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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

NCT03048344

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Acute Promyelocytic Leukemia
  • Chronic Myelomonocytic Leukemia
  • Mantle Cell Lymphoma
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasm
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: ORH2014-001
  • NCT ID: NCT03048344

Conditions

  • Advanced Hematological Disorders

Interventions

DrugSynonymsArms
ORH-2014Part 1
ORH-2014Part 2

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Part 1ExperimentalSubjects will receive oral ORH-2014 at a planned starting dose of 5 mg once daily (QD) in the fasted state. If escalation criteria are met, the administered dose will increase by 5 mg increments to a maximum of 50 mg QD. The starting daily dose is approximately half the typical IV dose (0.15 milligram per kilogram [mg/kg]) extrapolated to a 70-kg person.
  • ORH-2014
Part 2ExperimentalSubjects will receive a daily oral dose of ORH-2014 at the recommended dose identified in Part 1. ORH-2014 will be administered in the fasted state.
  • ORH-2014

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To identify the recommended dose
Time Frame:From baseline to Week 4
Safety Issue:
Description:The recommended dose is determined by the number of patients who experience a dose limiting toxicity (DLT).

Secondary Outcome Measures

Measure:To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by maximum observed concentration (Cmax)
Time Frame:Baseline up to Week 24
Safety Issue:
Description:
Measure:To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by time to maximum concentration (Tmax)
Time Frame:Baseline up to Week 24
Safety Issue:
Description:
Measure:To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent terminal elimination half-life (t1/2)
Time Frame:Baseline up to Week 24
Safety Issue:
Description:
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)
Time Frame:Baseline up to Week 24
Safety Issue:
Description:
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)
Time Frame:Baseline up to Week 24
Safety Issue:
Description:
Measure:To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent terminal elimination rate constant (λZ)
Time Frame:Baseline up to Week 24
Safety Issue:
Description:
Measure:To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent total clearance (CL/F)
Time Frame:Baseline up to Week 24
Safety Issue:
Description:
Measure:To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent total clearance normalized by body weight (CL/F/kg)
Time Frame:Baseline up to Week 24
Safety Issue:
Description:
Measure:To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent total volume of distribution (Vz/F)
Time Frame:Baseline up to Week 24
Safety Issue:
Description:
Measure:To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by accumulation ratio (AR)
Time Frame:Baseline up to Week 24
Safety Issue:
Description:
Measure:To evaluate the effect of ORH-2014 on QT-interval corrected for heart rate using Fridericia's formula (QTcF)
Time Frame:Baseline up to Week 28
Safety Issue:
Description:
Measure:Safety Assessment during the expansion phase of the study on the effect of oral ORH-2014 on safety parameters
Time Frame:Baseline up to Week 28
Safety Issue:
Description: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.
Measure:The number of participants with a complete response (CR) or partial response (PR) according to International Working Group (IWG) response criteria
Time Frame:Up to Week 24
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Orsenix LLC

Trial Keywords

  • acute promyelocytic leukemia
  • APL
  • arsenic trioxide

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