SAFETY AND PHARMACOKINETICS OF A NOVEL ORAL CAPSULE FORMULATION OF ARSENIC TRIOXIDE, ORH-2014, IN PATIENTS WITH ADVANCED HEMATOLOGIC DISORDERS
Author(s): ,
Farhad Ravandi-Kashani
Affiliations:
Dept of Leukemia,MD Anderson Cancer Center,Houston,United States
,
K. Vaddi
Affiliations:
Founder Orsenix,Wilmington,United States
,
A. Johri
Affiliations:
Consultant,N Jersey,United States
,
M. Pudipeddi
Affiliations:
Consultant,Wilmington,United States
,
S. Nidamarthy
Affiliations:
Orsenix,Wilmington,United States
,
G. Garcia-Manero
Affiliations:
MD Anderson,Houston ,United States
,
G. Borthakur
Affiliations:
MD Anderson,Houston,United States
,
K. Naqvi
Affiliations:
MD Anderson,Houston,United States
,
M. Meyer
Affiliations:
MD Anderson,Houston,United States
,
I. Koumenis
Affiliations:
Orsenix,Wilmington,United States
H. Kantarjian
Affiliations:
MD Anderson,Houston,United States
(Abstract release date: 05/17/18) EHA Library. Ravandi-Kashani F. 06/15/18; 214724; PF238
Dr. Farhad Ravandi-Kashani
Dr. Farhad Ravandi-Kashani
Contributions
Abstract

Abstract: PF238

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
The management of Acute Promyelocytic Leukemia (APL) has evolved significantly with the concurrent use of ATRA and ATO for induction, considered as standard of care, as proven by large randomized studies . These studies have demonstrated that non-high-risk APL patients (WBC< 10*109/L) can achieve sustained and prolonged clinical and molecular remission using ATRA and intravenous (IV) Arsenic Trioxide  (ATO), without chemotherapy. Similar results using oral arsenic formulations have been reported by Chinese investigators. Given the need for prolonged  daily administration of intravenous arsenic trioxide, oral arsenic derivatives represent an important advance in the treatment of APL.  

Aims
Orsenix set out to develop a simple, scalable and orally bioavailable capsule formulation manufactured by a unique lyophilization process that results in a drug substance, ORH-2014, that demonstrates high surface area and rapid dissolution.

Methods
A multicenter Phase I study, started in Dec 2016, to identify the recommended dose of ORH-2014 in patients with relapsed and/or refractory hematologic disorders. ORH-2014 was administered orally, once a day in the fasted state. A total of seven patients were enrolled in two cohorts: 3 patients in Cohort 1 at the 5 mg dose and 4 in cohort 2, at 10mg dose. The primary endpoint was to assess safety and tolerability of ORH-2014 and identify the recommended Phase II dose. Secondary endpoints were: pharmacokinetics (PK), effect on QTc, and efficacy. Dose Limiting Toxicities (DLT) were monitored for Days 1-29 of dosing, and plasma samples were collected for PK between Days 1-22 of dosing. Total arsenic concentrations in plasma were measured by a validated method using inductively coupled plasma mass spectrometry (ICP-MS).

Results
Patients with advanced myelodysplastic syndrome or acute myeloid leukemia were enrolled.  The median age of patients was 76 (45-78) years. There were no significant safety issues with no drug related severe adverse events including no significant QT prolongation and no DLTs.  Two patients were replaced due to progression of AML and early withdrawal from study (25 days and 22 days). Following oral administration of 10 mg QD ORH‑2014, for 15 days, geometric mean (geo CV% [min, max]) Cmax and AUC0-24 values of total arsenic were were 64.5 (43.2% [43.0, 115]) ng/mL and 1340 (43.9% [839, 2330]) h*ng/mL, respectively. The measured plasma exposure at Day 15 (AUC0-24) following 10 mg QD oral dosing was similar to that reported for the approved dose of IV ATO. Total Arsenic plasma concentrations after 5 and 10 mg ORH‑2014 QD ranged 21.8-36.9 ng/mL and 30.5-83.4 ng/mL, respectively, and these levels were similar to the Day 8 trough levels of 21.0-35.0 ng/mL following IV administration of 0.15 mg/kg Trisenox.

Conclusion
The 10 mg QD oral dose of ORH2014 provides similar exposure of total arsenic, measured in plasma, to that of the approved dose of IV ATO (0.15mg/kg). This safe and well tolerated dose of ORH104 is recommended for a future randomized trial for frontline therapy in standard risk APL patients.

 

 

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): APL, Arsenic trioxide, Oral

Abstract: PF238

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
The management of Acute Promyelocytic Leukemia (APL) has evolved significantly with the concurrent use of ATRA and ATO for induction, considered as standard of care, as proven by large randomized studies . These studies have demonstrated that non-high-risk APL patients (WBC< 10*109/L) can achieve sustained and prolonged clinical and molecular remission using ATRA and intravenous (IV) Arsenic Trioxide  (ATO), without chemotherapy. Similar results using oral arsenic formulations have been reported by Chinese investigators. Given the need for prolonged  daily administration of intravenous arsenic trioxide, oral arsenic derivatives represent an important advance in the treatment of APL.  

Aims
Orsenix set out to develop a simple, scalable and orally bioavailable capsule formulation manufactured by a unique lyophilization process that results in a drug substance, ORH-2014, that demonstrates high surface area and rapid dissolution.

Methods
A multicenter Phase I study, started in Dec 2016, to identify the recommended dose of ORH-2014 in patients with relapsed and/or refractory hematologic disorders. ORH-2014 was administered orally, once a day in the fasted state. A total of seven patients were enrolled in two cohorts: 3 patients in Cohort 1 at the 5 mg dose and 4 in cohort 2, at 10mg dose. The primary endpoint was to assess safety and tolerability of ORH-2014 and identify the recommended Phase II dose. Secondary endpoints were: pharmacokinetics (PK), effect on QTc, and efficacy. Dose Limiting Toxicities (DLT) were monitored for Days 1-29 of dosing, and plasma samples were collected for PK between Days 1-22 of dosing. Total arsenic concentrations in plasma were measured by a validated method using inductively coupled plasma mass spectrometry (ICP-MS).

Results
Patients with advanced myelodysplastic syndrome or acute myeloid leukemia were enrolled.  The median age of patients was 76 (45-78) years. There were no significant safety issues with no drug related severe adverse events including no significant QT prolongation and no DLTs.  Two patients were replaced due to progression of AML and early withdrawal from study (25 days and 22 days). Following oral administration of 10 mg QD ORH‑2014, for 15 days, geometric mean (geo CV% [min, max]) Cmax and AUC0-24 values of total arsenic were were 64.5 (43.2% [43.0, 115]) ng/mL and 1340 (43.9% [839, 2330]) h*ng/mL, respectively. The measured plasma exposure at Day 15 (AUC0-24) following 10 mg QD oral dosing was similar to that reported for the approved dose of IV ATO. Total Arsenic plasma concentrations after 5 and 10 mg ORH‑2014 QD ranged 21.8-36.9 ng/mL and 30.5-83.4 ng/mL, respectively, and these levels were similar to the Day 8 trough levels of 21.0-35.0 ng/mL following IV administration of 0.15 mg/kg Trisenox.

Conclusion
The 10 mg QD oral dose of ORH2014 provides similar exposure of total arsenic, measured in plasma, to that of the approved dose of IV ATO (0.15mg/kg). This safe and well tolerated dose of ORH104 is recommended for a future randomized trial for frontline therapy in standard risk APL patients.

 

 

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): APL, Arsenic trioxide, Oral

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