NCT02268383

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

Completed Phase 2 Results posted Last updated 29 July 2024

What this trial tests

Phase 2 trial testing Luspatercept in Myelodysplastic Syndromes in 75 participants. Completed in 19 March 2020.

Timeline

9 October 2014

Primary endpoint
19 March 2020

19 March 2020

Quick facts

Lead sponsor	Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	75
Start date	9 October 2014
Primary completion	19 March 2020
Estimated completion	19 March 2020
Sites	1 location across Germany

Drugs / interventions tested

• Luspatercept (LUSPATERCEPT) — full drug profile →

Conditions studied

• Myelodysplastic Syndromes — all drugs for Myelodysplastic Syndromes →

Sponsor

Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA — full company profile →

Who can join

18 and older, any sex, with Myelodysplastic Syndromes. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants Who Experienced an Adverse Event (AE) Primary · 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.

Group	Value	95% CI
Luspatercept Extension Population	75

Number of Participants Who Discontinued Study Treatment Due to an AE Primary · 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.

Group	Value	95% CI
Luspatercept Extension Population	23

Percentage of Participants With Modified Erythroid Response (mHI-E) Per International Working Group (IWG) 2006 Response Criteria Secondary · 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 uni

Group	Value	95% CI
Luspatercept Extension Population	81.3	70.7 – 89.4

Rate of Erythroid Response (HI-E) Per IWG 2006 Response Criteria Secondary · 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.

Group	Value	95% CI
Luspatercept Extension Population	80.0	69.2 – 88.4

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

Group	Value	95% CI
Luspatercept Extension Population	64.3	35.1 – 87.2

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

Group	Value	95% CI
Luspatercept Extension Population	36.4	10.9 – 69.2

Duration of HI-E in LTB Participants Per IWG 2006 Response Criteria Secondary · 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.

Group	Value	95% CI
Luspatercept Extension Population	299	± 378.3

Duration of HI-E in HTB Participants Per IWG 2006 Response Criteria Secondary · 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 inte

Group	Value	95% CI
Luspatercept Extension Population	328	± 286.8

Time to HI-E in LTB Participants Per IWG 2006 Response Criteria Secondary · 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.

Group	Value	95% CI
Luspatercept Extension Population	83	± 86.2

Time to HI-E in HTB Participants Per IWG 2006 Response Criteria Secondary · 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.

Group	Value	95% CI
Luspatercept Extension Population	13	± 22.6

Rate of RBC Transfusion Independence (RBC-TI) Secondary · 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.

Group	Value	95% CI
Luspatercept Extension Population	64.3	48.0 – 78.4

Mean Change From Baseline to Week 8 in RBC Transfusion Burden (TB) in HTB Participants Secondary · 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.

Group	Value	95% CI
Luspatercept Extension Population	-4.4	± 2.6

Adverse events — posted to ClinicalTrials.gov

Time frame: up to approximately 5 years. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Luspatercept 0.5 mg/kg

Serious: 1/1 (100%)

Deaths: 0/1

Luspatercept 0.75 mg/kg

Serious: 1/2 (50%)

Deaths: 0/2

Luspatercept 1 mg/kg

Serious: 19/73 (26%)

Deaths: 4/73

Luspatercept 1.33 mg/kg

Serious: 16/61 (26%)

Deaths: 3/61

Luspatercept 1.75 mg/kg

Serious: 34/49 (69%)

Deaths: 6/49

Serious adverse events (88 terms)

Reaction	System	Luspatercept 0.5 mg/kg	Luspatercept 0.75 mg/kg	Luspatercept 1 mg/kg	Luspatercept 1.33 mg/kg	Luspatercept 1.75 mg/kg
Erysipelas	Infections and infestations	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—
Femur fracture	Injury, poisoning and procedural complications	—	—	—	—	—
Myelodysplastic syndrome	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—
Transformation to acute myeloid leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—
Syncope	Nervous system disorders	—	—	—	—	—
Cardiac failure	Cardiac disorders	—	—	—	—	—
Cardiac failure chronic	Cardiac disorders	—	—	—	—	—
Device related infection	Infections and infestations	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—
Contusion	Injury, poisoning and procedural complications	—	—	—	—	—
Lumbar vertebral fracture	Injury, poisoning and procedural complications	—	—	—	—	—
Type 2 diabetes mellitus	Metabolism and nutrition disorders	—	—	—	—	—
Squamous cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—
Normal pressure hydrocephalus	Nervous system disorders	—	—	—	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—	—
Acute myocardial infarction	Cardiac disorders	—	—	—	—	—
Aortic valve stenosis	Cardiac disorders	—	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—	—
Cardiac failure acute	Cardiac disorders	—	—	—	—	—
Myocardial infarction	Cardiac disorders	—	—	—	—	—
Sinus node dysfunction	Cardiac disorders	—	—	—	—	—

Other adverse events (49 terms — click to expand)

Reaction	System	Luspatercept 0.5 mg/kg	Luspatercept 0.75 mg/kg	Luspatercept 1 mg/kg	Luspatercept 1.33 mg/kg	Luspatercept 1.75 mg/kg
Hypertension	Vascular disorders	—	—	—	—	—
Viral upper respiratory tract infection	Infections and infestations	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—	—
Vitamin D deficiency	Metabolism and nutrition disorders	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Folate deficiency	Metabolism and nutrition disorders	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—
Splenomegaly	Blood and lymphatic system disorders	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—
Weight decreased	Investigations	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—
Epistaxis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Haematoma	Vascular disorders	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—
Vertigo	Ear and labyrinth disorders	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—
Bronchitis	Infections and infestations	—	—	—	—	—
Oral herpes	Infections and infestations	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Tachycardia	Cardiac disorders	—	—	—	—	—
Pain	General disorders	—	—	—	—	—
Respiratory tract infection	Infections and infestations	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—
Depression	Psychiatric disorders	—	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—
Renal failure	Renal and urinary disorders	—	—	—	—	—
Dyspnoea exertional	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—
Cardiac failure	Cardiac disorders	—	—	—	—	—
Hepatic steatosis	Hepatobiliary disorders	—	—	—	—	—
Thrombosis	Vascular disorders	—	—	—	—	—

Most-reported serious reactions: Erysipelas, Sepsis, Pneumonia, Femur fracture, Myelodysplastic syndrome, Transformation to acute myeloid leukaemia, Syncope, Cardiac failure.

Data from ClinicalTrials.gov NCT02268383 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. 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.
   Platzbecker U, Germing U, Götze KS, Kiewe P, et al · · 2017 · cited 213× · PMID 28870615 · DOI 10.1016/s1470-2045(17)30615-0
2. TGF-β signaling in the tumor metabolic microenvironment and targeted therapies.
   Shi X, Yang J, Deng S, Xu H, et al · · 2022 · cited 188× · PMID 36115986 · DOI 10.1186/s13045-022-01349-6
3. TGF-beta signal transduction: biology, function and therapy for diseases.
   Tie Y, Tang F, Peng D, Zhang Y, et al · · 2022 · cited 97× · PMID 36534225 · DOI 10.1186/s43556-022-00109-9
4. The role of TGFβ in hematopoiesis and myeloid disorders.
   Bataller A, Montalban-Bravo G, Soltysiak KA, Garcia-Manero G. · · 2019 · cited 57× · PMID 30816330 · DOI 10.1038/s41375-019-0420-1
5. Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T): 2017 update on diagnosis, risk-stratification, and management.
   Patnaik MM, Tefferi A. · · 2017 · cited 45× · PMID 28188970 · DOI 10.1002/ajh.24637
6. Molecular Pathways: Understanding and Targeting Mutant Spliceosomal Proteins.
   Yoshimi A, Abdel-Wahab O. · · 2017 · cited 34× · PMID 27836865 · DOI 10.1158/1078-0432.ccr-16-0131
7. The use of luspatercept for thalassemia in adults.
   Cappellini MD, Taher AT. · · 2021 · cited 33× · PMID 33570654 · DOI 10.1182/bloodadvances.2020002725
8. Long-Term Efficacy and Safety of Luspatercept for Anemia Treatment in Patients With Lower-Risk Myelodysplastic Syndromes: The Phase II PACE-MDS Study.
   Platzbecker U, Götze KS, Kiewe P, Germing U, et al · · 2022 · cited 29× · PMID 35998303 · DOI 10.1200/jco.21.02476