Anemia, Myelofibrosis
Conditions
Keywords
TAK-226, Drug therapy
Brief summary
The main aim of this study is to find out how well elritercept works to improve anemia in participants with myelofibrosis (MF) who are taking ruxolitinib when compared to placebo. Other aims are to learn how elritercept improves anemia compared to placebo; to learn if elritercept reduces tiredness, improves symptoms related to MF, and helps participants do physical activities more easily. The study also aims to find out how elritercept affects the bone marrow, the spleen, and whether participants develop antibodies to the study drug. The study will also check how safe elritercept is compared to placebo, and if elritercept stays safe over a long period of time. Participants will receive study treatment for at least 9 months (36 weeks). After this period, participants who received placebo will have the option to switch to elritercept.
Interventions
DRUGPlacebo
Elritercept-matching placebo
DRUGElritercept
Elritercept, SC, injection
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Aged ≥18 years at the time of signing the informed consent form (ICF). 2. Able to understand the purpose and risks of the trial and voluntarily sign an ICF. 3. Diagnosed with primary myelofibrosis (PMF), post-essential thrombocythemia (post-ET MF) or post-polycythemia vera (post-PV MF) according to the 2022 WHO criteria (WHO Classification of Tumours Editorial Board 2024), confirmed by local pathology report. 4. Transfusion status as assessed in the 12 weeks immediately preceding randomization classified as Transfusion Dependent: 3 to 8 RBC units over 12 weeks. 5. Receiving ruxolitinib (as approved in the country of the trial site) as the standard of care treatment for MF for at least 12 consecutive weeks, and on a stable daily dose for at least the 8 weeks immediately preceding the date of randomization. 6. Eastern Cooperative Oncology Group score less than or equal to (≤) 2.
Exclusion criteria
1. Prior treatment with luspatercept, sotatercept, or other transforming growth factor beta inhibitors or activin receptor ligand traps. 2. Systemic treatment within 28 days before randomization with any of the following: 1. Androgens (including danazol). Participants on stable androgen dosing for hypogonadism for ≥8 weeks are allowed. 2. erythropoiesis-stimulating agents. 3. granulocyte colony stimulating factor or granulocyte-macrophage colony stimulating factor. 4. High dose corticosteroids. Participants on stable chronic steroid doses of prednisone ≤10 mg/day or corticosteroid equivalent for ≥4 weeks are allowed. Other treatments for autoimmune diseases may be allowed upon medical monitor review. 5. Hydroxyurea. 6. Immunomodulatory drugs (for example, thalidomide, pomalidomide, or lenalidomide). 7. Interferon. 8. Thrombopoietin receptor agonists. 9. Any investigational drug, including antihemojuvelin antibody. If the half-life of the investigational product is known, the exclusionary period prior to randomization is equal to 5 half-lives of the investigational product or 28 days, whichever is longer. 3. Initiation of new iron chelation therapy or dose adjustments to existing iron chelation therapy ≤8 weeks prior to randomization. Participants on stable doses of iron chelation therapy for ≥8 weeks are allowed. 4. Clinically significant anemia that is due to causes other than MF or Janus kinase (JAK) inhibitor therapy (for example, thalassemia, iron deficiency, vitamin B12 and/or folate deficiencies, autoimmune or hemolytic anemia, infections, or any active clinically significant bleeding or sequestration). 5. Receipt of RBC transfusion for any reason(s) other than underlying MF within 12 weeks before randomization. 6. Life expectancy \<12 months per investigator's judgment. 7. Clinically significant cardiovascular disease, defined as: 1. New York Heart Association heart disease Class III or IV; 2. Fridericia corrected QT interval \>500 millisecond (ms) during screening; 3. Uncontrolled arrhythmia, myocardial infarction, or unstable angina within 6 months before screening. 8. Uncontrolled hypertension, defined as repeated elevations of systolic blood pressure of ≥160 millimetres of mercury (mmHg) and/or diastolic blood pressure ≥100 mmHg despite adequate treatment. 9. Medical history of thromboembolic events within 6 months before screening, including history of cerebrovascular accident (including ischemic, embolic, and hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous thrombosis (including proximal and distal), pulmonary or arterial embolism, arterial thrombosis, or other venous thrombosis. Participants with prior superficial thrombophlebitis are allowed. 10. Prior history of malignancies, other than MF. Participants who are free of other malignant disease for ≥2 years and have completed treatment, including maintenance, are allowed. Participants with a history or concurrent diagnosis of the following conditions are allowed if not requiring systemic therapy: 1. Basal or squamous cell carcinoma of the skin; 2. Carcinoma in situ of the cervix; 3. Carcinoma in situ of the breast; and/or 4. Incidental histologic finding of prostate cancer (T1a or T1b using the Tumour, Node, and Metastasis (TNM) staging system); 5. Early papillary thyroid cancer (stage I \[T1-T2, N0, M0\]). 11. History of solid organ or bone marrow transplantation. 12. Active infection requiring intravenous antibiotics within 28 days or oral antibiotics within 7 days before randomization. Prophylactic antibiotics and/or antifungals for neutropenia are allowed. 13. Known positivity for Human Immunodeficiency Virus (HIV), active hepatitis B virus (HBV), or active hepatitis C virus (HCV). Participants without known history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines. 14. Body mass index ≥40 kilograms per square meter (kg/m\^2). 15. Major surgery within 28 days before randomization. 16. History of allergy/anaphylaxis to recombinant proteins, investigational product, or excipients (refer to the current elritercept investigator's brochure for a list of excipients), or ruxolitinib. 17. Any of the following local laboratory abnormalities: 1. Absolute neutrophil count \<500/microliter (μL) (0.5×109/ liter (L)). 2. Platelet count \<50,000/μL (50×109/L) or \>1,000,000/μL (1000×109/L). 3. Blasts \>5% as assessed in peripheral blood at screening or ≥10% in any historical bone marrow assessments. Participants with isolated transient elevations of peripheral blood blasts may be eligible after discussion between the investigator and medical monitor to confirm the blast count is not indicative of disease progression. 4. Serum aspartate aminotransferase or alanine aminotransferase ≥3× the upper limit of normal (ULN). 5. Total bilirubin ≥2×ULN. Participants with known history of Gilbert syndrome with unconjugated bilirubin less than (\<) 3×ULN are allowed. Higher levels if attributed to active RBC precursor destruction within the bone marrow (ineffective erythropoiesis) may be allowed upon medical monitor review. 6. Estimated glomerular filtration rate \<30 milliliters per minute per 1.73 square meters (mL/min/1.73 m\^2) as determined by the Chronic Kidney Disease Epidemiology Collaboration equation. 7. Ferritin ≤50 micrograms per liter (μg/L). 8. Folate ≤2.0 nanograms per milliliter (ng/mL). 9. Vitamin B12 ≤200 picograms per milliliter (pg/mL). 18. Ongoing participation in another interventional clinical trial. 19. Participant is unwilling or, in the opinion of the investigator, the participant is unable to comply with the requirements of the protocol. 20. Is a person of childbearing potential but does not agree to use at least 1 form of highly effective contraception from the time of signing the ICF until at least 60 days after the last dose of elritercept or placebo. 21. Participants of male birth who are fertile and who have partners of childbearing potential, who do not agree to use acceptable barrier contraception, that is, a male condom, during the entire treatment period until at least 60 days after the last dose of elritercept or placebo. 22. If applicable, participant with a positive serum pregnancy test during the screening period or known to be pregnant or a lactating participant who does not agree to forego breastfeeding during the entire treatment period until at least 60 days after the last dose of elritercept or placebo. 23. For participants in France: Persons under court protection, persons not affiliated with a social security system, and protected adults.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Are Red Blood Cell-Transfusion Independent (RBC-TI) for Any Consecutive Greater Than or Equal to (≥) 12-Week Period During the 36-Week Double-Blinded Treatment Period | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | RBC-TI is defined as no RBC transfusions administered for the specified time period during study treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Achieve ≥50 Percent (%) Reduction in RBC Transfusion Burden From Baseline Over Any Consecutive 12-Week Period | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | — |
| Proportion of Participants Who Are RBC-TI for Any Consecutive ≥16-Week Period | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | RBC-TI is defined as no RBC transfusions administered for the specified time period during study treatment. |
| Proportion of Participants Who Are RBC-TI for Any Consecutive ≥12-Week Period With Concurrent Mean Hemoglobin (Hgb) Increase ≥1.5 Grams per Deciliter (g/dL) From Baseline | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | RBC-TI is defined as no RBC transfusions administered for the specified time period during study treatment. |
| Proportion of Participants Who Are RBC-TI for Any Consecutive ≥24-Week Period | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | RBC-TI is defined as no RBC transfusions administered for the specified time period during study treatment. |
| Proportion of Participants Who Are RBC-TI for Any Consecutive ≥12-Week Period With Concurrent Mean Hgb Increase of ≥1.0 g/dL and ≥2.0 g/dL From Baseline | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | RBC-TI is defined as no RBC transfusions administered for the specified time period during study treatment. |
| Proportion of Participants Who Are RBC-TI for Any Consecutive 16- or 24-Week Period With a Concurrent Mean Hgb Increase of ≥1.0 g/dL, ≥1.5 g/dL, and ≥2.0 g/dL From Baseline | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | RBC-TI is defined as no RBC transfusions administered for the specified time period during study treatment. |
| Maximum Duration of RBC-TI for Participants Who Achieved RBC-TI for a Consecutive ≥12 Weeks | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | RBC-TI is defined as no RBC transfusions administered for the specified time period during study treatment. |
| Maximum Duration of RBC-TI With Concurrent Mean Hgb Increase of ≥1.5 g/dL for Participants Who Achieved Consecutive ≥12 Weeks RBC-TI With Concurrent Mean Hgb Increase of ≥1.5 g/dL | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | RBC-TI is defined as no RBC transfusions administered for the specified time period during study treatment. |
| Time to Onset of Anemia Response | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | Time to onset of anemia response is defined as the duration between the date of randomization and the date participant first achieved anemia response status. Anemia response is evaluated as: achievement of RBC-TI for any consecutive ≥12-week, ≥16-week, or ≥24-week period or ≥50% reduction in red blood cell transfusion burden from baseline over any consecutive 12 weeks. |
| Mean Change From Baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form v1.0 - Fatigue 7a T-Score at Week 36 | Baseline, Week 36 | PROMIS Short Form v1.0 - Fatigue 7a is a 7-item, patient-reported measure designed to assess fatigue symptoms and impact over the past 7 days. Response options are on a 5-point scale from never (1) to always (5). Raw scores are computed by summing responses to all 7 items and then converted to a standardized T-score on a scale from 0 to 100 with a mean of 50 and SD of 10 with higher scores representing worse fatigue. T-scores can be produced using a conversion table available from the instrument developer or using response pattern scoring performed by the Health Measures Scoring Service. |
| Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Fatigue Scale Score at Week 36 | Baseline, Week 36 | EORTC QLQ-C30 is a 30-item, participant-reported multidomain questionnaire designed to assess functioning, wellbeing, and symptom experience of participants with cancer. The questionnaire's items are divided among 5 multi-item scales measuring functioning (physical, role, emotional, cognitive, and social), 3 multi-item scales measuring symptoms (fatigue, nausea/vomiting, and pain), 6 items measuring symptoms (dyspnea, insomnia, appetite loss, constipation, and diarrhea) as well as financial difficulties, and a 2-item scale measuring global health status (GHS))/quality of life (QoL). Items included in GHS/QoL scale use a 7-point response metric ranging from very poor to excellent, while other items use a 4-point response metric with categories including not at all, a little, quite a bit, and very much. Scale scores are transformed to range from 0 to 100 with higher scores indicating better functioning, GHS/QoL, or worse symptomatology. |
| Proportion of Participants With Meaningful Improvement and Meaningful Deterioration in PROMIS Short Form v1.0 - Fatigue 7a T-score | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | PROMIS Short Form v1.0 - Fatigue 7a is a 7-item, patient-reported measure designed to assess fatigue symptoms and impact over the past 7 days. Response options are on a 5-point scale from never (1) to always (5). Raw scores are computed by summing responses to all 7 items and then converted to a standardized T-score on a scale from 0 to 100 with a mean of 50 and SD of 10 with higher scores representing worse fatigue. T-scores can be produced using a conversion table available from the instrument developer or using response pattern scoring performed by the Health Measures Scoring Service. Score cutoffs to define meaningful improvement and meaningful deterioration will be determined prior to the primary analysis based on analysis of blinded trial data in accordance with a prespecified psychometric analysis plan. |
| Time to Meaningful Improvement and Meaningful Deterioration in PROMIS Short Form v1.0 - Fatigue 7a T-Score From Baseline | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | PROMIS Short Form v1.0 - Fatigue 7a is a 7-item, patient-reported measure designed to assess fatigue symptoms and impact over the past 7 days. Response options are on a 5-point scale from never (1) to always (5). Raw scores are computed by summing responses to all 7 items and then converted to a standardized T-score on a scale from 0 to 100 with a mean of 50 and SD of 10 with higher scores representing worse fatigue. T-scores can be produced using a conversion table available from the instrument developer or using response pattern scoring performed by the Health Measures Scoring Service. Score cutoffs to define meaningful improvement and meaningful deterioration will be determined prior to the primary analysis based on analysis of blinded trial data in accordance with a prespecified psychometric analysis plan. |
| Proportion of Participants With Meaningful Improvement and Meaningful Deterioration in EORTC QLQ-C30 Fatigue Scale Score | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | EORTC QLQ-C30 is a 30-item, participant-reported multidomain questionnaire designed to assess functioning, wellbeing, and symptom experience of participant with cancer. The items are divided among 5 multi-item scales measuring functioning (physical, role, emotional, cognitive, and social), 3 multi-item scales measuring symptoms (fatigue, nausea/vomiting, pain), 6 items measuring symptoms (dyspnea, insomnia, appetite loss, constipation, diarrhea) as well as financial difficulties, and a 2-item scale measuring GHS and QoL. Items included in GHS/QoL scale use a 7-point response metric ranging from very poor to excellent, while other items use a 4-point response metric, categories including not at all, a little, quite a bit, and very much. Scale scores are transformed to range from 0 to 100 with higher scores indicating better functioning, better GHS/QoL, or worse symptomatology. Score cutoffs to define meaningful improvement/deterioration to be determined before primary analysis. |
| Time to Meaningful Improvement and Meaningful Deterioration in EORTC QLQ-C30 Fatigue Scale Score From Baseline | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | EORTC QLQ-C30 is a 30-item, participant-reported multidomain questionnaire designed to assess functioning, wellbeing, and symptom experience of participant with cancer. The items are divided among 5 multi-item scales measuring functioning (physical, role, emotional, cognitive, social), 3 multi-item scales measuring symptoms (fatigue, nausea/vomiting, pain), 6 items measuring symptoms (dyspnea, insomnia, appetite loss, constipation, diarrhea) as well as financial difficulties, and a 2-item scale measuring GHS and QoL. Items included in GHS/QoL scale use a 7-point response metric ranging from very poor to excellent, while other items use a 4-point response metric, categories including not at all, a little, quite a bit, and very much. Scale scores are transformed to range from 0 to 100 with higher scores indicating better functioning, better GHS/QoL, or worse symptomatology. Score cutoffs to define meaningful improvement/deterioration to be determined before primary analysis. |
| Mean Changes From Baseline in Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 7-Item Total Symptom Score at Week 36 | Baseline, Week 36 | MFSAF v4.0 is a unidimensional measure assessing 7 core MF symptoms: fatigue, night sweats, itching, abdominal discomfort, pain under ribs, early satiety, and bone pain. The questionnaire asks participants to rate each symptom at its worst during the past 7 days on a 0 to 10 numeric rating scale ranging from absent (0) to worst imaginable (10). The Total Symptom Score (TSS) is calculated as the average of the 7 individual item responses multiplied by 7, yielding a score range of 0 to 70 with higher scores representing worse symptom severity. |
| Proportion of Participants Achieving Confirmed 50% Reduction in MFSAF v4.0 Total Symptom Score (TSS50) | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | MFSAF v4.0 is a unidimensional measure assessing 7 core MF symptoms: fatigue, night sweats, itching, abdominal discomfort, pain under ribs, early satiety, and bone pain. The questionnaire asks participants to rate each symptom at its worst during the past 7 days on a 0 to 10 numeric rating scale ranging from absent (0) to worst imaginable (10). The TSS is calculated as the average of the 7 individual item responses multiplied by 7, yielding a score range of 0 to 70 with higher scores representing worse symptom severity. |
| Time to Symptom Response in MFSAF TSS50 From Baseline | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | MFSAF v4.0 is a unidimensional measure assessing 7 core MF symptoms: fatigue, night sweats, itching, abdominal discomfort, pain under ribs, early satiety, and bone pain. The questionnaire asks participants to rate each symptom at its worst during the past 7 days on a 0 to 10 numeric rating scale ranging from absent (0) to worst imaginable (10). The TSS is calculated as the average of the 7 individual item responses multiplied by 7, yielding a score range of 0 to 70 with higher scores representing worse symptom severity. |
| Mean Change From Baseline EORTC QLQ-C30 Physical Functioning Scale Score at Week 36 | Baseline, Week 36 | EORTC QLQ-C30 is a 30-item, participant-reported multidomain questionnaire designed to assess functioning, wellbeing, and symptom experience of participant with cancer. The questionnaire's items include 5 multi-item scales measuring functioning (physical, role, emotional, cognitive, and social). These items use a 4-point response metric with categories including not at all, a little, quite a bit, and very much. Scale scores are transformed to range from 0 to 100 with higher scores indicating better functioning. |
| Proportion of Participants With Meaningful Improvement and Meaningful Deterioration in EORTC QLQ-C30 Physical Functioning Scale Score | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | EORTC QLQ-C30 is a 30-item, participant-reported multidomain questionnaire designed to assess functioning, wellbeing, and symptom experience of participant with cancer. The questionnaire's items include 5 multi-item scales measuring functioning (physical, role, emotional, cognitive, and social). These items use a 4-point response metric with categories including not at all, a little, quite a bit, and very much. Scale scores are transformed to range from 0 to 100 with higher scores indicating better functioning. Score cutoffs to define meaningful improvement and meaningful deterioration will be determined prior to the primary analysis based on analysis of blinded trial data in accordance with a prespecified psychometric analysis plan. |
| Time to Meaningful Improvement and Meaningful Deterioration in EORTC QLQ-C30 Physical Functioning Scale Score From Baseline | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | EORTC QLQ-C30 is a 30-item, participant-reported multidomain questionnaire designed to assess functioning, wellbeing, and symptom experience of participant with cancer. The questionnaire's items include 5 multi-item scales measuring functioning (physical, role, emotional, cognitive, and social). These items use a 4-point response metric with categories including not at all, a little, quite a bit, and very much. Scale scores are transformed to range from 0 to 100 with higher scores indicating better functioning. Score cutoffs to define meaningful improvement and meaningful deterioration will be determined prior to the primary analysis based on analysis of blinded trial data in accordance with a prespecified psychometric analysis plan. |
| Proportion of Participants With Platelet Response During the 36-Week Double-Blinded Treatment Period | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | Platelet response includes a mean increase of ≥30×10\^9/ liter (L) from baseline, a \>50% increase from baseline with a count ≥50×10\^9/L, and conversion from \<100 to ≥100×10\^9/L, each sustained for ≥12 weeks. |
| Proportion of Participants Achieving Spleen Volume Reduction (SVR) From Baseline as Measured by Computed Tomography/Magnetic Resonance Imaging (CT/MRI) During the 36-Week Double-Blinded Treatment Period | From Cycle 1 Day 1 through Week 36 (each cycle is 28 days) | Proportion of participants achieving SVR of ≥10%, ≥25%, or ≥35% will be presented for this outcome measure. |
| Proportion of Participants Who Develop Accelerated Phase (AP) MF | Up to approximately 7 years | — |
| Time to Progression in Participants Who Develop AP MF | Up to approximately 7 years | — |
| Proportion of Participants Who Develop Blast Phase (BP) MF | Up to approximately 7 years | — |
| Time to Progression in Participants Who Develop BP MF | Up to approximately 7 years | — |
| Plasma Concentration-Time Data for Participants Treated With Elritercept | At multiple time points from Cycle 1 Day 1 (each cycle is 28 days) up to approximately 7 years | — |
| Proportion of Participants Treated With Elritercept who Have Antidrug Antibodies | At multiple time points from Cycle 1 Day 1 (each cycle is 28 days) up to approximately 7 years | — |
| Overall Survival (OS) | From randomization to 7 years | OS is defined as the time from randomization to the date of death due to any cause. |
Contacts
CONTACTTakeda Contact
STUDY_DIRECTORStudy Director
Takeda
Outcome results
None listed