Back to resultsA 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
Primary Purpose
Advanced Hematological Disorders
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
ORH-2014
ORH-2014
Sponsored by
About this trial
This is an interventional treatment trial for Advanced Hematological Disorders focused on measuring acute promyelocytic leukemia, APL, arsenic trioxide
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.
Sites / Locations
- Memorial Sloan-Kettering Cancer Center
- Weill Cornell Medical College
- Vanderbilt University
- MD Anderson
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Part 1
Part 2
Arm Description
Subjects 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.
Subjects 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.
Outcomes
Primary Outcome Measures
To identify the recommended dose
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
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 Outcome Measures
To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by maximum observed concentration (Cmax)
To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by time to maximum concentration (Tmax)
To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent terminal elimination half-life (t1/2)
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)
To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by area under the concentration-time curve extrapolated to infinity (AUC0-infinity)
To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent terminal elimination rate constant (λZ)
To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent total clearance (CL/F)
To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent total clearance normalized by body weight (CL/F/kg)
To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by apparent total volume of distribution (Vz/F)
To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by accumulation ratio (AR)
To evaluate the effect of ORH-2014 on QT-interval corrected for heart rate using Fridericia's formula (QTcF)
Safety Assessment during the expansion phase of the study on the effect of oral ORH-2014 on safety parameters
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
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03048344
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
Study Type
Interventional
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
December 2, 2016 (Actual)
Primary Completion Date
February 28, 2019 (Actual)
Study Completion Date
February 28, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Orsenix LLC
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Hematological Disorders
Keywords
acute promyelocytic leukemia, APL, arsenic trioxide
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
Part 1 of the study is parallel. Part 2 will be an expansion phase.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
12 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Part 1
Arm Type
Experimental
Arm Description
Subjects 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.
Arm Title
Part 2
Arm Type
Experimental
Arm Description
Subjects 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.
Intervention Type
Drug
Intervention Name(s)
ORH-2014
Intervention Description
ORH-2014 capsule 5 mg orally with dose escalations of 5 mg intervals.
Intervention Type
Drug
Intervention Name(s)
ORH-2014
Intervention Description
ORH-2014 capsule at recommended dose orally.
Primary Outcome Measure Information:
Title
To identify the recommended dose
Description
The recommended dose is determined by the number of patients who experience a dose limiting toxicity (DLT).
Time Frame
From baseline to Week 4
Title
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
Description
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 Outcome Measure Information:
Title
To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by maximum observed concentration (Cmax)
Time Frame
Baseline up to Week 24
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
To determine the plasma pharmacokinetic (PK) profiles of total arsenic as measured by accumulation ratio (AR)
Time Frame
Baseline up to Week 24
Title
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
Title
Safety Assessment during the expansion phase of the study on the effect of oral ORH-2014 on safety parameters
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.
Time Frame
Baseline up to Week 28
Title
The number of participants with a complete response (CR) or partial response (PR) according to International Working Group (IWG) response criteria
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.
Time Frame
Up to Week 24
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Farhad Ravandi-Kashani, MD
Organizational Affiliation
MD Anderson
Official's Role
Principal Investigator
Facility Information:
Facility Name
Memorial Sloan-Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Weill Cornell Medical College
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37240
Country
United States
Facility Name
MD Anderson
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
31558670
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.
Results Reference
derived
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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
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