Study of Luspatercept for the Treatment of Anemia in Patients With Myelodysplastic Syndrome (MDS) (MK-6143-001)

Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA116 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

116

Conditions

Anemia

Interventions

LuspaterceptDRUG

Participants receive luspatercept up to 1.75mg/kg subcutaneously (SC) every 3 weeks for up to 5 cycles (each cycle length = 21 days).

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (1)

Acceleron Investigative Site

Dresden, Germany

Outcomes

Primary Outcomes

Percentage of Low Transfusion Burden (LTB) Participants With Modified Erythroid Response (mHI-E)

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.

Time frame: Any consecutive 2 weeks during the study (up to approximately 75 weeks)

Percentage of High Transfusion Burden (HTB) Participants With mHI-E

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.

Time frame: Any consecutive 8 weeks during the study (up to approximately 75 weeks)

Secondary Outcomes

Number of Participants Who Experienced an Adverse Event (AE)

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.

Time frame: Up to approximately 24 weeks

Number of Participants Who Discontinued Study Treatment Due To an AE

Data from ClinicalTrials.gov

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Time frame: Up to approximately 12 weeks

Rate of Erythroid Response (HI-E) Per International Working Group (IWG) 2006 Response Criteria

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.

Time frame: Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks)

Rate of Platelet Response (HI-P) Per IWG 2006 Criteria

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 frame: Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks)

Rate of Neutrophil Response (HI-N) Per IWG 2006 Criteria

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.

Time frame: Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks)

Duration of HI-E Per IWG 2006 Response Criteria

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.

Time frame: up to approximately 75 weeks

Time to HI-E Per IWG 2006 Response Criteria

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.

Time frame: Any consecutive 8 weeks during the study (up to approximately 75 weeks)

Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions

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).

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Rate of RBC Transfusion Independence (RBC-TI)

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).

Time frame: Up to approximately 16 weeks

Time to Maximum Concentration (Tmax) of Luspatercept

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.

Time frame: 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)

Terminal Half-Life (t ½) of Luspatercept

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.

Time frame: 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)

Maximum Concentration (Cmax) of Luspatercept

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.

Time frame: 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)

Area Under the Concentration-Time Curve of Luspatercept From Time 0 to Day 21 (AUC0-21)

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.

Time frame: Cycle 1 Day 1: Predose, Cycle 1 Days 8, 11, 15 and Cycle 2 Day 1: Postdose (each cycle length = 21 days)

Percent Change From Baseline to Day 113 in Concentration of Serum Iron

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.

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Percent Change From Baseline to Day 113 in Total Iron Binding Capacity (TIBC)

Blood samples were collected at pre-specified time intervals to determine TIBC. The percentage change from baseline in TIBC was reported.

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Percent Change From Baseline to Day 113 in Concentration of Transferrin

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.

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Percent Change From Baseline to Day 113 in Concentration of Soluble Transferrin Receptor

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.

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Percent Change From Baseline to Day 113 in Concentration of Serum Ferritin

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.

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Percent Change From Baseline to Day 113 in Concentration of Non-Transferrin Bound Iron (NTBI)

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.

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Percent Change From Baseline to Day 113 in Concentration of Serum Hepcidin

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.

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Percent Change From Baseline to Day 113 in Concentration of Serum Erythropoietin

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.

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Percent Change From Baseline to Day 113 in Reticulocyte Count

Blood samples were collected at pre-specified time intervals to determine reticulocyte count. The percentage change from baseline in mean reticulocyte count was reported.

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Percent Change From Baseline to Day 113 in Direct Bilirubin Level

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.

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Percent Change From Baseline to Day 113 in Total Bilirubin Level

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.

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Percent Change From Baseline to Day 113 in Lactate Dehydrogenase Level

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.

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Percent Change From Baseline to Day 113 in Nucleated RBC (nRBC)

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.

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Percent Change From Baseline to Day 113 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP)

Blood samples were collected at pre-specified time intervals to determine serum BSAP concentration. The percentage change from baseline in concentration BSAP was reported.

Time frame: Baseline (prior to first dose of luspatercept) and Day 113

Percent Change From Baseline to Day 113 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX)

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 frame: Baseline (prior to first dose of luspatercept) and Day 113