Page 111 - Haematologica - Vol. 105 n. 6 - June 2020

Oral arsenic trioxide pharmacokinetics and safety
First, a cohort of three subjects received ORH-2014 at the dose 5 mg QD, and dose-limiting toxicities (DLT) were observed for four weeks (DLT definition in the Online Supplementary Materials and Methods). If none of the three subjects exhibited a DLT in the four-week period, then the study could advance to the next higher dose level. At any dose level, if 1 of 3 subjects exhibited a DLT, the cohort was to be expanded to six subjects. If 1 of 6 subjects exhib- ited a DLT, the next subject was to be enrolled at the next higher dose level. If ≥1 of 3 or 6 subjects exhibited a DLT, then the dose level below was considered the maximum tolerated dose (MTD). Subjects with no DLT continued to receive ORH-2014 at the same dose for an additional eight weeks, followed by bone marrow evaluation to analyze response. Subjects achieving CR or partial remission (PR) at the end of the 12-week treatment period were eligible to receive an additional 12 weeks of therapy. The study was approved by the institutional review board affiliated with each study site.
Results
ORH-2014 physical properties
ORH-2014 molecular formula is AS2O3, As4O6 in form (Figure 1), and its relative molecular mass is 197.8 g/mol. ORH-2014 oral capsule formulation was developed by a lyophilization process (see the Online Supplementary Materials and Methods), which significantly reduces the ATO particle size and increases the particle surface area
(Table 1). The aggregate particle size of the Lyopremix (see the Online Supplementary Materials and Methods) was about 5-10-fold smaller than that of the unprocessed ATO. The specific surface area of the Lyopremix was also significant- ly higher than that of the unprocessed ATO. Figure 2A shows the structure of ORH-2014 Lyopremix, which con- sists of a matrix of sodium lauryl sulfate with microscopic ATO crystals with well-defined morphology. The small particle size and the large surface area of the ATO Lyopremix in ORH-2014 allows rapid drug dissolution in the simulated gastric media of 0.1 N HCl (80% of the compound dissolved in 10 minutes; Figure 2B), potentially enhancing oral bioavailability.
Patient characteristics
The trial enrolled 12 patients (eight males; four females) with advanced hematologic malignancies: six with advanced MDS, four with refractory AML with NPM1
Table 1. ORH-2014 particle size and surface area. Unprocessed
Lyophilized ATO (ORH-2014)*
~16-30 μm ~2-8 m2/g
Particle size (D90)
Particle surface area
ATO
139 μm 0.05 m2/g
Table 2. Subjects’ demographic and baseline characteristics. 5 mg
10 mg n=6
73.0 (9.6) 76.5 (55, 81)
1 (16.7%)
5 (83.3%) 5 (83.3%)
−
1 (16.7%)
−
6 (100%)
72.83 (12.59) 73.95 (56.0, 91.0)
3 (50.0%)
15 mg n=3
66.0 (16.1) 71.0 (48, 79)
2 (66.7%)
1 (33.3%)
All subjects n=12
69.8 (12.9) 76.5 (45, 81)
4 (33.3%)
8 (66.7%)
*Range of values for nine batches of Lyopremix. See Online Supplementary Materials and Methods for ORH-2014 physical properties assessment. ATO: arsenic trioxide.
Age, years
Mean (SD) Median (min, max)
Sex, n (%)
Female
Male Race, n (%)
n=3
67.0 (19.1) 78.0 (45, 78)
1 (33.3%)
2 (66.7%) 3 (100%)
− −
2 (66.7%)
1 (33.3%)
87.50 (15.43) 84.80 (73.6, 104.1)
1 (33.3%)
White
Black/African American
Asian
Allother* − − − −
Ethnicity, n (%)
Hispanic/Latino
Not Hispanic/Latino Weight, kg
Mean (SD)
Median (min, max)
Type of hematologic malignancy
AML
−
3 (100%)
88.43 (6.25) 86.60 (83.3, 95.4)
0
2 (16.7%)
10 (83.3%)
80.40 (13.60) 81.50 (56.0, 104.1)
4 (33.3%)
2 (66.7%) 1 (33.3%) −
10 (83.3%) 1 (8.3%) 1 (8.3%)
APL 0000
MDS 2 (66.7%) 3 (50.0%) 1 (33.3%) 6 (50.0%)
CMML/MPN 0 0 2 (66.7%) 2 (16.7%)
MCL 0000
* All other races included Native Hawaiian or Pacific Islander, American Indian or Alaska Native, and other. AML: acute myeloid leukemia; APL: acute promyelocytic leukemia; MDS: myelodysplastic syndrome; CMML: chronic myelomonocytic leukemia; MPN: MDS/myeloproliferative neoplasm; MCL: mantle cell lymphoma.
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