A Phase 2, Intrapatient Dose Titration Study of KER-047 in Participants With Functional Iron Deficiency Anemia Associated With Myelodysplastic Syndromes, Myelofibrosis, and Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap Syndromes
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 试验地点
- 5
- 主要终点
- Heart rate
研究概览
简要总结
This study aims to explore the safety and preliminary efficacy of a response-guided dose titration of KER-047 in the treatment of functional IDA (Iron deficiency anemia) in MDS (Myelodysplastic syndrome), MF(Myelofibrosis), and MDS/MPN (Myeloproliferative neoplasm) overlap syndromes.
详细描述
This is a Phase 2 multicenter, open-label study being conducted to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of response-guided dose titration of KER-047 in adult participants with functional iron deficiency anemia (IDA) associated with myelodysplastic syndrome (MDS), myelofibrosis (MF), and myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes. Approximately 20 patients will be enrolled. Dosing of KER-047 may be adjusted based on safety/tolerability and treatment response. The study will be conducted in 2 parts: Part 1 Initial Titration Strategy and Part 2 Cohort Expansion or Alternate Titration Strategy.
The total planned duration of participation for an individual participant is approximately 32 weeks (4-week screening phase, 24-week treatment period, and 4-week follow-up period). For participants in the extension phase, the maximum duration of participation would be approximately 104 weeks (2 years) (4-week screening phase, 24-week treatment period, 18 month [72 weeks] extension period, and 4-week follow-up period).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Male or female ≥18 years of age, at the time of signing informed consent.
- •One of the following:
- •Diagnosis of MDS according to the 2016 World Health Organization (WHO) classification that meets Revised International Prognostic Scoring System (IPSS-R) classification of very low, low, or intermediate risk disease with bone marrow blast percentage <5% within 6 months prior to Day 1 (D1).
- •Diagnosis of primary myelofibrosis, post polycythemia vera MF, or post-essential thrombocytopenia MF according to the 2017 WHO criteria with bone marrow and peripheral blood blast percentage <2%, or stable between 2% to 5% over 6 months.
- •Diagnosis of MDS/MPN overlap syndromes according to the 2016 WHO classification, with bone marrow blast percentage <5% within 6 months prior to D
- •Anemia with iron-restricted erythropoiesis as assessed by laboratory criteria during screening.
- •Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information in accordance with national and local study participant privacy regulations.
- •Females of childbearing potential and sexually active males must meet the contraception requirements as outlined in the protocol.
排除标准
- •Active infection within 14 days of D
- •IPSS-R score indicating high or very high risk MDS, accelerated myelofibrosis (defined as >10% blasts), or diagnosis of acute leukemia.
- •Diagnosis of hemolytic anemia.
- •Diagnosis of porphyria.
- •Anemia due to blood loss 28 days prior to D
- •Diagnosis of thalassemia, thalassemia trait, or other hemoglobinopathy.
- •History of drug or alcohol abuse, as defined by the Investigator, within the past 2 years.
- •History of stroke, arterial embolism, or deep venous thrombosis within 6 months prior to D
- •Known positive for human immunodeficiency virus, active infectious hepatitis B virus or active infectious hepatitis C virus.
研究组 & 干预措施
Part 1 (Initial Titration Strategy)
KER-047(30 mg, 60mg or 80mg) oral tablet daily (or every other day) for up to 24 weeks.
干预措施: KER-047 (Drug)
Part 2 (Cohort Expansion or Alternate Titration Strategy)
The starting dose regimen and titration schedule of KER-047 oral tablet will be based on the SRC (Safety Review Committee) recommendation from Part 1.
干预措施: KER-047 (Drug)
结局指标
主要结局
Heart rate
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Fridericia corrected QT interval via 12-lead Electrocardiogram (ECG)
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Percentage of participants experiencing Treatment-emergent adverse events (TEAEs)
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Dose limiting toxicities (DLTs)
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Diastolic Blood Pressure
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
QT interval via 12-lead Electrocardiogram (ECG)
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Body weight (in kg)
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Systolic Blood Pressure
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Respiratory rate
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
PR interval via 12-lead Electrocardiogram (ECG)
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Percentage of participants experiencing Treatment-related AEs (Adverse events)
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Number of participants discontinuing due to AEs (Adverse events)
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Change from Baseline in clinical laboratory values
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine the safety and tolerability based on changes from baseline in select clinical laboratory parameters including: Alkaline phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Gamma Glutamyl Transferase, Glucose, Potassium, Sodium, Total bilirubin, Folate, WBC count, Platelet Count, Reticulocyte Count, Transferrin Saturation percentage. Note - Select safety parameters will be listed as separate outcomes during results update.
Body temperature
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
QRS interval via 12-lead Electrocardiogram (ECG)
时间窗: Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension
To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
次要结局
- Determination of steady-state (as appropriate)(Up to 25 weeks)
- Change from baseline in hepcidin concentration(Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension)
- Proportion of participants who have Hgb increase of ≥1.5 g/dL (0.9 mmol/L)(Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension)
- Estimated peak plasma concentration (Cmax)(Week 1 and Week 13 in Part 1 and 2)
- Plasma KER-047 and metabolites of interest accumulation (Rac)(Up to 25 weeks)
- Proportion of participants who have Hgb increase of ≥1.0 g/dL (0.6 mmol/L)(Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension)
- Change from baseline in hemoglobin (Hgb)(Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension)
- Proportion of RBC-transfused participants who achieve ≥8 weeks of transfusion independence during any consecutive period up to End of Treatment(Up to 29 weeks or up to 101 weeks if in the treatment extension)
- Time to peak plasma concentration (Tmax)(Week 1 and Week 13 in Part 1 and 2)
- Area under the plasma KER-047 concentration curve (AUClast)(Week 1 and Week 13 in Part 1 and 2)
- Mean trough (Ctrough) plasma KER-047 and metabolites of interest concentration(Up to 25 weeks)
- Change from baseline in reticulocyte hemoglobin content (RET-He)(Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension)
- Plasma KER-047 and any metabolites concentration, summarized by time point(Week 1 and Week 13 in Part 1 and 2)