Extension Study to Evaluate Long-Term Effects of Luspatercept in Patients With Myelodysplastic Syndromes (MDS) (A536-05/MK-6143-003)

Phase 2

Completed

Conditions: Myelodysplastic Syndromes

Interventions: Drug: Luspatercept

Registration Number: NCT02268383

Lead Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 75

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Luspatercept Extension population	Luspatercept	Luspatercept 1.0 mg/kg once every 3 weeks by subcutaneous injection.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Discontinued Study Treatment Due to an AE	Up to approximately 5 years	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 luspatercept due to an AE was reported.
Number of Participants Who Experienced an Adverse Event (AE)	Up to approximately 5 years	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 was reported.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Modified Erythroid Response (mHI-E) Per International Working Group (IWG) 2006 Response Criteria	Any consecutive 8 weeks during the study (up to approximately 5 years)	The mHI-E was defined as a mean hemoglobin (Hgb) increase ≥1.5 g/dL over an 8-week period as compared to baseline, not influenced by red blood cell (RBC) transfusion in low transfusion burden (LTB) participants and a decrease of ≥4 units or ≥50% of units of RBCs transfused over a period of 8 weeks, relative to the number of units of RBCs transfused in the 8 weeks immediately prior to baseline in high transfusion burden (HTB) participants. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. HTB participants were those who required a transfusion of ≥4 units of RBCs in the 8 weeks prior to baseline. Rolling 8 weeks was defined as any consecutive 8 weeks during the study.
Rate of Neutrophil Response (HI-N) Per IWG 2006 Response Criteria	Any consecutive 8 Weeks during the study (up to approximately 5 years)	Per IWG 2006 response criteria, HI-N response was defined for participants with baseline absolute neutrophil count (ANC) \<1.0×10\^9/L as the percentage increase ≥100% and an absolute mean increase \>0.5 ×10\^9/L during any rolling 8-week window on treatment compared with baseline. The rolling 8-week was defined as any consecutive 8 weeks during the study. Percentage of participants with HI-N response were reported.
Rate of Platelet Response (HI-P) Per IWG 2006 Response Criteria	Any consecutive 8 Weeks during the study (up to approximately 5 years)	Per IWG 2006 response criteria, HI-P response was defined for participants with baseline platelet count \<100×10\^9/L as the following: 1) For participants with baseline ≥20×10\^9/L, an absolute increase of ≥30×10\^9/L during any rolling 8-week window on treatment and 2) For participants with baseline \<20×10\^9/L, mean value of \>20×10\^9/L and percentage increase ≥100% during any rolling 8-week window on treatment. The rolling 8-week was defined as any consecutive 8 weeks during the study. Percentage of participants with HI-P response were reported.
Duration of HI-E in LTB Participants Per IWG 2006 Response Criteria	up to approximately 5 years	For LTB participants, HI-E was defined as all Hgb increase ≥1.5 g/dL during any rolling 8 weeks window. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. Per IWG 2006 response criteria, duration of HI-E was defined as the time from the first day of the first rolling 8 weeks interval of showing response to the last day of the last consecutive rolling 8 weeks interval of showing response. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. When there were multiple disjointed intervals with response, the longest interval was used.
Duration of HI-E in HTB Participants Per IWG 2006 Response Criteria	up to approximately 5 years	For HTB participants, HI-E was defined as RBC transfusion reduction ≥4 units during any rolling 8 weeks. HTB participants were those who required a transfusion of ≥4 units of RBCs in the 8 weeks prior to baseline. Per IWG 2006 response criteria, duration of HI-E was defined as the time from the first day of the first rolling 8 weeks interval of showing response to the last day of the last consecutive rolling 8 weeks interval of showing response. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. When there were multiple disjointed intervals with response, the longest interval was used.
Time to HI-E in HTB Participants Per IWG 2006 Response Criteria	Any consecutive 8 weeks during the study (up to approximately 5 years)	For HTB participants, HI-E was defined as RBC transfusion reduction ≥4 units during any rolling 8 weeks. HTB participants were those who required a transfusion of ≥4 units of RBCs in the 8 weeks prior to baseline. Per IWG 2006 response criteria, time to HI-E was defined as the first date of the rolling 8 weeks interval of showing response minus first dose date plus 1. Rolling 8 weeks was defined as any consecutive 8 weeks during the study.
Rate of RBC Transfusion Independence (RBC-TI)	Any consecutive 8 Weeks during the study (up to approximately 5 years)	Per protocol, RBC-TI response was defined as not requiring RBC transfusion for 8 or more weeks while on treatment among participants with ≥2 units of RBC transfusions at baseline. The rate of RBC-TI was defined as the percentage of participants with ≥2 units of RBC transfusions at baseline with RBC-TI.
Mean Change From Baseline to Week 8 in RBC Transfusion Burden (TB) in HTB Participants	Baseline and up to 5 years	RBC TB was defined as ≥4 units or 50% reduction during rolling 8 weeks among HTB participants. The rolling 8-week was defined as any consecutive 8 weeks during the study. HTB participants are those who required a transfusion of ≥4 units of RBCs in the 8 weeks prior to baseline. Mean change from baseline to Week 8 in reduction in RBC TD in HTB participants was reported.
Time to HI-E in LTB Participants Per IWG 2006 Response Criteria	up to approximately 5 years	For LTB participants, HI-E was defined as all Hgb increase ≥1.5 g/dL during any rolling 8 weeks window. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. Per IWG 2006 response criteria, time to HI-E was defined as the first date of the rolling 8 weeks interval of showing response minus first dose date plus 1. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. When there were multiple disjointed intervals with response, the longest interval was used.
Rate of Erythroid Response (HI-E) Per IWG 2006 Response Criteria	Any consecutive 8 weeks during the study (up to approximately 5 years)	Per IWG 2006 response criteria, the rate of HI-E was defined as the percentage of participants with an HI-E response by an Hgb increase of ≥1.5 g/dL for participants not transfused or as defined by having received less than 4 units of RBCs within 8 weeks of baseline or reduction by ≥4 units of RBCs transfused (for a Hgb≤9.0 g/dL) during any 8-week period on study, compared with the 8-week period prior to study day 1.
Mean Change From Baseline to Week 8 in Hemoglobin Levels ≥1.5 Grams/dL in LTB Participants	Baseline and Week 8	Baseline hemoglobin levels were the documented pre-transfusion hemoglobin values during the 12 weeks prior to treatment. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. Mean change from baseline to Week 8 in hemoglobin levels ≥1.5 grams/dL in LTB participants were reported.
Serum Concentration of Luspatercept	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	Blood samples were collected at pre-determined time points to determine the serum concentration of luspatercept. Serum concentrations that were below the limit of quantitation (LOQ) of the assay prior to the first dose were assigned a numerical value of zero. Post-treatment serum concentrations that were below the LOQ of the assay were treated as missing. Serum concentrations assigned a value of missing were omitted from the analysis. The LOQ of the assay was 50 ng/mL.
Percent Change From Baseline to Day 1853 in Concentration of Serum Iron	Baseline (prior to first dose of luspatercept) and Day 1853	Blood samples were collected at pre-specified time intervals to determine serum iron concentration. The percentage change from baseline to Day 1853 in concentration of serum iron was reported.
Percent Change From Baseline to Day 1853 in Total Iron Binding Capacity (TIBC)	Baseline (prior to first dose of luspatercept) and Day 1853	Blood samples were collected at pre-specified time intervals to determine TIBC. The percentage change from baseline to Day 1853 in TIBC was reported.
Percent Change From Baseline to Day 1853 in Concentration of Transferrin	Baseline (prior to first dose of luspatercept) and Day 1853	Blood samples were collected at pre-specified time intervals to determine serum transferrin concentration. The percentage change from baseline to Day 1853 in concentration of transferrin was reported.
Percent Change From Baseline to Day 1853 in Concentration of Soluble Transferrin Receptor	Baseline (prior to first dose of luspatercept) and Day 1853	Blood samples were collected at pre-specified time intervals to determine soluble transferrin receptor concentration. The percentage change from baseline to Day 1853 in concentration of soluble transferrin receptor was reported.
Percent Change From Baseline to Day 1853 in Concentration of Serum Ferritin	Baseline (prior to first dose of luspatercept) and Day 1853	Blood samples were collected at pre-specified time intervals to determine serum ferritin concentration. The percentage change from baseline to Day 1853 in concentration of serum ferritin was reported.
Percent Change From Baseline to Day 1853 in Concentration of Serum Hepcidin	Baseline (prior to first dose of luspatercept) and Day 1853	Blood samples were to be collected at pre-specified time intervals to determine concentration of serum hepcidin. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Percent Change From Baseline to Day 1853 in Concentration of Serum Erythropoietin	Baseline (prior to first dose of luspatercept) and Day 1853	Blood samples were collected at pre-specified time intervals to determine serum erythropoietin concentration. The percentage change from baseline to Day 1853 in concentration of serum erythropoietin was reported.
Percent Change From Baseline to Day 1853 in Concentration of Non-Transferrin Bound Iron (NTBI)	Baseline (prior to first dose of luspatercept) and Day 1853	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 1853 in Total Bilirubin Level	Baseline (prior to first dose of luspatercept) and Day 1853	Blood samples were collected at pre-specified time intervals to determine total bilirubin concentration. The percentage change from baseline to Day 1853 in concentration of total bilirubin was reported.
Percent Change From Baseline to Day 1853 in Lactate Dehydrogenase Level	Baseline (prior to first dose of luspatercept) and Day 1853	Blood samples were collected at pre-specified time intervals to determine serum lactate dehydrogenase level. The percentage change from baseline to Day 1853 in concentration of lactate dehydrogenase level was reported.
Percent Change From Baseline to Day 1853 in Reticulocyte Count	Baseline (prior to first dose of luspatercept) and Day 1853	Blood samples were collected at pre-specified time intervals to determine reticulocyte count. The percentage change from baseline to Day 1853 in reticulocyte count was reported.
Percent Change From Baseline to Day 1853 in Nucleated RBC (nRBC) Count	Baseline (prior to first dose of luspatercept) and Day 1853	Blood samples were to be collected at pre-specified time intervals to determine nRBC. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Percent Change From Baseline to Day 1853 in Direct Bilirubin Level	Baseline (prior to first dose of luspatercept) and Day 1853	Blood samples were collected at pre-specified time intervals to determine serum direct bilirubin concentration. The percentage change from baseline to Day 1853 in concentration of direct bilirubin was reported.
Percent Change From Baseline to Day 1853 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP)	Baseline (prior to first dose of luspatercept) and Day 1853	Blood samples were to be collected at pre-specified time intervals to determine BSAP. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Percent Change From Baseline to Day 1853 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX)	Baseline (prior to first dose of luspatercept) and Day 1853	Blood samples were to be collected at pre-specified time intervals to determine CTX. Baseline was prespecified to be the last measurement prior to the first dose of study drug.