Myelodysplastic Syndromes, Cytopenia
Conditions
Keywords
Transfusion, Drug Therapy, Elritercept, TAK-226, KER-050
Brief summary
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.
Detailed description
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.
Interventions
DRUGElritercept
Elritercept SC injection.
Sponsors
Takeda
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Ascending dose study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 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. 2. Male or female ≥ 18 years of age, at the time of signing informed consent. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (if related to anemia). 4. Females of childbearing potential and sexually active males must agree to use highly effective methods of contraception. 5. 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: 1. 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. 2. Less than (\<)5percent (%) blasts in bone marrow during the Pretreatment Period. 3. Peripheral blood white blood cell (WBC) count \<13,000/microliter (μL) during the Pretreatment Period. 4. Anemia defined as: 1. In non-transfused participants, having received no RBC transfusions within 8 weeks, Hgb concentration ≤ 10.0 g/dL during the Pretreatment Period OR 2. In LTB participants, having received 1 to 3 units of RBCs for Hgb ≤ 9.0 g/dL within 8 weeks of the Pretreatment Period. OR 3. 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: 1. Previously completed 4 cycles of elritercept in Part 1 with no dose-limiting toxicities (DLTs). 2. Participant has the potential to benefit from administration of elritercept, in the opinion of the Investigator. 3. \< 5% blasts in bone marrow. 4. 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: 1. Cohort A: * 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). 2. Cohort B: * 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 C1D1. 3. Cohort C: * 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 C1D1. 4. Cohort D: * 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 C1D1. * OR * Received at least 2 units of RBC transfusions for anemia in the 8 weeks before C1D1. 5. Cohort E: * 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 C1D1. * 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 C1D1. * Treated with stable dose of iron chelation therapy for ≥ 8 weeks prior to C1D1. 6. Cohort F: * 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 C1D1. * 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 C1D1. * 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. 7. Cohort G: * 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 C1D1. * Erythropoietin (EPO) \< 500 international units per liter (U/L) at Baseline. * Last dose of luspatercept is ≥ 3 weeks and \< 12 months from C1D1. 8. \< 5% blasts in bone marrow assessed by bone marrow aspirate during the Pretreatment Period. Part 1
Exclusion criteria
Participants are excluded from Part 1 of the study if any of the following criteria apply. Medical History 1. Diagnosis of MDS with deletion of chromosome 5q (Del5q). 2. Active infection requiring parenteral antibiotic therapy within 28 days prior to C1D1 or oral antibiotics within 14 days of C1D1. Prophylactic antibiotics and/or antifungals for neutropenia are allowed. 3. Presence of uncontrolled heart disease or New York Heart Association (NYHA) Class III or IV heart failure. 4. History of drug or alcohol abuse (as defined by the Investigator) within the past 2 years. 5. History of stroke, deep venous thrombosis (DVT), or arterial embolism within 6 months prior to C1D1. 6. Major surgery within 28 days prior to C1D1. Participants must be completely recovered from any previous surgery prior to C1D1. 7. 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. 8. 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 C1D1. 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). 9. History of solid organ or hematological transplantation. 10. Presence of uncontrolled hypertension, defined as systolic blood pressure (BP) ≥ 150 mmHg or diastolic BP ≥ 100 mmHg despite adequate treatment. 11. Body mass index (BMI) ≥ 40 kilograms per meter square (kg/m\^2) during the Pretreatment Period. 12. History of severe allergic or anaphylactic reaction(s) or hypersensitivity to recombinant proteins or excipients in the investigational medicinal product (IMP). Treatment History 1. Prior treatment with azacitidine, decitabine, lenalidomide, luspatercept, or sotatercept. 2. Treatment with ESA within 56 days prior to C1D1. 3. Prior or concurrent chronic treatment with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). 4. Iron chelation therapy if initiated within 8 weeks prior to C1D1. 5. Vitamin B12 therapy initiated within 8 weeks prior to C1D1. Participants on stable replacement doses for ≥ 8 weeks and without concurrent vitamin B12 or folate deficiency are allowed. 6. 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) 1. Platelet count \> 450 ✕ 10\^9/L or \< 30 ✕ 10\^9/L. 2. Transferrin saturation \< 15%. 3. Ferritin \< 50 nanograms per milliliter (ng/mL). 4. Folate \< 4.5 nanomoles per liter (nmol/L) (\< 2.0 ng/mL). 5. Vitamin B12 \< 148 picomoles per liter (pmol/L) (\< 200 picograms per milliliter \[pg/mL\]). 6. 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. 7. Positive for HIV. Miscellaneous 1. Pregnant or lactating females. 2. Any other condition not specifically noted above which, in the opinion of the Investigator, would preclude the participant from participating in the study. 3. 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 -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | The progression to higher risk MDS or AML will be assessed as per the World Health Organization (WHO) 2016 criteria. |
| 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) | Participants with LTB and HTB achieving RBC TI greater than or equal to (≥) 8 weeks, overall RBC TI and based on RS status will be assessed. |
| 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) | The response is defined as a mean hemoglobin (Hgb) increase of ≥1.5 grams per deciliter (g/dL) from Baseline during any 8-week period during the treatment period for LTB participants and participants with non-transfused anemia, and is defined as a reduction by ≥ 4 units of RBCs transfused during any 8-week period on study compared with the 8-week period prior to study cycle 1 day 1 (C1D1) (cycle length = 28 days) for HTB participants. Participants achieving overall HI-E response and based on RS status will be assessed. |
| Percentage of Participants who Achieve Overall Erythroid Response | Up to approximately 11.2 years | The response is defined as a mean hemoglobin (Hgb) increase of ≥1.5 grams per deciliter (g/dL) from Baseline during any 8-week period during the treatment period for LTB participants and participants with non-transfused anemia, and is defined as a reduction by ≥ 4 units of RBCs transfused during any 8-week period on study compared with the 8-week period prior to study cycle 1 day 1 (C1D1) (cycle length = 28 days) for HTB participants. TI is defined as RBC transfusion independence for ≥ 8 weeks. Overall erythroid response is defined as HI-E or TI over any 8-week period. Participants achieving overall erythroid response and based on RS status will be assessed. |
| Percentage of Participants who Achieve Erythropoietic Improvement | Up to approximately 11.2 years | The improvement is defined as a mean Hgb increase of ≥1.5 g/dL from Baseline for ≥14 days (in the absence of RBC transfusions) for LTB participants and participants with non-transfused anemia and is defined as a reduction of ≥50% or ≥4 RBC units transfused compared with pretreatment over an 8-week period for HTB participants. Participants achieving overall improvement and based on RS status will be assessed. |
| Mean Change from Baseline in Hgb | Baseline, multiple timepoints post treatment up to 11.2 years | At each visit, the mean of the change from baseline in Hgb will be calculated across participants. |
| Time to HI-E Response | Up to approximately 11.2 years | The response is defined as a mean hemoglobin (Hgb) increase of ≥1.5 grams per deciliter (g/dL) from Baseline during any 8-week period during the treatment period for LTB participants and participants with non-transfused anemia, and is defined as a reduction by ≥ 4 units of RBCs transfused during any 8-week period on study compared with the 8-week period prior to study cycle 1 day 1 (C1D1) (cycle length = 28 days) for HTB participants. |
| Duration of HI-E Response | Up to approximately 11.2 years | The response is defined as a mean hemoglobin (Hgb) increase of ≥1.5 grams per deciliter (g/dL) from Baseline during any 8-week period during the treatment period for LTB participants and participants with non-transfused anemia, and is defined as a reduction by ≥ 4 units of RBCs transfused during any 8-week period on study compared with the 8-week period prior to study cycle 1 day 1 (C1D1) (cycle length = 28 days) for HTB participants. |
| Time to TI Response | Up to approximately 11.2 years | TI is defined as RBC transfusion independence for ≥ 8 weeks. |
| Duration of TI response | Up to approximately 11.2 years | TI is defined as RBC transfusion independence for ≥ 8 weeks. |
| 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 | The red cell parameters including reticulocyte count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and reticulocyte cell Hgb will be assessed. |
Countries
Australia, Czechia, France, Germany, Israel, New Zealand, Spain, United States
Contacts
CONTACTTakeda Contact
STUDY_DIRECTORStudy Director
Takeda
Outcome results
None listed