Study of ACE-536 for the Treatment of Anemia in Patients With Myelodysplastic Syndromes (MDS)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effects of ACE-536 on anemia in patients with low or intermediate-1 risk MDS.

Official Title
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A Phase 2, Open Label, Ascending Dose Study of ACE-536 for the Treatment of Anemia in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS)

Conditions
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Anemia

Intervention / Treatment
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* Drug: ACE-536


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Documented diagnosis of idiopathic/de novo MDS or non-proliferative chronic myelomonocytic leukemia (CMML), according to WHO criteria (white blood count, 13,000/uL), that meets International Prognostic Scoring System (IPSS) classification of low or intermediate-1 risk disease as determined by microscopic and standard cytogenetic analyses of the bone marrow and peripheral complete blood count (CBC) obtained during screening. Anemia defined as: Mean hemoglobin concentration < 10.0 g/dL of 2 measurements (one performed within one day prior to Cycle 1 Day 1 and the other performed 7-28 days prior to Cycle 1 Day 1, not influenced by RBC transfusion within 7 days of measurement) for non-transfusion dependent patients (defined as having received < 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1), OR Transfusion dependent, defined as having received ≥ 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1. Serum erythropoietin levels and prior erythropoiesis-stimulating agent (ESA) treatment: Dose escalation cohorts and expansion cohort 1 patients: Serum erythropoietin level > 500 U/L, OR, if ≤ 500 U/L, patient is non-responsive, refractory, or intolerant to erythropoiesis-stimulating agents (ESAs), or ESAs are contraindicated or unavailable. Expansion cohort 2 patients: If patient is RS+ (defined as having ≥ 15% ring sideroblasts in the bone marrow), no prior ESA treatment and serum erythropoietin level ≤ 200 U/L. If a patient is RS- (defined as having < 15% ring sideroblasts in the bone marrow), prior ESA treatment and any serum erythropoietin level is allowed. No alternative treatment options, per applicable MDS guidelines, are available and/or appropriate for the patient, at the discretion of the investigator. ECOG performance status of 0, 1, or 2 (if related to anemia). Adequate renal (creatinine ≤ 2 x upper limit of normal [ULN]) and hepatic (total bilirubin < 2 x ULN and AST and ALT < 3 x ULN) function. Adequate transferrin saturation (≥ 15%), ferritin (≥ 50 µg/L), folate (≥ 4.5 nmol/L [≥ 2.0 µg/L]) and vitamin B12 (≥ 148 pmol/L [≥ 200 pg/mL]) during screening (supplementation and retest during screening is acceptable). Females of child bearing potential (defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal ≥ 24 consecutive months) must have negative urine or blood pregnancy test prior to enrollment and use adequate birth control methods (abstinence, oral contraceptives, barrier method with spermicide, or surgical sterilization) during study participation and for 12 weeks following the last dose of ACE-536. Males must agree to use a latex condom during any sexual contact with females of child-bearing potential while participating in the study and for 12 weeks following the last dose of ACE 536, even if he has undergone a successful vasectomy. Patients must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of ACE-536. Patients are able to adhere to the study visit schedule, understand and comply with all protocol requirements. Patients understand and are able to provide written informed consent. Key Exclusion Criteria: Prior treatment with azacitidine or decitabine. Treatment within 28 days prior to Cycle 1 Day 1 with: i) Erythropoiesis stimulating agent (ESA), ii) Granulocyte colony-stimulating factor (G-CSF) and granulocyte- macrophage colony stimulating factor (GM-CSF), iii) Lenalidomide. Iron chelation therapy if initiated within 56 days prior to Cycle 1 Day 1. Treatment with another investigational drug or device, or approved therapy for investigational use ≤ 28 days prior to Cycle 1 Day 1, or if the half-life of the previous product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever is longer. Major surgery within 28 days prior to Cycle 1 Day 1. Patients must have completely recovered from any previous surgery prior to Cycle 1 Day 1. Platelet count < 30 x 109/L. Any active infection requiring parenteral antibiotic therapy within 28 days prior to Cycle 1 Day 1 or oral antibiotics within 14 days of Cycle 1 Day 1. History of stroke, deep venous thrombosis (DVT) or arterial embolism within 6 months prior to Cycle 1 Day 1. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B (HBV) or active infectious hepatitis C (HCV). Any malignancy other than MDS which has not been in remission and/or has required systemic therapy including radiation, chemotherapy, hormonal therapy or surgery, within the last year prior to Cycle 1 Day 1. Uncontrolled hypertension, defined as systolic blood pressure (BP) ≥ 150 mm Hg or diastolic BP ≥ 100 mm Hg. Pregnant or lactating females. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug. Any other condition not specifically noted above which, in the judgment of the investigator, would preclude the patient from participating in the study. Transfusion event within 7 days prior to Cycle 1 Day 1. Prior treatment with sotatercept (ACE-011) or ACE-536. Secondary MDS.

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: ACE-536<br>Subjects assigned to 1 of 7 possible dosing groups. | Drug: ACE-536<br>* Subjects receive ACE-536 administered subcutaneously (SC) every 3 weeks for up to 5 cycles.<br>* Other names: luspatercept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who have a modified erythroid response (mHI-E). | mHI-E defined as a hemoglobin increase of ≥ 1.5 g/dL from baseline for ≥ 14 days (in the absence of red blood cell [RBC] transfusions) in non-transfusion dependent patients, or, a reduction of either ≥ 4 units or ≥ 50% of units of RBCs transfused compared to pre treatment in transfusion dependent patients. | Assessed at approximately 28 weeks from patient screening. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of ACE-536, as determined by the number of patients with adverse events. |  | From treatment initiation to End-of-Study visit (approximately 28 weeks later). | 
| Rates of erythroid, neutrophil and platelet (HI-E, HI-N and HI-P) responses. |  | Measured during any 8 week period on study, up to 28 weeks from patient screening, compared with the 8-week period prior to study day 1. | 
| Time to mHI-E response and HI-E response and duration of mHI-E and HI-E response. |  | Measured over the course of study, up to approximately 24 weeks from initiation of dosing on study day 1. | 
| Frequency of RBC transfusions in transfusion-dependent patients. |  | Approximately 28 weeks from patient screening. | 
| ACE-536 serum half-life (T1/2) |  | Measured at multiple time points over the course of treatment, from study day 1 to approximately 24 weeks | 
| ACE-536 peak serum concentration (Cmax) |  | Measured at multiple time points over the course of treatment, from study day 1 to approximately 24 weeks | 
| Time to peak serum concentration of ACE-536 (Tmax) |  | Measured at multiple time points over the course of treatment, from study day 1 to approximately 24 weeks | 
| ACE-536 exposure (Area Under the serum Concentration Curve, AUC0-t) |  | Measured at multiple time points over the course of treatment, from study day 1 to approximately 24 weeks | 
| Determination of total serum iron concentration (ug/dL) |  | From treatment initiation to End-of-Study visit (approximately 28 weeks later) | 
| Determination of Total Iron Binding Capacity (ug/dL) |  | From treatment initiation to End-of-Study visit (approximately 28 weeks later) | 
| Determination of soluble transferrin receptor (ug/mL) |  | From treatment initiation to End-of-Study visit (approximately 28 weeks later) | 
| Determination of serum ferritin (ng/mL) |  | From treatment initiation to End-of-Study visit (approximately 28 weeks later) | 
| Determination of non-transferrin bound iron (umoles/L) |  | From treatment initiation to End-of-Study visit (approximately 28 weeks later) | 
| Determination of serum hepcidin (ng/mL) |  | From treatment initiation to End-of-Study visit (approximately 28 weeks later) | 
| Determination of serum erythropoietin concentration (mU/mL) |  | From treatment initiation to End-of-Study visit (approximately 28 weeks later) | 
| Reticulocyte count (%) |  | From treatment initiation to End-of-Study visit (approximately 28 weeks later) | 
| Determination of serum levels of bone-specific alkaline phosphatase (ug/L) |  | From treatment initiation to End-of-Study visit (approximately 28 weeks later) | 
| Determination of serum levels of cross-linked C-telopeptide of type I collagen (ng/L) |  | From treatment initiation to End-of-Study visit (approximately 28 weeks later) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelodysplastic Syndrome