Clinical trial NCT02268383: Extension Study to Evaluate Long-Term Effects of Luspatercept in Patients With Myelodysplastic Syndromes (MDS) (A536-05/MK-6143-003)
Official title: An Open-Label Extension Study to Evaluate the Long-Term Effects of ACE-536 for the Treatment of Anemia in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) Previously Enrolled in Study A536-03
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myelodysplastic Syndromes
Lead sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Sponsor class: INDUSTRY
First posted: 2014-10-20
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is an open-label extension study for participants previously enrolled in study MK-6143-001 (formerly called A536-03, ClinicalTrials.gov Identifier NCT01749514), to evaluate the long-term safety and tolerability of luspatercept (MK-6143) in participants with low or intermediate-1 risk MDS.

Detailed description: This study is an open-label extension study to evaluate the safety, tolerability, and pharmacodynamic effects of up to 24 months of luspatercept treatment in participants with low or intermediate-1 risk myelodysplastic syndromes previously treated with luspatercept for up to 3 months in MK-6143-001 study (NCT01749514). The starting dose level in this study will be 1.0 mg/kg by subcutaneous (SC) injection every 3 weeks. Dose titration/modification rules will be followed for individual participants and will be based upon safety and efficacy data collected during the course of treatment.

Eligibility criteria: Inclusion Criteria:

* Completion of the treatment period in the base study MK-6143-001 (ClinicalTrials.gov Identifier: NCT01749514)
* Adequate birth control measures
* Patient is able to adhere to the study visit schedule, understand and comply with all protocol requirements
* Patient understands and is able to provide written informed consent
* In addition, patients with treatment interruption (defined as patients who complete their end-of-study visit in MK-6143-001 and cannot directly roll over to MK-6143-003) must also meet the following criteria:

  * Documented diagnosis of idiopathic/de novo MDS or non-proliferative chronic myelomonocytic leukemia (CMML) according to the World Health Organization (WHO) criteria 16 (white blood count (WBC) \< 13,000/μL) 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), for non-transfusion dependent (NTD) patients (defined as having received ˂ 4 units of red blood cells (RBCs) within 8 weeks prior to Cycle 1 Day 1), OR
  * Transfusion Dependent (TD), defined as having received ≥ 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1
* Platelet count ≥ 30 x 109/L
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (if related to anemia)
* Adequate renal (creatinine ≤ 2.0 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

Exclusion Criteria:

* Discontinuation/withdrawal from the base study A536-03 (due to patient request, patient unwillingness or inability to comply with the protocol, pregnancy, use of prohibited medication \[e.g. azacitidine\], medical reason or adverse event (AE), hypersensitivity reaction to the study drug, at the discretion of the sponsor, or loss to follow-up) prior to completion of the treatment period
* Prior treatment with azacitidine or decitabine
* Treatment within 28 days prior to Cycle 1 Day 1 with:

  * An 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 (including sotatercept \[ACE-011\]) or device, or approved therapy for investigational use ≤ 28 days prior to Cycle 1 Day 1, or if the half-life of the previous investigational 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
* Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B (HBV) or active infectious hepatitis C (HCV)
* Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 150 mm Hg or diastolic blood pressure (DBP) ≥ 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

Primary outcomes:
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 5 years
measure: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to approximately 5 years
Secondary outcomes:
measure: Percentage of Participants With Modified Erythroid Response (mHI-E) Per International Working Group (IWG) 2006 Response Criteria
timeFrame: Any consecutive 8 weeks during the study (up to approximately 5 years)
measure: Rate of Erythroid Response (HI-E) Per IWG 2006 Response Criteria
timeFrame: Any consecutive 8 weeks during the study (up to approximately 5 years)
measure: Rate of Neutrophil Response (HI-N) Per IWG 2006 Response Criteria
timeFrame: Any consecutive 8 Weeks during the study (up to approximately 5 years)
measure: Rate of Platelet Response (HI-P) Per IWG 2006 Response Criteria
timeFrame: Any consecutive 8 Weeks during the study (up to approximately 5 years)
measure: Duration of HI-E in LTB Participants Per IWG 2006 Response Criteria
timeFrame: up to approximately 5 years
measure: Duration of HI-E in HTB Participants Per IWG 2006 Response Criteria
timeFrame: up to approximately 5 years
measure: Time to HI-E in LTB Participants Per IWG 2006 Response Criteria
timeFrame: up to approximately 5 years
measure: Time to HI-E in HTB Participants Per IWG 2006 Response Criteria
timeFrame: Any consecutive 8 weeks during the study (up to approximately 5 years)
measure: Rate of RBC Transfusion Independence (RBC-TI)
timeFrame: Any consecutive 8 Weeks during the study (up to approximately 5 years)
measure: Mean Change From Baseline to Week 8 in RBC Transfusion Burden (TB) in HTB Participants
timeFrame: Baseline and up to 5 years
measure: Mean Change From Baseline to Week 8 in Hemoglobin Levels ≥1.5 Grams/dL in LTB Participants
timeFrame: Baseline and Week 8
measure: Serum Concentration of Luspatercept
timeFrame: Day 1: Cycles 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, and 81 (each cycle length = 21 days); End of treatment (EOT) Day 1853
measure: Percent Change From Baseline to Day 1853 in Concentration of Serum Iron
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
measure: Percent Change From Baseline to Day 1853 in Total Iron Binding Capacity (TIBC)
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
measure: Percent Change From Baseline to Day 1853 in Concentration of Transferrin
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
measure: Percent Change From Baseline to Day 1853 in Concentration of Soluble Transferrin Receptor
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
measure: Percent Change From Baseline to Day 1853 in Concentration of Serum Ferritin
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
measure: Percent Change From Baseline to Day 1853 in Concentration of Non-Transferrin Bound Iron (NTBI)
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
measure: Percent Change From Baseline to Day 1853 in Concentration of Serum Hepcidin
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
measure: Percent Change From Baseline to Day 1853 in Concentration of Serum Erythropoietin
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
measure: Percent Change From Baseline to Day 1853 in Reticulocyte Count
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
measure: Percent Change From Baseline to Day 1853 in Nucleated RBC (nRBC) Count
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
measure: Percent Change From Baseline to Day 1853 in Direct Bilirubin Level
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
measure: Percent Change From Baseline to Day 1853 in Total Bilirubin Level
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
measure: Percent Change From Baseline to Day 1853 in Lactate Dehydrogenase Level
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
measure: Percent Change From Baseline to Day 1853 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP)
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
measure: Percent Change From Baseline to Day 1853 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX)
timeFrame: Baseline (prior to first dose of luspatercept) and Day 1853
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.