Clinical trial NCT01749514: Study of Luspatercept for the Treatment of Anemia in Patients With Myelodysplastic Syndrome (MDS) (MK-6143-001)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Anemia
Keywords: Myelodysplastic Syndrome
Lead sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Sponsor class: INDUSTRY
First posted: 2012-12-13
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the effects of luspatercept (MK-6143, formerly called ACE-536) on anemia in patients with low or intermediate-1 risk myelodysplastic syndrome (MDS). There is no primary hypothesis in this study.


Eligibility criteria: Key Inclusion Criteria:

* Documented diagnosis of idiopathic/de novo myelodysplastic syndrome (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 red blood cell (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
* Eastern Cooperative Oncology Group (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 aspartate aminotransferase (AST) and alanine aminotransferase (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 luspatercept. 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 luspatercept, 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 luspatercept
* 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:

  * Erythropoiesis stimulating agent (ESA)
  * Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF)
  * 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 (MK-7962, formerly called ACE-011) or luspatercept.
* Secondary MDS

Primary outcomes:
measure: Percentage of Low Transfusion Burden (LTB) Participants With Modified Erythroid Response (mHI-E)
timeFrame: Any consecutive 2 weeks during the study (up to approximately 75 weeks)
measure: Percentage of High Transfusion Burden (HTB) Participants With mHI-E
timeFrame: Any consecutive 8 weeks during the study (up to approximately 75 weeks)
Secondary outcomes:
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 24 weeks
measure: Number of Participants Who Discontinued Study Treatment Due To an AE
timeFrame: Up to approximately 12 weeks
measure: Rate of Erythroid Response (HI-E) Per International Working Group (IWG) 2006 Response Criteria
timeFrame: Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks)
measure: Rate of Platelet Response (HI-P) Per IWG 2006 Criteria
timeFrame: Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks)
measure: Rate of Neutrophil Response (HI-N) Per IWG 2006 Criteria
timeFrame: Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks)
measure: Duration of HI-E Per IWG 2006 Response Criteria
timeFrame: up to approximately 75 weeks
measure: Time to HI-E Per IWG 2006 Response Criteria
timeFrame: Any consecutive 8 weeks during the study (up to approximately 75 weeks)
measure: Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Rate of RBC Transfusion Independence (RBC-TI)
timeFrame: Up to approximately 16 weeks
measure: Time to Maximum Concentration (Tmax) of Luspatercept
timeFrame: Cycle 1 Day 1: Predose, Cycle 1: Days 8, 11, 15: Postdose; Cycle 2 Day 1, Cycle 2 Day 8, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 5 Days 8, 15: Postdose (each cycle length = 21 days)
measure: Terminal Half-Life (t ½) of Luspatercept
timeFrame: Cycle 1 Day 1: Predose, Cycle 1: Days 8, 11, 15: Postdose; Cycle 2 Day 1, Cycle 2 Day 8, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 5 Days 8, 15: Postdose (each cycle length = 21 days)
measure: Maximum Concentration (Cmax) of Luspatercept
timeFrame: Cycle 1 Day 1: Predose, Cycle 1: Days 8, 11, 15: Postdose; Cycle 2 Day 1, Cycle 2 Day 8, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 5 Days 8, 15: Postdose (each cycle length = 21 days)
measure: Area Under the Concentration-Time Curve of Luspatercept From Time 0 to Day 21 (AUC0-21)
timeFrame: Cycle 1 Day 1: Predose, Cycle 1 Days 8, 11, 15 and Cycle 2 Day 1: Postdose (each cycle length = 21 days)
measure: Percent Change From Baseline to Day 113 in Concentration of Serum Iron
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Percent Change From Baseline to Day 113 in Total Iron Binding Capacity (TIBC)
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Percent Change From Baseline to Day 113 in Concentration of Transferrin
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Percent Change From Baseline to Day 113 in Concentration of Soluble Transferrin Receptor
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Percent Change From Baseline to Day 113 in Concentration of Serum Ferritin
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Percent Change From Baseline to Day 113 in Concentration of Non-Transferrin Bound Iron (NTBI)
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Percent Change From Baseline to Day 113 in Concentration of Serum Hepcidin
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Percent Change From Baseline to Day 113 in Concentration of Serum Erythropoietin
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Percent Change From Baseline to Day 113 in Reticulocyte Count
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Percent Change From Baseline to Day 113 in Direct Bilirubin Level
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Percent Change From Baseline to Day 113 in Total Bilirubin Level
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Percent Change From Baseline to Day 113 in Lactate Dehydrogenase Level
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Percent Change From Baseline to Day 113 in Nucleated RBC (nRBC)
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Percent Change From Baseline to Day 113 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP)
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
measure: Percent Change From Baseline to Day 113 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX)
timeFrame: Baseline (prior to first dose of luspatercept) and Day 113
Other outcomes:
Locations:
city: Dresden
country: Germany
facility: Acceleron Investigative Site
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Platzbecker U, Gotze KS, Kiewe P, Germing U, Mayer K, Radsak M, Wolff T, Chromik J, Sockel K, Oelschlagel U, Haase D, Illmer T, Al-Ali HK, Silling G, Reynolds JG, Zhang X, Attie KM, Shetty JK, Giagounidis A. Long-Term Efficacy and Safety of Luspatercept for Anemia Treatment in Patients With Lower-Risk Myelodysplastic Syndromes: The Phase II PACE-MDS Study. J Clin Oncol. 2022 Nov 20;40(33):3800-3807. doi: 10.1200/JCO.21.02476. Epub 2022 Aug 23.
citation: Platzbecker U, Germing U, Gotze KS, Kiewe P, Mayer K, Chromik J, Radsak M, Wolff T, Zhang X, Laadem A, Sherman ML, Attie KM, Giagounidis A. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017 Oct;18(10):1338-1347. doi: 10.1016/S1470-2045(17)30615-0. Epub 2017 Sep 1.