Study of Luspatercept for the Treatment of Anemia in Patients With Myelodysplastic Syndrome (MDS) (MK-6143-001)
- Registration Number
- NCT01749514
- Lead Sponsor
- Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 116
-
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
-
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Luspatercept 0.50mg/kg (Cohort 3) Luspatercept Participants receive luspatercept titrated up to 0.50mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days). Luspatercept 0.25mg/kg (Cohort 2) Luspatercept Participants receive luspatercept titrated up to 0.25mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days). Luspatercept 0.125mg/kg (Cohort 1) Luspatercept Participants receive luspatercept 0.125mg/kg as a subcutaneous (SC) injection every 3 weeks (Q3W) on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days). Luspatercept 1.00mg/kg (Cohort 5) Luspatercept Participants receive luspatercept titrated up to 1.00mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days). Luspatercept 0.75mg/kg (Cohort 4) Luspatercept Participants receive luspatercept titrated up to 0.75mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days). Luspatercept 1.75mg/kg (Cohort 7) Luspatercept Participants receive luspatercept titrated up to 1.75mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days). Luspatercept 1.33mg/kg (Cohort 6) Luspatercept Participants receive luspatercept titrated up to 1.33mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days). Expansion Cohort Luspatercept Participants receive an initial dose of luspatercept 1.0mg/kg SC on Day 1 of the Cycle 1 (Cycle length = 21 days). For each subsequent cycle (up to 5 cycles), the dose was titrated via Fibonacci scheme up to a maximum dose of 1.75mg/kg based on the safety review team (SRT) recommendations
- Primary Outcome Measures
Name Time Method Percentage of High Transfusion Burden (HTB) Participants With mHI-E Any consecutive 8 weeks during the study (up to approximately 75 weeks) The mHI-E for HTB participants was defined as a ≥4 units or ≥50% reduction in RBC transfusion burden during any rolling 8-week window compared to baseline. HTB participants were those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. The percentage of HTB participants with mHI-E were reported.
Percentage of Low Transfusion Burden (LTB) Participants With Modified Erythroid Response (mHI-E) Any consecutive 2 weeks during the study (up to approximately 75 weeks) The mHI-E for LTB participants was defined as a hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 days or rolling 2 weeks (in the absence of red blood cell \[RBC\] transfusions). Hemoglobin measurements within 7 days following RBC transfusion were excluded from analysis. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. Rolling 2 weeks was defined as any consecutive 2 weeks during the study. The percentage of LTB participants with mHI-E were reported.
- Secondary Outcome Measures
Name Time Method Number of Participants Who Discontinued Study Treatment Due To an AE Up to approximately 12 weeks An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The number of participants who discontinued study treatment due to an AE were reported.
Rate of Erythroid Response (HI-E) Per International Working Group (IWG) 2006 Response Criteria Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks) Per IWG 2006 response criteria, rate of HI-E is defined as the percentage of participants for whom the mean of all hemoglobin value from baseline during any rolling 8-week increased ≥1.5 g/dL in the absence of transfusion for LTB participants, or a reduction by ≥4 units of RBCs transfusion over any rolling 8-week window for HTB patients. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. HTB participants were those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline. Rolling 8 weeks was defined as any consecutive 8 weeks during the study.
Number of Participants Who Experienced an Adverse Event (AE) Up to approximately 24 weeks An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The number of participants who experienced an AE were reported.
Rate of Platelet Response (HI-P) Per IWG 2006 Criteria Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks) Per IWG 2006 response criteria, HI-P was defined for participants with baseline value ≥20 x 10\^9/L as the platelet increase in any rolling 8 weeks ≥30 x 10\^9 and for participants with baseline value \<20 x 10\^9/L as the platelet increase in any rolling 8 weeks \>20 x 10\^9/L with increase of at least 100%. The rolling 8-week was defined as any consecutive 8 weeks during the study. The percentage of participants with HI-P were reported.
Time to Maximum Concentration (Tmax) of Luspatercept 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) Blood samples were collected at specified intervals for the determination of Tmax. Tmax was defined as time to the maximum concentration of luspatercept reached. Tmax was based on non-compartmental analysis and a mean Tmax value was presented.
Percent Change From Baseline to Day 113 in Concentration of Serum Iron Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were to be collected at pre-specified time intervals to determine serum iron concentration. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Percent Change From Baseline to Day 113 in Concentration of Serum Hepcidin Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were collected at pre-specified time intervals to determine soluble hepcidin concentration. The percentage change from baseline in concentration of soluble hepcidin was reported.
Percent Change From Baseline to Day 113 in Total Bilirubin Level Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were collected at pre-specified time intervals to determine total bilirubin concentration. The percentage change from baseline in mean concentration total bilirubin was reported.
Rate of Neutrophil Response (HI-N) Per IWG 2006 Criteria Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks) Per IWG 2006 response criteria, HI-N was defined as the neutrophil increase in any rolling 8 weeks is at last 100% and an absolute increase \> 0.5 x 10\^9/L. The rolling 8-week was defined as any consecutive 8 weeks during the study. The percentage of participants with HI-N response were reported.
Area Under the Concentration-Time Curve of Luspatercept From Time 0 to Day 21 (AUC0-21) Cycle 1 Day 1: Predose, Cycle 1 Days 8, 11, 15 and Cycle 2 Day 1: Postdose (each cycle length = 21 days) Blood samples were collected at specified intervals for the determination of AUC0-21. AUC0-21 was defined as the area under the concentration-time curve of luspatercept from time zero to Study Day 21. AUC0-21 was based on non-compartmental analysis and a mean AUC0-21 value was presented.
Percent Change From Baseline to Day 113 in Reticulocyte Count Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were collected at pre-specified time intervals to determine reticulocyte count. The percentage change from baseline in mean reticulocyte count was reported.
Percent Change From Baseline to Day 113 in Direct Bilirubin Level Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were collected at pre-specified time intervals to determine serum direct bilirubin concentration. The percentage change from baseline in mean concentration direct bilirubin was reported.
Duration of HI-E Per IWG 2006 Response Criteria up to approximately 75 weeks Per IWG 2006 response criteria, duration of HI-E response was defined as the time from the first day of the first rolling 8-week interval of showing response to the last day of the last consecutive rolling 8-week interval of showing response. HI-E response for LTB participants was defined as hemoglobin increase ≥ 1.5 g/dL during any rolling 8-week window and for HTB HI-E was defined as RBC transfusion reduction ≥4 units during any rolling 8 weeks. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. HTB participants were those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline. The rolling 8-week was defined as any consecutive 8 weeks during the study.
Rate of RBC Transfusion Independence (RBC-TI) Up to approximately 16 weeks Rate of RBC-TI was defined as percentage of participants with ≥2 units of RBC transfusions at baseline who experienced transfusion independence which was defined as ≥8 weeks without a transfusion while on treatment. Per protocol, rate of RBC-TI was reported in HTB participants (those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline).
Percent Change From Baseline to Day 113 in Concentration of Transferrin Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were to be collected at pre-specified time intervals to determine concentration of transferrin. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Percent Change From Baseline to Day 113 in Concentration of Soluble Transferrin Receptor Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were collected at pre-specified time intervals to determine soluble transferrin receptor concentration. The percentage change from baseline in concentration of soluble transferrin receptor was reported.
Maximum Concentration (Cmax) of Luspatercept 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) Blood samples were collected at specified intervals for the determination of Cmax. Cmax was defined as the maximum concentration of luspatercept reached. Cmax was based on non-compartmental analysis and a mean Cmax value was presented.
Percent Change From Baseline to Day 113 in Concentration of Serum Erythropoietin Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were collected at pre-specified time intervals to determine serum erythropoietin concentration. The percentage change from baseline in concentration of serum erythropoietin was reported.
Percent Change From Baseline to Day 113 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX) Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were collected at pre-specified time intervals to determine serum CTX. The percentage change from baseline in concentration of CTX was reported.
Time to HI-E Per IWG 2006 Response Criteria Any consecutive 8 weeks during the study (up to approximately 75 weeks) Per IWG 2006 response criteria, the time to HI-E response was defined as the first date of the rolling 8-week interval of showing response minus first dose date plus 1. HI-E response for LTB participants was defined as hemoglobin increase ≥ 1.5 g/dL during any rolling 8 weeks window and for HTB HI-E was defined as RBC transfusion reduction ≥4 units during any rolling 8 weeks. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. HTB participants were those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline. The rolling 8-week was defined as any consecutive 8 weeks during the study.
Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions Baseline (prior to first dose of luspatercept) and Day 113 Frequency of RBC transfusion was defined as the total number of RBC transfusions received. Per protocol, the mean change from baseline to Day 113 in frequency of RBC transfusion was reported in the HTB participants (those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline).
Terminal Half-Life (t ½) of Luspatercept 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) Blood samples were collected at specified intervals for the determination of t½. t½ was defined as the time required to divide the luspatercept plasma concentration by two after reaching pseudo-equilibrium, following a single dose of luspatercept. t½ was based on non-compartmental analysis and a mean t1/2 value was presented.
Percent Change From Baseline to Day 113 in Total Iron Binding Capacity (TIBC) Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were collected at pre-specified time intervals to determine TIBC. The percentage change from baseline in TIBC was reported.
Percent Change From Baseline to Day 113 in Concentration of Serum Ferritin Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were collected at pre-specified time intervals to determine serum ferritin concentration. The percentage change from baseline in concentration of serum ferritin was reported.
Percent Change From Baseline to Day 113 in Lactate Dehydrogenase Level Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were collected at pre-specified time intervals to determine serum lactate dehydrogenase level. The percentage change from baseline in mean concentration lactate dehydrogenase level was reported.
Percent Change From Baseline to Day 113 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP) Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were collected at pre-specified time intervals to determine serum BSAP concentration. The percentage change from baseline in concentration BSAP was reported.
Percent Change From Baseline to Day 113 in Concentration of Non-Transferrin Bound Iron (NTBI) Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were to be collected at pre-specified time intervals to determine concentration of NTBI. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Percent Change From Baseline to Day 113 in Nucleated RBC (nRBC) Baseline (prior to first dose of luspatercept) and Day 113 Blood samples were to be collected at pre-specified time intervals to determine concentration of nRBC. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Trial Locations
- Locations (1)
Acceleron Investigative Site
🇩🇪Dresden, Germany