A Phase 2, Open-Label, Ascending Dose Study of KER-050 for the Treatment of Anemia in Patients With Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MDS)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 160
- 试验地点
- 74
- 主要终点
- Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
研究概览
简要总结
The main aim of this study is to learn how safe elritercept is and how well adults with anemia associated with lower-risk MDS tolerate treatment with different doses of elritercept. Other aims are to learn how safe elritercept is by looking at how many participants have MDS that worsens during the study and learn about the effects of elritercept on anemia linked to MDS. The study will also look to learn how elritercept affects the production of healthy RBCs.
详细描述
Elritercept (KER-050) is a recombinant fusion protein being studied to increase red blood cell production by inhibiting the signaling of a subset of the transforming growth factor beta (TGF-ß) family of proteins.
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
- •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.
- •Male or female ≥ 18 years of age, at the time of signing informed consent.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (if related to anemia).
- •Females of childbearing potential and sexually active males must agree to use highly effective methods of contraception.
- •In the opinion of the Investigator, the participant is able and willing to comply with the requirements of the protocol (e.g., all study procedures, return for follow-up visits).
- •Part 1 Inclusion Criteria
- •Participants are eligible to be included in Part 1 of the study only if all the following criteria apply:
- •Diagnosis of MDS according to WHO classification that meets International Prognostic Scoring System-Revised (IPSS-R) classification of very low, low, or intermediate risk disease.
- •Less than (<)5percent (%) blasts in bone marrow during the Pretreatment Period.
- •Peripheral blood white blood cell (WBC) count <13,000/microliter (μL) during the Pretreatment Period.
- •Anemia defined as:
- •In non-transfused participants, having received no RBC transfusions within 8 weeks, Hgb concentration ≤ 10.0 g/dL during the Pretreatment Period OR
- •In LTB participants, having received 1 to 3 units of RBCs for Hgb ≤ 9.0 g/dL within 8 weeks of the Pretreatment Period.
- •In HTB participants, having received ≥ 4 units of RBCs for Hgb ≤ 9.0 g/dL within 8 weeks of the Pretreatment Period.
- •Part 1 Extension - Abbreviated Inclusion Criteria
- •Participants from Part 1 are eligible to be included in Part 1 Extension of the study only if all the following criteria apply:
- •Previously completed 4 cycles of elritercept in Part 1 with no dose-limiting toxicities (DLTs).
- •Participant has the potential to benefit from administration of elritercept, in the opinion of the Investigator.
- •< 5% blasts in bone marrow.
- •Peripheral WBC count < 13,000/μL during the 28 days prior to cycle 5 day 1 (C5D1).
- •Part 2 Inclusion Criteria
- •Participants are eligible to be included in Part 2 of the study only if all the following criteria apply:
- •Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
- •ring sideroblast (RS)-positive as defined by WHO 2016 criteria.
- •Requiring at least 2 units of RBC transfusions in the preceding 8 weeks before cycle 1 day 1 (C1D1).
- •Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
- •Non-RS as defined by WHO 2016 criteria.
- •Requiring at least 2 units of RBC transfusions in the 8 weeks before C1D
- •Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
- •Has anemia, defined by Hgb ≤ 10 g/dL during the Pretreatment Period, and received no RBC transfusion in the 8 weeks before C1D
- •Diagnosis of CMML according to WHO classification.
- •Has anemia, defined by Hgb ≤ 10 g/dL during the Pretreatment Period, and received no RBC transfusion in the 8 weeks before C1D
- •Received at least 2 units of RBC transfusions for anemia in the 8 weeks before C1D
- •Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
- •Requiring ≥ 2 units of RBC transfusions in the preceding 8 weeks before C1D
- •Receipt of ≥ 20 units of RBC in transfusion over the participant's lifetime.
- •Serum ferritin > 1000 nanograms per milliliter (ng/mL) on ≥ 2 assessments in the preceding 8 weeks before C1D
- •Treated with stable dose of iron chelation therapy for ≥ 8 weeks prior to C1D
- •Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
- •Requiring ≥ 2 units of RBC transfusions in the preceding 8 weeks before C1D
- •Receipt of ≥ 20 units of RBC in transfusion over the participant's lifetime.
- •Serum ferritin > 1000 ng/mL on ≥ 2 assessments in the preceding 8 weeks before C1D
- •Not treated with iron chelation therapy in the preceding 8 weeks before C1D1 and not eligible to initiate iron chelation therapy in the opinion of the Investigator and in accordance with local treatment guidelines for initiation of iron chelation therapy.
- •Diagnosis of MDS according to WHO classification that meets IPSS-R classification of very low, low, or intermediate risk disease.
- •RS-positive as defined by WHO 2016 criteria OR non-RS as defined by WHO 2016 criteria.
- •Relapsed, refractory, or intolerant to frontline luspatercept treatment and have not received an interceding therapy (for example, erythropoiesis-stimulating agent [ESA])
- •Relapsed is defined as documentation of response to luspatercept therapy and subsequent development of a need for transfusion(s).
- •Refractory is defined as documentation of no response with luspatercept ≥ 1 mg/kg administered for ≥ 12 weeks duration.
- •Intolerant is defined as documentation of discontinuation of luspatercept therapy due to intolerance or an AE at any time after introduction.
- •Requiring ≥ 2 units of RBC transfusions over 8 weeks prior to C1D
- 另有 3 项未显示
排除标准
- •Participants are excluded from Part 1 of the study if any of the following criteria apply.
- •Medical History
- •Diagnosis of MDS with deletion of chromosome 5q (Del5q).
- •Active infection requiring parenteral antibiotic therapy within 28 days prior to C1D1 or oral antibiotics within 14 days of C1D
- •Prophylactic antibiotics and/or antifungals for neutropenia are allowed.
- •Presence of uncontrolled heart disease or New York Heart Association (NYHA) Class III or IV heart failure.
- •History of drug or alcohol abuse (as defined by the Investigator) within the past 2 years.
- •History of stroke, deep venous thrombosis (DVT), or arterial embolism within 6 months prior to C1D
- •Major surgery within 28 days prior to C1D
- •Participants must be completely recovered from any previous surgery prior to C1D
- •Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B virus (HBV), or active infectious hepatitis C virus (HCV). Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
- •Any malignancy other than MDS that has not been in remission and/or has required systemic therapy including radiation, chemotherapy, hormonal therapy, or surgery, within 1 year prior to C1D
- •Diagnosis of secondary MDS (i.e., MDS known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases).
- •History of solid organ or hematological transplantation.
- •Presence of uncontrolled hypertension, defined as systolic blood pressure (BP) ≥ 150 mmHg or diastolic BP ≥ 100 mmHg despite adequate treatment.
- •Body mass index (BMI) ≥ 40 kilograms per meter square (kg/m^2) during the Pretreatment Period.
- •History of severe allergic or anaphylactic reaction(s) or hypersensitivity to recombinant proteins or excipients in the investigational medicinal product (IMP).
- •Treatment History
- •Prior treatment with azacitidine, decitabine, lenalidomide, luspatercept, or sotatercept.
- •Treatment with ESA within 56 days prior to C1D
- •Prior or concurrent chronic treatment with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF).
- •Iron chelation therapy if initiated within 8 weeks prior to C1D
- •Vitamin B12 therapy initiated within 8 weeks prior to C1D
- •Participants on stable replacement doses for ≥ 8 weeks and without concurrent vitamin B12 or folate deficiency are allowed.
- •Treatment with another investigational drug or device or approved therapy for investigational use ≤ 28 days prior to C1D1, or, if the half-life of the previous product is known, within 5 times the half-life prior to C1D1, whichever is longer.
- •Laboratory Exclusions (during Pretreatment Period)
- •Platelet count > 450 ✕ 10^9/L or < 30 ✕ 10^9/L.
- •Transferrin saturation < 15%.
- •Ferritin < 50 nanograms per milliliter (ng/mL).
- •Folate < 4.5 nanomoles per liter (nmol/L) (< 2.0 ng/mL).
- •Vitamin B12 < 148 picomoles per liter (pmol/L) (< 200 picograms per milliliter [pg/mL]).
- •Estimated glomerular filtration rate (GFR) < 30 milliliter per minute per 1.73 meter square (mL/min/1.73 m^2), as determined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
- •Positive for HIV.
- •Miscellaneous
- •Pregnant or lactating females.
- •Any other condition not specifically noted above which, in the opinion of the Investigator, would preclude the participant from participating in the study.
- •Participants who are investigational site staff members directly involved in the conduct of the trial and their immediate family members, site staff members otherwise supervised by the Investigator, or participants who are Sponsor or contract research organization (CRO) employees directly involved in the conduct of the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
- •Part 1 Extension - Exclusion Criteria
- •Participants from Part 1 are excluded from Part 1 Extension of the study if any of the following criteria apply.
- •Medical History
- •Discontinuation of IMP in Part 1 for any reason.
- •Has not completed a study visit in the past 12 months.
- •Active infection requiring parenteral antibiotic therapy within 28 days prior to C5D1 or oral antibiotics within 14 days of C5D
- •Prophylactic antibiotics and/or antifungals for neutropenia are allowed.
- •Presence of uncontrolled heart disease or NYHA Class III or IV heart failure.
- •History of drug or alcohol abuse (as defined by the Investigator) within the past 2 years.
- •History of stroke, DVT, or arterial embolism within 6 months prior to C5D
- •Major surgery within 28 days prior to C5D
- •Participants must be completely recovered from any previous surgery prior to C5D
- •Known positive for HIV, active infectious HBV, or active infectious HCV. Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
- 另有 78 项未显示
研究组 & 干预措施
Experimental: Part 2: Elritercept Dose Confirmation Cohort D
Participants with chronic myelomonocytic leukemia (CMML) and anemia will be administered Elritercept at 3.75 mg/kg, SC injection, on Day 1, every 4 weeks for up to 24 cycles (each cycle = 28 days). The dose can be modified based on participant's response.
干预措施: Elritercept (Drug)
Part 2: Elritercept Dose Confirmation Cohort E
Participants with MDS (either RS-positive or non-RS) who are requiring RBC transfusions, have iron-overload, and are receiving iron chelation therapy will be administered Elritercept at 3.75 mg/kg, SC injection, on Day 1, every 4 weeks for up to 24 cycles (each cycle = 28 days). The dose can be modified based on participant's response.
干预措施: Elritercept (Drug)
Part 2: Elritercept Dose Confirmation Cohort F
Participants with MDS (either RS-positive or non-RS) who are requiring RBC transfusions, have iron-overload, and are not receiving iron chelation therapy will be administered Elritercept at 3.75 mg/kg, SC injection, on Day 1, every 4 weeks for up to 24 cycles (each cycle = 28 days). The dose can be modified based on participant's response.
干预措施: Elritercept (Drug)
Long-term Extension Cohort
Participants from Part 1 and 2 cohorts who may have potential benefit from continued elritercept treatment, in the opinion of the Investigator, may elect to continue in the LTE at the same dose they were being administered in Part 1 and 2, SC injection, on day 1, every 4 weeks until end of treatment (EOT) (approximately 122 months).
干预措施: Elritercept (Drug)
Part 1: Elritercept Cohort 4
Participants will be administered elritercept at 3.75 mg/kg, SC injection, every 4 weeks on Day 1 of each cycle for up to 4 cycles (each cycle = 28 days). Following the above dose regimen, participants will continue to receive elritercept, administered SC, on Day 1, every 4 weeks up to 24 cycles (each cycle = 28 days).
干预措施: Elritercept (Drug)
Part 1: Elritercept Cohort 5
Participants will be administered elritercept at 5.0 mg/kg, SC injection, every 4 weeks on Day 1 of each cycle for up to 4 cycles (each cycle = 28 days). Following the above dose regimen, participants will continue to receive elritercept, administered SC, on Day 1, every 4 weeks up to 24 cycles(each cycle = 28 days).
干预措施: Elritercept (Drug)
Part 2: Elritercept Dose Confirmation Cohort A
Participants with ring sideroblasts (RS)-positive Myelodysplastic syndrome (MDS) who are requiring red blood cell (RBC) transfusions will be administered Elritercept at 3.75 mg/kg, SC injection, on Day 1, every 4 weeks for up to 24 cycles (each cycle = 28 days). The dose can be modified based on participant's response.
干预措施: Elritercept (Drug)
Part 2: Elritercept Dose Confirmation Cohort B
Participants with non-RS MDS who are requiring RBC transfusions will be administered Elritercept at 3.75 mg/kg, SC injection, on Day 1, every 4 weeks for up to 24 cycles (each cycle = 28 days). The dose can be modified based on participant's response.
干预措施: Elritercept (Drug)
Part 2: Elritercept Dose Confirmation Cohort C
Participants who are non-transfused with either RS-positive MDS or non-RS MDS will be administered Elritercept at 3.75 mg/kg, SC injection, on Day 1, every 4 weeks for up to 24 cycles (each cycle = 28 days). The dose can be modified based on participant's response.
干预措施: Elritercept (Drug)
Part 1: Elritercept Cohort 1
Participants will be administered elritercept at 0.75 milligrams per kilogram (mg/kg), subcutaneous (SC) injection, every 4 weeks on Day 1 of each cycle for up to 4 cycles (each cycle = 28 days). Following the above dose regimen, participants will continue to receive elritercept, administered SC, on Day 1, every 4 weeks up to 24 cycles (each cycle = 28 days).
干预措施: Elritercept (Drug)
Part 1: Elritercept Cohort 2
Participants will be administered elritercept at 1.5 mg/kg, SC injection, every 4 weeks on Day 1 of each cycle for up to 4 cycles (each cycle = 28 days). Following the above dose regimen, participants will continue to receive elritercept, administered SC, on Day 1, every 4 weeks up to 24 cycles (each cycle = 28 days).
干预措施: Elritercept (Drug)
Part 1: Elritercept Cohort 3
Participants will be administered elritercept at 2.5 mg/kg, SC injection, every 4 weeks on Day 1 of each cycle for up to 4 cycles (each cycle = 28 days). Following the above dose regimen, participants will continue to receive elritercept, administered SC, on Day 1, every 4 weeks up to 24 cycles (each cycle = 28 days).
干预措施: Elritercept (Drug)
Part 2: Elritercept Dose Confirmation Cohort G
Participants with MDS (either RS-positive or non-RS) who require RBC transfusions and have either relapsed, become refractory to, or intolerant to frontline luspatercept treatment will be administered Elritercept at 3.75 mg/kg, SC injection, on Day 1, every 4 weeks for up to 24 cycles (each cycle = 28 days). The dose can be modified based on participant's response.
干预措施: Elritercept (Drug)
结局指标
主要结局
Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
时间窗: From treatment initiation to end of study (up to 11.2 years)
An AE is defined as any untoward medical occurrence, in a clinical study participant administered a medicinal product, that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not it is related to the medicinal (investigational) product. An SAE is any untoward medical occurrence that, at any dose: results in death, is life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a medically important event.
次要结局
- Number of Participants with Progression to Higher Risk MDS or Acute Myeloid Leukemia (AML)(From study day 1 through end of study (up to 11.2 years))
- Percentage of Participants with Low Transfusion Burden (LTB) and High Transfusion Burden (HTB) who Achieve RBC Transfusion Independence (TI)(From study day 1 through end of study (up to 11.2 years))
- Percentage of Participants who Achieve Hematologic Improvement Erythroid (HI-E) Response Based on Modified 2006 International Working Group (IWG)(From study day 1 to end of study (up to 11.2 years))
- Percentage of Participants who Achieve Overall Erythroid Response(Up to approximately 11.2 years)
- Percentage of Participants who Achieve Erythropoietic Improvement(Up to approximately 11.2 years)
- Mean Change from Baseline in Hgb(Baseline, multiple timepoints post treatment up to 11.2 years)
- Time to HI-E Response(Up to approximately 11.2 years)
- Duration of HI-E Response(Up to approximately 11.2 years)
- Time to TI Response(Up to approximately 11.2 years)
- Duration of TI response(Up to approximately 11.2 years)
- Percentage of LTB and HTB Participants who Achieve TI(Weeks 12, 16, 24 and 48)
- Number of Participants with Change from Baseline in Red Cell Parameters(Up to approximately 11.2 years)