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
- D46D63.0Myelodysplastic syndromesAnaemia in neoplastic disease
- Registration Number
- DRKS00004531
- Lead Sponsor
- Acceleron Pharma, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- All
- Target Recruitment
- 72
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] < 13,000/µL) that meets International Prognostic Scoring System (IPSS) classification (Appendix 2) 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.
3. 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.
4. 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.
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 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. 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.
10. Patients are able to adhere to the study visit schedule, understand and comply with all protocol requirements.
11. Patient understands and is able to provide written informed consent.
1. Prior treatment with azacitidine or decitabine.
2. Treatment within 28 days prior to Cycle 1 Day 1 with:
- Erythropoiesis stimulating agent (ESA),
- Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF),
- 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 is 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 109/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.
Study & Design
- Study Type
- interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 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 pre-treatment in transfusion dependent patients.
- Secondary Outcome Measures
Name Time Method To evaluate safety and tolerability of ACE-536,<br>To examine rates of erythroid, neutrophil and platelet (HI-E, HI-N and HI-P) responses,<br>To evaluate time to mHI-E and HI-E response and duration of mHI-E and HI-E response,<br>To evaluate frequency of RBC transfusions in transfusion dependent patients,<br>To examine the pharmacokinetic (PK) profile of ACE-536;<br>To examine other pharmacodynamic (PD) effects (e.g., iron metabolism, erythropoietin, reticulocytes and bone biomarkers).<br><br>Exploratory:<br>To evaluate biomarkers related to the TGF-beta superfamily;<br>Evaluation of self-reported quality of life in the expansion cohort using the FACT-An questionnaire.