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).

Study Overview
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Brief Summary
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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
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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).

Official Title
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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

Conditions
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Iron Deficiency Anemia

Intervention / Treatment
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* Drug: KER-047


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 D1. 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 2 parts: Part 1 Initial Titration Strategy and Part 2 Cohort Expansion or Alternate Titration Strategy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 (Initial Titration Strategy)<br>KER-047(30 mg, 60mg or 80mg) oral tablet daily (or every other day) for up to 24 weeks. | Drug: KER-047<br>* Oral tablet, daily (or every other day) administration<br>|
| Experimental: Part 2 (Cohort Expansion or Alternate Titration Strategy)<br>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. | Drug: KER-047<br>* Oral tablet, daily (or every other day) administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants experiencing Treatment-emergent adverse events (TEAEs) | To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| Dose limiting toxicities (DLTs) | To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| Percentage of participants experiencing Treatment-related AEs (Adverse events) | To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| Number of participants discontinuing due to AEs (Adverse events) | To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| Change from Baseline in clinical laboratory values | 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. | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| Systolic Blood Pressure | To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| Diastolic Blood Pressure | To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| Respiratory rate | To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| Heart rate | To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| Body temperature | To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| Fridericia corrected QT interval via 12-lead Electrocardiogram (ECG) | To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| QT interval via 12-lead Electrocardiogram (ECG) | To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| QRS interval via 12-lead Electrocardiogram (ECG) | To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| PR interval via 12-lead Electrocardiogram (ECG) | To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| Body weight (in kg) | To determine safety and tolerability of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in reticulocyte hemoglobin content (RET-He) | 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 | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| Change from baseline in hepcidin concentration | 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 | Up to 29 weeks in Part 1 or up to 101 weeks if continuing in the treatment extension | 
| Change from baseline in hemoglobin (Hgb) | To evaluate the effect of KER-047 on anemia in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | 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 ≥1.0 g/dL (0.6 mmol/L) | To evaluate the effect of KER-047 on anemia in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | 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) | To evaluate the effect of KER-047 on anemia in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | 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 | To evaluate the effect of KER-047 on anemia in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 29 weeks or up to 101 weeks if in the treatment extension | 
| Plasma KER-047 and any metabolites concentration, summarized by time point | To evaluate the Pharmacokinetic (PK) of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Week 1 and Week 13 in Part 1 and 2 | 
| Estimated peak plasma concentration (Cmax) | To evaluate the Pharmacokinetic (PK) of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Week 1 and Week 13 in Part 1 and 2 | 
| Time to peak plasma concentration (Tmax) | To evaluate the Pharmacokinetic (PK) of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Week 1 and Week 13 in Part 1 and 2 | 
| Area under the plasma KER-047 concentration curve (AUClast) | To evaluate the Pharmacokinetic (PK) of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Week 1 and Week 13 in Part 1 and 2 | 
| Mean trough (Ctrough) plasma KER-047 and metabolites of interest concentration | To evaluate the Pharmacokinetic (PK) of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 25 weeks | 
| Plasma KER-047 and metabolites of interest accumulation (Rac) | To evaluate the Pharmacokinetic (PK) of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 25 weeks | 
| Determination of steady-state (as appropriate) | To evaluate the Pharmacokinetic (PK) of KER-047 in participants with functional IDA associated with MDS, MF, and MDS/MPN overlap syndromes | Up to 25 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Functional Iron Deficiency Anemia (Functional IDA), Myelodysplastic Syndromes (MDS), Myelofibrosis (MF), Myelodysplastic Syndrome (MDS), Myeloproliferative Neoplasm Overlap Syndromes (MPN)