Advanced Hematological Disorders
Conditions
Keywords
acute promyelocytic leukemia, APL, arsenic trioxide
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.
Interventions
DRUGORH-2014
ORH-2014 capsule 5 mg orally with dose escalations of 5 mg intervals.
Sponsors
Orsenix LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Part 1 of the study is parallel. Part 2 will be an expansion phase.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To identify the recommended dose | From baseline to Week 4 | The recommended dose is determined by the number of patients who experience a dose limiting toxicity (DLT). |
| 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 | Up to Week 28 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent terminal elimination half-life (t1/2) | Baseline up to Week 24 | — |
| 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) | Baseline up to Week 24 | — |
| To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by area under the concentration-time curve extrapolated to infinity (AUC0-infinity) | Baseline up to Week 24 | — |
| To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent terminal elimination rate constant (λZ) | Baseline up to Week 24 | — |
| To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent total clearance (CL/F) | Baseline up to Week 24 | — |
| To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by maximum observed concentration (Cmax) | Baseline up to Week 24 | — |
| To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent total volume of distribution (Vz/F) | Baseline up to Week 24 | — |
| To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by accumulation ratio (AR) | Baseline up to Week 24 | — |
| To evaluate the effect of ORH-2014 on QT-interval corrected for heart rate using Fridericia's formula (QTcF) | Baseline up to Week 28 | — |
| Safety Assessment during the expansion phase of the study on the effect of oral ORH-2014 on safety parameters | Baseline up to Week 28 | During the expansion phase of the study, an aggregate clinical data review (ACDR) will be conducted. This review will collect data from electronic data capture, the ECG central review vendor (ERT), and other sources to include but is not limited to: * NCI-CTCAE Grade 3 and 4 AEs, SAEs, deaths; * Laboratory results; * Vital signs; * ECG's; * Individual subject profiles including, but not limited to: medical history, AEs, concomitant medications, laboratory results, and vital signs; * Subject disposition and screen failure rates. |
| The number of participants with a complete response (CR) or partial response (PR) according to International Working Group (IWG) response criteria | Up to Week 24 | Bone marrow aspirates and/or biopsies will be obtained at the designated timepoints for evaluation of efficacy. Response criteria will be according to the International Working Group. Responders are participants who obtain complete remission (CR) or partial remission (PR), with or without cytogenetic response, and marrow complete remission. |
| To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent total clearance normalized by body weight (CL/F/kg) | Baseline up to Week 24 | — |
| To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by time to maximum concentration (Tmax) | Baseline up to Week 24 | — |
Countries
United States
Outcome results
None listed