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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Orsenix LLC
- 入组人数
- 12
- 试验地点
- 4
- 主要终点
- To identify the recommended dose
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Part 1
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.
干预措施: ORH-2014 (Drug)
Part 2
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.
干预措施: ORH-2014 (Drug)
结局指标
主要结局
To identify the recommended dose
时间窗: 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
时间窗: 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.
次要结局
- 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 maximum observed concentration (Cmax)(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)
- 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 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)
- 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)
- 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 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)
- Safety Assessment during the expansion phase of the study on the effect of oral ORH-2014 on safety parameters(Baseline up to Week 28)