A Safety and Efficacy Study to Evaluate Luspatercept in Subjects With Myeloproliferative Neoplasm-associated Myelofibrosis Who Have Anemia With and Without Red Blood Cell-transfusion Dependence

Study Overview
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Brief Summary
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This is a Phase 2, multicenter, open-label study to evaluate the efficacy and safety of luspatercept in subjects with MPN-associated myelofibrosis and anemia with and without RBC-transfusion dependence. The study is divided into a Screening Period, a Treatment Period (consisting of a Primary Phase, a Day 169 Disease Response Assessment, and an Extension Phase), followed by a Posttreatment Follow-up Period.

Detailed Description
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Subjects satisfying the eligibility criteria will be assigned to 1 of the following cohorts (which are enrolling in parallel) based on their eligibility: Cohort 1 (subjects with anemia only that are not currently receiving RBC transfusions) - Cohort 2: (subjects that are RBC-transfusion dependent) Cohort 3A: (subjects on ruxolitinib as part of their standard of care therapy that have anemia only) Cohort 3B: (subjects on ruxolitinib as part of their standard of care therapy that are RBC-transfusion dependent) Overall, the study will enroll approximately 100 subjects worldwide.

Official Title
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A Phase-2 Study To Determine Efficacy and Safety of Luspatercept in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia With or Without Red Blood Cell-Transfusion Dependence

Conditions
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Primary Myelofibrosis, Anemia

Intervention / Treatment
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* Drug: Luspatercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must satisfy the following criteria to be enrolled in the study (with the enrollment date defined as the date in which the subject is assigned a cohort in Integrated Response Technology [IRT]) and receive their first dose of luspatercept: Subject is ≥18 years of age at the time of signing the informed consent form (ICF). Subject has Myeloproliferative neoplasm (MPN)-associated myelofibrosis (PMF, post- Post-polycythemia vera myelofibrosis (PV MF), and/or Post-essential thrombocythemia myelofibrosis (post-ET MF)) as confirmed from the most recent local bone marrow biopsy report according to the World Health Organization 2016 criteria. Subject has anemia defined as: Cohorts 1 and 3A Obtain ≥ 3 Hemoglobin (Hgb) levels of ≤ 9.5 g/dL recorded on ≥ 3 different days, including the day of dosing, in the 84-day period immediately up to the C1D1 date. There must be ≥ 14 days in between each Hgb measurement. No subjects with an interval ≥ 42 days between hemoglobin measurements will be enrolled. There must not be any Red blood cell (RBC) transfusions within the 84-day period immediately up to the C1D1 date. Cohorts 2 and 3B Average RBC-transfusion frequency: 4 to 12 RBC units/84 days immediately up to the C1D1 date. There must be no interval > 56 days without ≥ 1 RBC-transfusion. Subjects must have a Hgb value of < 13 g/dL on C1D1 prior to luspatercept administration. Only RBC transfusions given when the Hgb ≤ 9.5 g/dL are scored in determining eligibility. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2. Subject is not anticipated during the 6 months from the C1D1 date to receive a hematopoietic cell transplant. A female of childbearing potential (FCBP) for this study is defined as a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). FCBP participating in the study must: Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence* from heterosexual contact. Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception** without interruption, 28 days prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal halflife of luspatercept based on multiple-dose pharmacokinetics [PK] data) after discontinuation of study therapy. Male subjects must: a. Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks (approximately 5 times the mean terminal half-life of luspatercept based on multiple-dose PK data) following investigational product discontinuation, even if he has undergone a successful vasectomy Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. Subject is willing and able to adhere to the study visit schedule and other protocol requirements. Exclusion Criteria: The presence of any of the following will exclude a subject from enrollment (with the enrollment date defined as the date in which the subject is assigned a cohort in Integrated Response Technology (IRT)): Subject use of hydroxyurea or other drugs with potential effects on hematopoiesis or ongoing adverse events from previous treatment ≤ 112 days immediately up to the enrollment date. a. Systemic corticosteroids are permitted for nonhematological conditions providing the subject is receiving a stable or decreasing dose for ≥ 84 days immediately up to enrollment and is receiving a constant dose equivalent to ≤ 10 mg prednisone for the 28 days immediately up to enrollment. Cohort 1 and 2 only: subjects treated with Janus kinase 2 gene (JAK2) inhibitors ≤ 112 days immediately up to the enrollment date or if anticipated/substantial likelihood for subject to receive ruxolitinib within the first 168 days on the study. Cohort 3 only: subjects not receiving ruxolitinib: for at least 280 days (40 weeks) without interruptions exceeding 2 consecutive weeks on a stable daily dose for at least 112 days (16 weeks) immediately up to the enrollment date as part of their standard-of-care therapy. Subject use of ESAs or androgenic steroids ≤ 112 days immediately up to the enrollment date. Initiation of iron chelation therapy (ICT) or change with ICT dose within ≤ 112 days up to the enrollment date. Subject with anemia from iron deficiency, B12 and folate deficiencies, hemolytic anemia, infection, or bleeding. Pregnant or breastfeeding females. Subject with blood myeloblasts ≥ 5%. Subject with major surgery within 8 weeks up to the enrollment date. Subject must have completely recovered from any previous surgery immediately up to the enrollment date. Subject with prior history of malignancies, other than disease under study, unless the subject has been free of the disease for ≥ 5 years. However, subject with the following history/concurrent conditions is allowed: Basal or squamous cell carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ of the breast Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system) Subject with prior therapy of luspatercept or sotatercept. Subject participation in any other clinical protocol or investigational trial that involves administration of experimental therapy and/or therapeutic devices within 30 days immediately up to the enrollment date. Subject with prior hematopoietic cell transplant. Subject with any of the following laboratory abnormalities: Neutrophils < 1 x 109/L White blood count (WBC) > 100 x 109/L Platelets Cohorts 1 and 2: < 25 x 109/L Cohort 3A and 3B: < 50 x 109/L All Cohorts: > 1000 x 109/L Estimated glomerular filtration rate < 45 mL/min/1.73 m2 (via the 4-variable modification of diet in renal disease [Modification of diet in renal disease (MDRD)] formula) Aspartate aminotransferase (AST) or alanine transaminase (ALT) > 3.0 x upper limit of normal (ULN) Direct bilirubin ≥ 2 x ULN higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis) Uncontrolled hyperthyroidism or hypothyroidism Subject with stroke, deep venous thrombosis, pulmonary or arterial embolism within 6 months immediately up to the enrollment date. Subject with diastolic blood pressure ≥ 90 mmHg or systolic blood pressure ≥ 140 mmHg measured during the Screening Period despite appropriate treatment. Subject with inadequately controlled heart disease and/or have a known left ventricular ejection fraction <35%. Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product (see luspatercept Investigator's Brochure (IB)). Subject with uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment). Subject with human immunodeficiency virus (HIV), evidence of active infectious Hepatitis B (HepB), and/or evidence of active Hepatitis C (HepC). Subject with any significant medical condition, laboratory abnormality, psychiatric illness, or is considered vulnerable by local regulations (eg, imprisoned or institutionalized) that would prevent the subject from participating in the study. Subject with any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. Subject with any condition or concomitant medication that confounds the ability to interpret data from the study. Subject on anticoagulant therapy not under appropriate control or subject not on a stable dose of anticoagulant therapy for ≥ 8 weeks up to the enrollment date. Subject on anagrelide within 28 days immediately up to the enrollment date. Subject with a major bleeding event (defined as symptomatic bleeding in a critical area or organ and/or bleeding causing a decrease in hemoglobin of ≥ 2g/dL or leading to transfusion of ≥ 2 units of packed red cells) in the last 6 months prior to enrollment.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Luspatercept in subjects with MPN-associated myelofibrosis<br>Subjects across each of the cohorts (Cohort 1, Cohort 2, Cohort 3A, and Cohort 3B) will receive luspatercept. | Drug: Luspatercept<br>* Luspatercept is a recombinant fusion protein consisting of a modified form of the extracellular domain of the human active in receptor type IIB linked to the IgG1 Fc domain. Luspatercept, through a mechanism of action different from erythropoietin, works to correct ineffective erythropoiesis by promoting late-stage maturation of erythroblasts.<br>* Other names: ACE-536;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants With Anemia Responses Over Any 84-Day Period During the Primary Treatment Period | The number of participants that achieved anemia response as it relates to hemoglobin (Hgb) increase and red blood cell (RBC)-transfusion independence is defined below: Cohorts 1 (anemia only) and 3A: The number of participants achieving ≥ 1.5 g/dL hemoglobin increase from baseline over any consecutive 84-day period without an RBC transfusion from Day 1 up through and including Day 168. Cohorts 2 (RBC-transfusion dependent) and 3B: The number of participants who become RBC-transfusion free over any consecutive 84-day period from Day 1 up through and including Day 168. Baseline value is defined as the last value (including unscheduled) measured on or before the first dose. | Any consecutive rolling 84-day period from Day 1 through and including Day 168 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Anemia Response During the Primary Treatment Period | Time to anemia response follows the definitions below: Cohorts 1 (anemia only) and 3A: Time between first administration of luspatercept and the first hemoglobin increase of ≥ 1.5 g/dL from baseline that starts a consecutive 84-day period of consecutive increase ≥ 1.5 g/dL without RBC transfusions. Cohorts 2 (RBC-transfusion dependent) and 3B: Time between first administration of luspatercept and the first day of an RBC transfusion-free period of 84 days. Baseline value is defined as the last value (including unscheduled) measured on or before the first dose. | From first dose up to first onset of anemia response (calculated from Day 1 through and including Day 168) | 
| Duration of Anemia Response | The duration of anemia response is defined as the duration of time from first day of longest response to the last day of longest response. Participants who achieved and maintained the anemia response at the time of the analysis are censored at the efficacy cutoff date. For Cohorts 1 and 3A, an anemia responder was defined as a subject with ≥ 1.5 g/dL hemoglobin increase from baseline over any consecutive 84-day period without an RBC transfusion. For Cohorts 2 and 3B, an anemia responder was defined as a subject who becomes RBC transfusion free over any consecutive 84-day period. Baseline value is defined as the last value (including unscheduled) measured on or before the first dose. | From first dose through last day of longest response (calculated from Day 1 through end of treatment, up to approximately 232 weeks) | 
| The Number of RBC Units Transfused Per Participant Per 28 Days (Cohorts 2 and 3B Only) | Frequency of RBC transfusion is defined as the mean number of RBC units transfused per participant every 4 weeks (28 days). The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. | From Day 1 through end of treatment (up to approximately 232 weeks). | 
| The Number Participants Achieving >=50% RBC Transfusion Burden Reduction From Baseline Over Any 84-Day Period (Cohorts 2 and 3B Only) | The number of participants who reduce their transfusion burden by ≥ 50% from baseline over any consecutive 84-day period. Baseline is defined as average number of RBC units per 28 days over the 84 days period on or prior to the C1D1 date. The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. | Baseline and from Day 1 through end of treatment (up to approximately 232 weeks). | 
| The Number of Participants Who Achieve ≥ 50% Reduction in Fatigue Symptom as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) | Symptoms response improvement will be assessed using the number of participants who achieve ≥ 50% reduction in fatigue symptoms. Fatigue is 1 out of 10 total symptoms scored on a 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be). The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. Baseline is defined as the last value on or before the first dose of study drug. Last Available = Last available assessment on or before the end of the treatment period. Mean = Mean value of the weekly assessments over the treatment period. | Baseline and from Day 1 through end of treatment (up to approximately 232 weeks) | 
| The Number of Participants Who Achieve ≥ 50% Reduction in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) | TSS includes 10 items - worst fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers, scored on a 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be). For participants who completed at least six of these 10 items, the MPN-SAF TSS was computed as the average of the observed items multiplied by 10 to achieve a 0-to-100 scale. The MPN-SAF TSS thus had a possible range of 0 to 100. The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. Baseline is defined as the last value on or before the first dose of study drug. Last Available = Last available assessment on or before the end of the treatment period. Mean = Mean value of the weekly assessments over the treatment period. | Baseline and from Day 1 through end of treatment (up to approximately 232 weeks) | 
| Mean Changes in the Functional Assessment of Cancer Therapy - Anemia (FACT-An) Total Scores Over the Study Compared to Baseline | The Functional Assessment of Cancer Therapy - Anemia (FACT-An) questionnaire includes 47 items rating on a 5-point Likert scale from 0 (not at all) to 4 (very much) on five primary subscales: Physical well-being (sum of 7 items, score range from 0-28) Social/Family well-being (sum of 7 items, score range from 0-28) Emotional well-being (sum of 6 items, score range from 0-24) Functional well-being (sum of 7 items, score range from 0-28) Anemia-related symptoms (sum of 20 items, score range from 0-80) A total score for the FACT-An can be calculated by summing the five primary subscales with a score range from 0-188. Higher scores representing better quality of life. Baseline is defined as the last value on or before the first dose of study drug. | Day 169 and End of treatment (up to approximately 232 weeks) | 
| Mean Change in EQ-5D-5L Utility Score Compared to Baseline | The European Quality of Life 5D-5L Scale (EQ-5D-5L) assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Responses are coded so that a '1' indicates no problem, and '5' indicates the most serious problem. The responses for the 5 dimensions are combined in a 5-digit number. The EQ-5D-5L health utility index for this analysis will be derived using the United Kingdom (UK) value sets based on UK time trade-off (TTO) valuation techniques and will use the Decision Support Unit (DSU) model to cross-walk to the EQ-5D-3L value set from the UK to derive a single index value. The EQ-5D-3L health utility index based on the UK population weights range from -0.594 to 1.0 with higher scores indicating higher health utility. | Day 169 and End of treatment (up to approximately 232 weeks) | 
| The Number of Participants Treatment-Emergent Adverse Events (TEAE) | TEAE is defined as any AEs that begin or worsen on or after the day of the first dose. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. An SAE is any AE occurring at any dose that: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or constitutes an important medical event. The severity/intensity of AEs will be graded based on the Common Terminology Criteria for Adverse Events (CTCAE, version 4.03) where Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death. | From first dose through 42 days after the last dose (up to approximately 238 weeks) | 
| CL/F (L/Day) | Apparent clearance | C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment. | 
| V1/F (L) | Apparent volume of distribution of the central compartment | C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment. | 
| Ka (Day-1) | First-order rate constant of absorption | C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment. | 
| T1/2 (Day) | Elimination half-life | C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment. | 
| Tmax (Day) | Time to reach the maximum concentration for the first dose (Cmax) | C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment. | 
| Cmax (µg/mL) | Maximum concentration for the first dose | C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment. | 
| Cmax.ss (µg/mL) | Maximum concentration for the first dose (Cmax) at steady state for the starting dose | C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment. | 
| AUCss (Day* µg/mL) | Area under the concentration-time curve at the steady state for the starting dose | C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment. | 
| The Number of Participants With Antidrug Antibody (ADA) Measurements | The ADA status of a participant during treatment is determined based on the longitudinal ADA results as follows: Negative: All samples (baseline and post-baseline) are negative. Positive to treatment-emergent ADA: At least one post-baseline sample is positive if the baseline sample is negative, or at least one post-baseline sample is positive with a titer ≥ 4-fold of the baseline titer if the baseline sample is positive | C1D1 (pre- dose), C2D1, C4D1, C6D1, C8D1, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment. | 
| Mean Changes in Hemoglobin Over the Study Compared to Baseline in the Absence of RBC Transfusions (Cohorts 1 and 3A) | Calculated based on average hemoglobin measurements collected during the treatment period.The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. The baseline RBC transfusion is defined as average number of RBC units/28 days over the 84 days period immediately prior to the C1D1 date. | Baseline and Day 1 through end of treatment (up to approximately 232 weeks) | 
| The Number of Participants With a Mean Hemoglobin Increase >= 1.5 g/dL From Baseline Over Any Consecutive 84-day Period (Cohorts 1 and 3A) | The number of participants with a Mean hemoglobin increase of ≥ 1.5 g/dL from baseline over any consecutive 84-day period without an RBC transfusion. The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. Baseline is defined as all non-missing Hgb records within 28 days on or prior to date of first dose (or date of enrollment if not treated). | Baseline and Day 1 through end of treatment (up to approximately 232 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ACE-536, Luspatercept, Myeloproliferative Neoplasm-Associated Myelofibrosis, Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia, Anemia, Red Blood Cell (RBC) Transfusion, Ruxolitinib