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An open-label, randomized, phase 2, parallel, dose-ranging, multicenter study of sotatercept for the treatment of patients with anemia and low- or intermediate-1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic leukemia (CMML)
|Leukemia, Chronic Myelomonocytic (CMML)
|Myelodysplastic Syndrome (MDS)
- The primary objective of this study is to determine a safe, tolerable and effective dose of sotatercept that results in the greatest frequency of erythroid hematological improvement (HI-E) in patients with anemia and low- or intermediate-1 risk MDS.
- Safety of sotatercept
- Rate of RBC transfusion independence in transfusion-dependent subjects
- Time to HI-E
- Duration of HI-E
- Time to progression to acute myeloid leukemia (AML)
- Time to progression to events of higher risk MDS (ie, int-2 or high risk IPSS)
- Progression-free survival (PFS)
- Overall survival (OS)
- Pharmacokinetics (PK) of sotatercept
- Frequency of neutrophil hematological improvement (HI-N)
- Frequency of platelet hematological improvement (HI-P)
- Changes in cell morphology in smears of bone marrow and peripheral blood
- Association between hematologic improvement and biomarkers in serum:
- Activin A and other mechanism-based serum markers (ie, follistatin,, GDF-11, myostatin, TGF-B,etc.)
- Bone specific alkaline phosphatase (BSALP)
- C-terminal and N-terminal Type 1 Collagen Telopeptide (CTX/NTX)
- Luteinizing hormone (LH)
- Markers of iron storage and metabolism (eg, iron, transferrin, transferrin receptor, total iron binding capacity, and ferritin)
- Association between hematologic improvement and biomarkers in aspirates of bonemarrow:
- Erythroid progenitor and precursor populations as measured by multi-parameter flow cytometry
- Erythroid progenitor colony-formation (BFU-E/CFU-E, CFU-GM)
- Changes in TGF-B signaling molecules, including SMAD family members-2 and 4 and corresponding phosphorylated forms, and assessment of apoptotic index, osteoblast density and trabecular bone thickness assessed by immunohistochemistry of bone marrow biopsy specimens
- Change in renal function biomarkers via urinalysis measuring urine albumin / creatinine ratio, urine protein / creatinine ratio and other biomarkers of glomerular and/or tubular injury - urine kidney injury molecule-1 (KIM-1), urine cystatin C, and urine B2- microglobulin
- Relationship between exposure and response (ie, safety, efficacy, and biomarkers)
- Provide written informed consent prior to the conduct of any study-related assessment or procedure.
- Age ≥ 18 years at the time of signing the informed consent form.
- Able to adhere to the study visit schedule and other requirements of the protocol.
- Documented diagnosis of MDS or non-proliferative chronic myelomonocytic leukemia (CMML, WBC ≤ 13,000/mm^3, World Health organization), Vardiman, 2009) that meets International Prognostic Scoring System (IPSS, Appendix B) criteria for low- or intermediate-1 risk disease.
- Anemia defined as requiring transfusion ≥ 2 units of RBCs within 84 days of enrollment for Hgb ≤ 9.0 g/dL.
- No response to prior treatment with epoetin alpha (≥ 40,000 U/wk x 8), or darbepoetin alpha (≥ 500 mcg Q3W x 4), or low chance of response to erythroid stimulating factors reflected by endogenous serum erythropoietin (EPO) concentration > 500 mU/ml.
- All previous therapy, including erythropoiesis-stimulating agents, granulocyte colonystimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GMCSF), must have been discontinued > 28 days before enrollment
- Eastern Cooperative Group (ECOG) performance status (Appendix D) ≤ 2.
- Creatinine < 1.5 X ULN.
- Total bilirubin ≤ 3.0 mg/dL, except if associated with primary shunt hyperbilirubinemia (idiopathic dyserythropoietic jaundice).
- AST (SGOT) and ALT (SGPT) ≤ 3.0 x upper limit of normal (ULN).
- Females of childbearing potential participating in the study are to use highly effective methods of birth control during study participation and for 112 days (approximately five times the mean terminal half-life of sotatercept [23 days] based on multiple-dose PK data) following the last dose of sotatercept. Females of childbearing potential must have a negative serum beta-human chorionic gonadotropin (B-HCG) pregnancy test within three days of sotatercept dosing (Day 1). Subjects must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of sotatercept. A females of childbearing potential is a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy or who has not been postmenopausal for at least 24 consecutive months (ie, who has had menses at some time in the preceding 24 months).
- 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 112 days following the last dose of sotatercept, even if he has undergone a successful vasectomy. Subjects must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of sotatercept.
- Free of metastatic malignancy (other than MDS) for ≥ 2 years.
- Patients with MDS with chromosome 5q deletion.
- Women who are pregnant or breast feeding (Women who are lactating must agree not to breast feed) or planning to become pregnant or breast feed during the period of treatment and for 112 days following the last dose of sotatercept.
- Males who do not agree to use a latex condom or non-latex condom NOT made of natural (animal) membrane during sexual contact with females of childbearing potential or a pregnant female while participating in the study and for at least 112 days following the last dose of sotatercept, even if he has undergone successful vasectomy.
- Major surgery within 30 days prior to Day 1
- Incomplete recovery or incomplete healing of wounds from previous surgery.
- Subjects with classification of 3 or higher heart failure as classified by the New York History of thrombosis, deep vein thrombosis, pulmonary emboli, or embolic stroke if not stable on anticoagulants and/or occurring within the past 6 months. Local central line thrombosis is allowed.Heart Association (NYHA) (Appendix E).
- History of thrombosis, deep vein thrombosis, pulmonary emboli, or embolic stroke if not stable on anticoagulants and/or occurring within the past 6 months. Local central line thrombosis is allowed.
- History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in the investigational product (Refer to the Investigators Brochure for further information).
- A condition, including laboratory abnormality, that, as determined by the Investigator, places the subject at unacceptable risk if he/she were to participate in the study or that potentially confounds interpretation of data from the study.
- Concurrent use of anti-cancer cytotoxic chemotherapeutic agent or treatment.
- Known positive for human immunovirus (HIV) or infectious hepatitis type C or active infectious hepatitis type B.
- Clinically significant anemia unrelated to myelodysplastic disease (eg, iron, B12 or folate deficiencies, autoimmune or hereditary hemolysis, active gastrointestinal bleeding, and chronic renal insufficiency).
- Thrombocytopenia (platelet count < 30,000/uL
- Uncontrolled hypertension (systolic blood pressure [SBP] ≥ 140 or diastolic blood pressure [DBP] ≥ 90). Controlled hypertension for this protocol is considered ≤ Grade 1 according to NCI CTCAE version 4.0 (current active minor version) (Appendix F).
- Treatment with another investigational drug or device within 28 days prior to Day 1, or if the half life of the previous product is known, within 5 times the half life prior to dosing, whichever is longer.
- Prior exposure to sotatercept (ACE-011).
- Any significant medical condition, laboratory abnormality, or psychiatric illness that, as determined by the Investigator, would prevent the subject from participating in the study or providing written informed consent.
- Any condition including the presence of laboratory abnormality that, as determined by the Investigator, places the subject at unacceptable risk if he/she were to participate in the study.
- Any condition that, as determined by the Investigator, confounds the interpretation of data from the study.
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