Clinical trial NCT03048344: A Phase I, Two-part Study to Determine the Recommended Dose and Evaluate the Safety and Tolerability of a Novel Oral Arsenic Trioxide Formulation (ORH-2014) in Subjects With Advanced Hematological Disorders
Official title: A Phase I, Two-part Study to Determine the Recommended Dose and Evaluate the Safety and Tolerability of a Novel Oral Arsenic Trioxide Formulation (ORH-2014) in Subjects With Advanced Hematological Disorders
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Hematological Disorders
Keywords: acute promyelocytic leukemia
APL
arsenic trioxide
Lead sponsor: Orsenix LLC
Sponsor class: INDUSTRY
First posted: 2017-02-09
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Part 1 of the study is parallel. Part 2 will be an expansion phase.
Primary purpose: TREATMENT

Brief summary: Part 1 will be conducted as an open-label, non-randomized, non-placebo-controlled dose escalation study using pre-specified doses. Subjects with the following advanced hematological disorders and no available therapies, and who satisfy all inclusion/exclusion criteria will be enrolled. The purpose is to identify the recommended dose of oral ORH-2014 in subjects with advanced hematological disorders.

Part 2 will be an expansion phase conducted as a single-arm, open-label study to further evaluate the safety and tolerability of ORH-2014 at the maximum tolerated dose (MTD) or recommended dose determined from Part 1 in the fasted state. Subjects with the same disease types as in Part 1 will be enrolled. All subjects will receive oral ORH-2014, in the fasted state, at the recommended dose for an initial period of up to 12 weeks. The purpose is to evaluate the safety and tolerability of oral ORH-2014 in a population of subjects with advanced hematological disorders when administered at the recommended dose.


Eligibility criteria: Inclusion Criteria:

* Female and male subjects ≥18 years of age with one of the following:

  * Relapsed or refractory acute myelocytic leukemia (AML) with nucleophosmin-1 (NPM1) mutations and no available therapies.
  * Relapsed or refractory acute promyelocytic leukemia (APL), with no available therapies. Note: Prior exposure to arsenic trioxide is allowed; however, subjects who have failed arsenic trioxide within the last 12 months are not allowed.
  * Relapsed or refractory myelodysplastic syndrome (MDS), International Prognostic Scoring System intermediate or high-risk, with no available therapies
  * Relapsed or refractory chronic myelomonocytic leukemia (CMML), and other MDS/myeloproliferative neoplasm (MPN) overlap syndromes, with no available therapies
  * Relapsed or refractory mantle cell lymphoma (MCL) with no adequate therapies.
* Negative pregnancy test at the Screening visit for women of childbearing potential and willingness to use adequate birth control
* Not willing to undergo, not a candidate for, or not having a donor for immediate (within 3 months from the Screening date) bone marrow transplantation.

Exclusion Criteria:

* Eastern Cooperative Oncology Group performance status of ≥3;
* Absolute myeloblast count ≥20,000/mm\^3;
* Administration of any antineoplastic therapy within 5 half-lives of the antineoplastic therapy before the first dose of ORH-2014, with the exception of hydroxyurea that should be discontinued 1 day prior to the first dose of ORH-2014
* Presence of any remaining toxicities due to previous chemotherapy
* Participation in other clinical trials within at least 2 weeks of the first ORH-2014 dose;
* Clinical evidence of active central nervous system leukemia;
* Active and uncontrolled infection
* Major surgery within 2 weeks prior to trial entry;
* Liver function tests above the following limits at Screening: total bilirubin \>1.5 x upper limit of normal (ULN) unless related to Gilbert's syndrome or hemolysis; aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \>2.5 x ULN; for subjects with liver involvement, AST and/or ALT \>5 x ULN;
* Serum creatinine \>1.5 x ULN and/or creatinine clearance or estimated glomerular filtration rate \<30 mL/min
* Impaired cardiac function
* Myocardial infarction of unstable angina within 6 months prior to the planned start date of study drug.

Primary outcomes:
measure: To identify the recommended dose
timeFrame: From baseline to Week 4
measure: Number of Participants With Adverse Events (AE) as a Measure of Safety and Tolerability of ORH-2014 when administered at the MTD or recommended dose
timeFrame: Up to Week 28
Secondary outcomes:
measure: To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by maximum observed concentration (Cmax)
timeFrame: Baseline up to Week 24
measure: To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by time to maximum concentration (Tmax)
timeFrame: Baseline up to Week 24
measure: To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent terminal elimination half-life (t1/2)
timeFrame: Baseline up to Week 24
measure: To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by area under the concentration-time curve from 0 to 24 hours (AUC0-24)
timeFrame: Baseline up to Week 24
measure: To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by area under the concentration-time curve extrapolated to infinity (AUC0-infinity)
timeFrame: Baseline up to Week 24
measure: To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent terminal elimination rate constant (λZ)
timeFrame: Baseline up to Week 24
measure: To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent total clearance (CL/F)
timeFrame: Baseline up to Week 24
measure: To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent total clearance normalized by body weight (CL/F/kg)
timeFrame: Baseline up to Week 24
measure: To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent total volume of distribution (Vz/F)
timeFrame: Baseline up to Week 24
measure: To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by accumulation ratio (AR)
timeFrame: Baseline up to Week 24
measure: To evaluate the effect of ORH-2014 on QT-interval corrected for heart rate using Fridericia's formula (QTcF)
timeFrame: Baseline up to Week 28
measure: Safety Assessment during the expansion phase of the study on the effect of oral ORH-2014 on safety parameters
timeFrame: Baseline up to Week 28
measure: The number of participants with a complete response (CR) or partial response (PR) according to International Working Group (IWG) response criteria
timeFrame: Up to Week 24
Other outcomes:
Locations:
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Houston
country: United States
facility: MD Anderson
state: Texas
Study officials:
affiliation: MD Anderson
name: Farhad Ravandi-Kashani, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ravandi F, Koumenis I, Johri A, Tallman M, Roboz GJ, Strickland S, Garcia-Manero G, Borthakur G, Naqvi K, Meyer M, Pudipeddi M, Nidarmarthy S, Vaddi K, Kantarjian H. Oral arsenic trioxide ORH-2014 pharmacokinetic and safety profile in patients with advanced hematologic disorders. Haematologica. 2020 Jun;105(6):1567-1574. doi: 10.3324/haematol.2019.229583. Epub 2019 Sep 26.