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

Orsenix LLC12 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Advanced Hematological Disorders

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (4)

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Weill Cornell Medical College

New York, New York, United States

Vanderbilt University

Nashville, Tennessee, United States

MD Anderson

Houston, Texas, United States

Outcomes

Primary Outcomes

To identify the recommended dose

The recommended dose is determined by the number of patients who experience a dose limiting toxicity (DLT).

Time frame: From baseline to Week 4

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

To evaluate safety and tolerability the aggregate review will include but is not limited to: * NCI-CTCAE Grade 3 and 4 AEs, serious adverse events (SAEs), deaths; * Laboratory results; * Vital signs; * ECGs; * Individual subject profiles including, but not limited to: medical history, AEs, concomitant medications, laboratory results, and vital signs; * Subject disposition and screen failure rates.

Time frame: Up to Week 28

Secondary Outcomes

To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by maximum observed concentration (Cmax)