table 4). The approximately 5-fold accu- mulation indicated an effective half-life of three days. Visual inspection of trough total arsenic concentrations also indicated that a steady-state reached by day 15 (Figure 3). The observed time to reach steady-state (15 days) is consistent with an effective half-life of three days, since 97% of steady-state is achieved after five half-lives (5x3 days = 15 days).
ORH-2014 at the 15 mg dose is comparable to the IV ATO approved dose (0.15 mg/kg) for adult patients. Exposure to 15 mg ORH-2014 was compared to exposure to IV ATO at the approved dose, using IV ATO historical data (Table 4). After daily administration of 10 mg ORH- 2014 for 15 days, ORH-2014 Cmax was about half of IV- ATO Cmax at day 8 (mean: 66 vs. 124 ng/mL, respectively) but its AUC0-24 was similar (1,340 vs. 1,302 h*ng/mL, respectively). At 15 mg, ORH-2014’s Cmax was similar to IV-ATO’s (mean: 114 vs. 124 ng/mL, respectively) but its AUC0-24 was higher (2,140 vs. 1,302 h*ng/mL).
Pharmacokinteics of arsenical species
The pharmacokinetic (PK) of arsenical species ([AsIII], [AsV], [MMAV], [DMAV]) was determined for all subjects in this study (see the Online Supplementary Materials and
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Figure 1. Arsenic oxide structural formula. Atoms are represented as spheres, with oxygen in red and arsenic in purple.