A Study to Evaluate the Safety and Preliminary Efficacy of a Response-guided Dose Titration of KER-047 in the Treatment of Functional IDA (Iron Deficiency Anemia).
- Conditions
- Iron Deficiency Anemia
- Interventions
- Drug: KER-047
- Registration Number
- NCT05927012
- Lead Sponsor
- Keros Therapeutics, Inc.
- Brief Summary
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.
- Detailed Description
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).
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
-
Male or female ≥18 years of age, at the time of signing informed consent.
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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 D1.
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Anemia with iron-restricted erythropoiesis as assessed by laboratory criteria during screening.
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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.
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Females of childbearing potential and sexually active males must meet the contraception requirements as outlined in the protocol.
- Active infection within 14 days of D1.
- 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 D1.
- 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 D1.
- Known positive for human immunodeficiency virus, active infectious hepatitis B virus or active infectious hepatitis C virus.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 2 (Cohort Expansion or Alternate Titration Strategy) KER-047 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. Part 1 (Initial Titration Strategy) KER-047 KER-047(30 mg, 60mg or 80mg) oral tablet daily (or every other day) for up to 24 weeks.
- Primary Outcome Measures
Name Time Method Heart rate 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) 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) 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) 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 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) 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) 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 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 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) 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) 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) 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 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 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) 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
- Secondary Outcome Measures
Name Time Method Determination of steady-state (as appropriate) Up to 25 weeks To evaluate the Pharmacokinetic (PK) of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Plasma KER-047 and metabolites of interest accumulation (Rac) Up to 25 weeks To evaluate the Pharmacokinetic (PK) of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Change from baseline in hepcidin concentration Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension To evaluate the Pharmacodynamic (PD) effects of KER-047 on iron metabolism in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
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 To evaluate the effect of KER-047 on anemia in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Estimated peak plasma concentration (Cmax) Week 1 and Week 13 in Part 1 and 2 To evaluate the Pharmacokinetic (PK) of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
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 To evaluate the effect of KER-047 on anemia in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Change from baseline in hemoglobin (Hgb) Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension To evaluate the effect of KER-047 on anemia in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
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 To evaluate the effect of KER-047 on anemia in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Time to peak plasma concentration (Tmax) Week 1 and Week 13 in Part 1 and 2 To evaluate the Pharmacokinetic (PK) of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Area under the plasma KER-047 concentration curve (AUClast) Week 1 and Week 13 in Part 1 and 2 To evaluate the Pharmacokinetic (PK) of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Mean trough (Ctrough) plasma KER-047 and metabolites of interest concentration Up to 25 weeks To evaluate the Pharmacokinetic (PK) of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
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 To evaluate the Pharmacodynamic (PD) effects of KER-047 on iron metabolism in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Plasma KER-047 and any metabolites concentration, summarized by time point Week 1 and Week 13 in Part 1 and 2 To evaluate the Pharmacokinetic (PK) of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes
Trial Locations
- Locations (5)
Laniado Hospital - Sanz Medical Center
🇮🇱Netanya, Israel
Hadassah University Medical Center
🇮🇱Jerusalem, Israel
Galilee Medical Center
🇮🇱Nahariya, Israel
Shamir Medical Center (Assaf Harofeh Medical Center)
🇮🇱Zrifin, Israel
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia