Page 110 - Haematologica - Vol. 105 n. 6 - June 2020

F. Ravandi et al.
observed in 66% of patients in one study.4 In other stud- ies, up to 90% of relapsed patients with APL and over 70% of newly diagnosed patients achieved responses.5,6 Following this success, several clinical studies conducted in the USA established the safety and efficacy of IV ATO in patients with APL who had relapsed after prior ATRA + anthracycline therapy. In the first pilot study, 92% of the 12 patients treated achieved a CR with IV ATO alone, and 67% had undetectable PML-RAR transcripts.7 In a larger trial (n=40), 85% of patients with relapsed APL achieved CR; more than three-quarters of the patients were alive after 2 years.8 This trial formed the basis for the approval of IV ATO, Trisenox®, in the USA in 2000 and in Europe in 2002 for second line therapy of patients with APL who are refractory to - or have relapsed from - ATRA + anthra- cycline chemotherapy.9 Since 2000, ATO has been used as the standard-of-care for relapsed APL, with remission rates greater than 80% as a single agent after two 25-day cycles.
Several investigators have examined the role of IV ATO in frontline therapy of patients with newly diagnosed APL and have demonstrated that this approach is feasible.10-13 Recently, two large randomized trials have shown that the combination of ATRA and IV ATO for induction is supe- rior to ATRA + chemotherapy in the treatment of APL patients with standard-risk disease.14,15 Moreover, long- term follow-up of these patients showed that patients treated with ATRA + IV ATO had a significantly higher event-free and overall survival and a significantly lower cumulative relapse rate compared with the ATRA + chemotherapy cohort.16 These findings have led to new recommendations for the use of IV ATO as a first-line therapy in combination with ATRA for the management of patients with standard-risk APL (white blood cell [WBC] count ≤10×109/L), with additional chemotherapy reserved for patients with high-risk disease (WBC count >10×109/L).17,18 The combination of IV ATO + ATRA is also safe and effective in patients who are not suitable candidates for anthracycline-based chemotherapy, such as those with significant cardiac disease or older adults.14,15
As a front-line therapy for APL, ATO needs to be admin- istered IV daily for over 100 doses, which is inconvenient, costly, and leads to a decreased quality of life for the patients. Therefore, the introduction of an oral ATO for- mulation could improve patients’ quality of life, and drug compliance, while reducing costs.
Two oral formulations of ATO have been developed in Hong Kong. One is a liquid formulation of As2O3 at 1 mg/mL (pH 7.2), which was found to be highly bioavail- able.19 In relapsed APL patients, the formulation was high- ly active, showing an efficacy comparable to IV ATO.20 As a maintenance regimen in APL patients with first com- plete remission, the formulation was effective in the long term, with a 3-year leukemia-free-survival, event-free sur- vival, and overall-survival of 87.7%, 83.7%, and 90.6%, respectively.21 Oral ATO incorporation into frontline treat- ment with ATRA and chemotherapy in newly diagnosed APL is safe and reduces relapses.22 This oral liquid formu- lation did not induce QT prolongation or cardiac arrhyth- mias,20,21,23 and the severity and incidence of other side effects (leucocytosis, LFT abnormalities, and skin rashes) was comparable to that of IV ATO.20
However, commercializing a liquid oral formulation intended to be self-administered by patients could repre- sent a safety challenge in handling and dosing. Therefore,
a solid oral formulation of ATO is preferable. The other oral formulation developed in China is a pill termed RIF containing Realgar, a naturally occurring mixture contain- ing tetra arsenic tetra sulfide (As4S4; 30 mg per pill), Indigo naturalis, Radix salvia miltiorrhizae, and Radix pseudostellari- ae.24 In a phase 2 clinical trial conducted in China, the for- mulation demonstrated a CR rate of 96.7% and a reason- able safety profile in newly diagnosed APL patients.25 In a phase 3 study, RIF + ATRA was not inferior to IV ATO + ATRA as first-line treatment for APL, and adverse events (AE) were similar in the two arms.26 RIF has been commer- cialized and is available in China.
However, these oral ATO formulations are not available in Western markets. Therefore, a unique oral powder cap- sule formulation of ATO, ORH-2014, was developed, for the treatment of APL and other hematologic malignancies. Herein we report the results of the first-in-human study with ORH-2014 in subjects with relapsed advanced hema- tological disorders. ORH-2014 safety profile, recommend- ed dose, pharmacokinetic profile, and preliminary efficacy data are reported and discussed.
Methods
For ORH-2014 formulation development and physical proper- ties, see the Online Supplementary Materials and Methods.
We conducted a multicenter phase 1 open-label, dose-escalating study to evaluate the safety, tolerability, pharmacokinetics and to determine the recommended dose and preliminary efficacy of oral ORH-2014 in patients with advanced hematologic malignancies. ORH-2014 dose-escalation was designed as 5-mg increments starting from 5 mg and could potentially go up to 50 mg, in a stan- dard 3x3 dose-escalation scheme (described below). The starting dose (5 mg) was chosen to be approximately half of the IV ATO approved dose of 0.15 mg/kg for a 70-kg person (i.e. 5.25 mg). ORH-2014 was administered orally once daily (QD) in the fasted state. Dose-escalation was to be stopped when the mean area under the concentration-time curve from 0 to 24 hours (AUC0-24) and/or the maximum observed concentration (Cmax) of total arsenic in plasma at a given dose of ORH-2014 was ≥30% higher than that for IV ATO at the approved dose or if the maximum tolerated dose (MTD) was reached. Anticancer agents other than ORH- 2014 (including systemic chemotherapy, radiation therapy, or bio- logic response modifiers) were not permitted during the study, except for the temporary use of hydroxyurea. Supportive care was allowed, including antibiotics, IV electrolytes, platelet transfu- sions, and steroids.
Male and non-pregnant female subjects ≥18 years of age with the following advanced hematological disorders and no available therapies were eligible for enrolment: (i) Relapsed or refractory AML with nucleophosmin-1 (NPM1) mutations; (ii) relapsed or refractory APL; (iii) relapsed or refractory intermediate or high-risk myelodysplastic syndrome (MDS); (iv) relapsed or refractory chronic myelomonocytic leukemia (CMML) and other MDS/myeloproliferative neoplasm (MPN) overlapping syn- dromes; or (v) relapsed or refractory mantle cell lymphoma (MCL). Subjects were excluded if they had an Eastern Cooperative Oncology Group performance status >3; absolute myeloblast count ≥20,000/mm3; remaining toxicities (>grade I) due to previ- ous chemotherapy; abnormal liver function tests (above specified limits); impaired cardiac function; or had received any antineo- plastic therapy (except hydroxyurea) within <5 half-lives before ORH-2014 administration. All participants gave written informed consent before entering the study.
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