Myelodysplastic Syndromes (MDS) MedDRA version: 20.0 Level: SOC Classification code 10029104 Term: Neoplasms benign, malignant and unspecified (incl cysts and polyps) System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: HLT Classification code 10028536 Term: Myelodysplastic syndromes System Organ Class: 100000004851
Conditions
Sponsors
Acceleron Pharma Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Men or women = 18 years of age. 2.Documented diagnosis of idiopathic/de novo MDS or non-proliferative chronic myelomonocytic leukemia (CMML) according to WHO criteria16 (white blood count [WBC] 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), has less than 4 weeks' exposure to ESAs 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. - Expansion cohort 3 patients: baseline EPO levels = 500 U/L, no prior ESA, and RS- (defined as having < 15% ring sideroblasts in the bone marrow). 5.No alternative treatment options, per national MDS guidelines, are available and/or appropriate for the patient, at the discretion of the investigator. 6.ECOG performance status of 0, 1, or 2 (if related to anemia). 7.Adequate renal (creatinine = 2.0 x upper limit of normal [ULN]) and hepatic (total bilirubin < 2 x ULN and AST and ALT < 3 x ULN) function. 8.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). 9.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.
Exclusion criteria
Exclusion criteria: 1.Prior treatment with azacitidine or decitabine. 2.Treatment within 28 days prior to Cycle 1 Day 1 with: a.Erythropoiesis stimulating agent (ESA), b.Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF), c.Lenalidomide. 3.Iron chelation therapy if initiated within 56 days prior to Cycle 1 Day 1. 4.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 may be longer. 5.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. 6.Platelet count < 30 x 10^9/L. 7.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. 8.History of stroke, deep venous thrombosis (DVT) or arterial embolism within 6 months prior to Cycle 1 Day 1. 9.Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B (HBV) or active infectious hepatitis C (HCV). 10.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. 11.Uncontrolled hypertension defined as systolic blood pressure (BP) = 150 mm Hg or diastolic BP = 100 mm Hg. 12.Pregnant or lactating females. 13.History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug. 14.Any other condition not specifically noted above which, in the judgment of the investigator, would preclude the patient from participating in the study. 15. Transfusion event within 7 days prior to Cycle 1 Day 1. 16. Prior treatment with sotatercept (ACE-011) or ACE-536. 17. Secondary MDS
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the proportion of patients who have a modified erythroid response (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 pretreatment in transfusion-dependent patients;Secondary Objective: Secondary: -To evaluate safety and tolerability of ACE-536 -To examine rates of erythroid, neutrophil and platelet (HI-E, HI-N and HI-P) responses (International Working Group [IWG] 2006 criteria) -To evaluate time to mHI-E and HI-E response and duration of mHI-E and HI-E response -To evaluate frequency of RBC transfusions in transfusion dependent patients -To examine the pharmacokinetic (PK) profile of ACE-536 -To examine other pharmacodynamic (PD) effects (e.g., iron metabolism, erythropoietin, reticulocytes, and bone biomarkers) Exploratory: -To evaluate biomarkers related to the TGFb superfamily -Evaluation of self-reported quality of life in the expansion cohort using tools including but not limited to the FACT-An questionnaire;Primary end point(s): The primary efficacy endpoint is modified erythroid response (mHI-E), defined as the proportion of patients who have a hemoglobin increase of = 1.5 g/dL from baseline for = 14 days (in the absence of RBC transfusions) in non-transfusion dependent patients, or, a reduction of either = 4 units or = 50% of units of RBCs transfused over a period of 8 consecutive weeks, compared to the number of units of RBCs transfused in the 8 weeks immediately prior to Cycle 1 Day 1 in transfusion dependent patients (defined as having received = 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1).;Timepoint(s) of evaluation of this end point: End of Treatment (day 113) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary efficacy/pharmacodynamic analysis will be performed using the ITT and EE populations and include: - Modified erythroid response (mHI-E), as described above for primary endpoint, performed using the ITT population. - HI-E response rate as defined by IWG 2006 criteria (Appendix 5). Improvements must last = 8 weeks. For non-transfusion dependent patients, an increase of = 1.5 g/dL from pretreatment hemoglobin. For transfused patients, a reduction by = 4 units of RBCs transfused (for a hemoglobin = 9.0 g/dL) during any 8-week period on study, compared with the 8-week period prior to Cycle 1 Day 1. - Time to mHI-E and HI-E response and duration of mHI-E and HI-E response as per the IWG 2006 criteria. - Frequency of RBC transfusion, and rate of RBC transfusion independence in transfusion-dependent patients. - Other pharmacodynamic (PD) endpoints including: o Biomarkers for iron metabolism o Biomarkers for bone metabolism o Relationship of biomarkers to response o Rates of HI-N and HI-P The exploratory endpoints will include: - Evaluation of biomarkers related to the TGFb superfamily - Evaluation of self-reported quality of life in the expansion cohort using tools including but not limited to the FACT-An questionnaire;Timepoint(s) of evaluation of this end point: End of Treatment (day 113) | — |
Countries
Germany
Contacts
Public ContactPeter G. Linde
Acceleron Pharma Inc.
Outcome results
None listed