TriangleNCT02631070 · CITED IN SOURCE DOCUMENTS
A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes
An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.
- Phase
- PHASE3
- Status at capture
- COMPLETED
- Registry last update
- 2021-12-17
The study will be conducted in compliance with the International Council on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements. This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) versus placebo in participants with anemia due to the Revised International Prognostic Scoring System (IPSS-R) very low, low, or intermediate MDS with ring sideroblasts who require red blood cell (RBC) transfusions.
Open the original ClinicalTrials.gov record → · Download preserved record
What did the study report?
Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.
Participant flow
Baseline characteristics
Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24
Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24
Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48
Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48
Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period
Percentage of Participants Who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over Any Consecutive 56-Day Period
Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over Any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions
Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24
Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score
Percentage of Participants Who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) Over Any Consecutive 56-day Period
Percentage of Participants Who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over Any Consecutive 56-day Period
Change From Baseline in Mean Serum Ferritin
Change From Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT)
Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24
Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48
Percentage of Participants Who Progressed to Acute Myeloid Leukemia (AML)
Time to Acute Myeloid Leukemia (AML) Progression
Overall Survival
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss)
Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)
Adverse events
Limitations, agreements, and source contact
Who could take part
- eligibility Criteria
- Inclusion Criteria: Subjects must satisfy the following criteria to be enrolled in the study: 1. Subject is ≥ 18 years of age the time of signing the informed consent form (ICF). 2. Documented diagnosis of MDS according to World Health Organization (WHO)/French American British (FAB) classification that meets IPSS R classification of very low, low, or intermediate risk disease, and: Ring sideroblast ≥ 15% of erythroid precursors in bone marrow or ≥ 5% (but \< 15%) if SF3B1 mutation is present. * \< 5% blasts in bone marrow * Peripheral blood white blood cell (WBC) count \< 13,000/µL 3. Requires red blood cell RBC transfusions 4. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 5. Subjects who are refractory/intolerant/ineligible to prior erythropoietin-stimulating agents (ESA) treatment, defined as: * Refractory to prior - erythropoietin stimulating agents treatment: documentation of non-response or response that is no longer maintained to prior ESA-containing regimen, either as single agent or combination (eg, with granulocyte colony stimulating factor (G-CSF); ESA regimen must have been either recombinant human erythropoietin (rHu EPO) ≥ 40,000 IU/wk for at least 8 doses or equivalent OR darbepoetin alpha ≥ 500 μg Q3W for at least 4 doses or equivalent * Intolerant to prior ESA treatment: documentation of discontinuation of prior ESA-containing regimen, either as single agent or combination (eg, with G-CSF), at any time after introduction due to intolerance or an adverse event * ESA ineligible: low chance of response to ESA base on endogenous serum erythropoietin level \> 200 U/L for subjects not previously treated with ESAs Exclusion Criteria: The presence of any of the following will exclude a subject from enrollment: 1. Prior therapy with disease modifying agents for underlying MDS disease. 2. Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011) 3. MDS associated with del 5q cytogenetic abnormality 4. Secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases. 5. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding \- iron deficiency to be determined by serum ferritin less than or equal to 15 ug/L and additional testing if clinically indicated (eg, calculated transferrin saturation \[iron/total iron binding capacity less than or equal to 20%\] or bone marrow aspirate stain for iron). 6. Prior allogeneic or autologous stem cell transplant 7. Known history of diagnosis of acute myeloid leukemia (AML) 8. Use of any of the following within 5 weeks prior to randomization: * anticancer cytotoxic chemotherapeutic agent or treatment * corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to randomization for medical conditions other than MDS * iron-chelating agents, except for subjects on a stable or decreasing dose for at least 8 weeks prior to randomization * other RBC hematopoietic growth factors (eg, Interleukin-3) * investigational drug or device, or approved therapy for investigational use. If the half-life of the previous investigational product is known, use within 5 times the half-life prior to randomization or within 5 weeks, whichever is longer is excluded. 9. Prior history of malignancies, other than MDS, unless the subject has been free of the disease (including completion of any active or adjuvant treatment for prior malignancy) for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed: * Basal or squamous cell carcinoma of the skin * Carcinoma in situ of the cervix * Carcinoma in situ of the breast * Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis \[TNM\] clinical staging system) 10. Major surgery within 8 weeks prior to randomization. Subjects must have completely recovered from any previous surgery prior to randomization
- healthy Volunteers
- false
- minimum Age
- 18 Years
- sex
- ALL
- std Ages
- ADULT
- OLDER_ADULT
Treatment arms and interventions
- arm Groups
- description
- Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks
- intervention Names
- Drug: Luspatercept
- label
- Experimental Arm - Luspatercept (ACE-536)
- type
- EXPERIMENTAL
- description
- Subcutaneous injection every 3 weeks
- intervention Names
- Other: Placebo
- label
- Control Arm: Placebo
- type
- PLACEBO_COMPARATOR
- interventions
- arm Group Labels
- Experimental Arm - Luspatercept (ACE-536)
- name
- Luspatercept
- other Names
- ACE-536
- type
- DRUG
- arm Group Labels
- Control Arm: Placebo
- name
- Placebo
- type
- OTHER
Study design
- allocation
- RANDOMIZED
- intervention Model
- PARALLEL
- masking Info
- masking
- QUADRUPLE
- who Masked
- PARTICIPANT
- CARE_PROVIDER
- INVESTIGATOR
- OUTCOMES_ASSESSOR
- primary Purpose
- TREATMENT
Enrollment
- count
- 229
- type
- ACTUAL
Registered outcome plans (not posted results)
- primary Outcomes
- description
- RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during the first 24 weeks of study treatment. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 24 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to or on the cut-off date were counted as non-responders.
- measure
- Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24
- time Frame
- From Week 1 through Week 24 of study treatment
- secondary Outcomes
- description
- RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 24 weeks of treatment.
- measure
- Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24
- time Frame
- From Week 1 through Week 24 of study treatment
- description
- RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 48 weeks of treatment.
- measure
- Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48
- time Frame
- From Week 1 through Week 48 of study treatment
- description
- RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during Week 1 through Week 48. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 48 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to Week 48 were counted as non-responders.
- measure
- Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48
- time Frame
- From Week 1 through Week 48 of study treatment
- description
- Mean change in total number of Red Blood Cells (RBC) units transfused over a fixed 16-week period (Week 9-24 or Week 33-48) from the total number of RBC units transfused in the 16 weeks immediately on or prior to first dose of study treatment.
- measure
- Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period
- time Frame
- At Baseline (16 weeks prior to first dose of study treatment) and Weeks 9 to 24 or Weeks 33 to 48
- description
- A modified HI-E response was defined as the percentage of participants meeting the modified HI-E per the International Working Group (IWG) sustained over 56-day consecutive period during the Treatment period. For participants with a baseline RBC transfusion burden of ≥ 4 units/8 weeks, a mHI-E was defined as a reduction in RBC transfusion of at least 4 units/8 weeks; for participants with baseline RBC transfusion burden of \<4 units/8 weeks, mHI-E, was defined as a mean increase in hemoglobin of ≥ 1.5 g/dL for 8 weeks in the absence of RBC transfusions.
- measure
- Percentage of Participants Who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over Any Consecutive 56-Day Period
- time Frame
- Week 1 through 24 or Week 1 Through Week 48
- description
- A mean hgb increase of ≥ 1.0 g/dL was analyzed as the percentage of participants with a hgb increase ≥ 1.0 g/dL compared with baseline (after applying the 14/3 day rule) that was sustained over any consecutive 56-day (8-week) period in the absence of RBC transfusions during the treatment period. (Week 1 through Week 24 and Week 1 through Week 48).
- measure
- Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over Any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions
- time Frame
- Week 1 though Week 24 and Week 1 through 48
- description
- Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 24. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.
- measure
- Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24
- time Frame
- From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks
- description
- Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 48. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.
- measure
- Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48
- time Frame
- From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks
- description
- The EORTC questionnaire is a validated health-related quality of life (HRQoL) measure applicable to participants with any cancer diagnosis. Version 3.0 of the questionnaire was used in the study. It is composed of 30 items that address 15 domains, including one global health status, functional domains, and symptom domains. Domain scores are transformed to a 0 to 100 scale, where higher scores on the global quality of life score indicate better function. As such, a positive change from Baseline score indicates an improvement in quality of life.
- measure
- Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score
- time Frame
- Baseline and Cycle 3, Day 1 (C3 D1), C5 D1, C7 D1, Week 25, every other cycle during extension phase (C1 D1, C3 D1, C5 D1, etc. up to C59 D1) and end of treatment. Each cycle is composed of 21 days.
- description
- Percentage of participants who achieved a hematologic improvement in neutrophil response (HI-N) per IWG criteria sustained over any consecutive 56-day (8-week) period, during the treatment period (Week 1 to Week 24 and Week 1 to Week 48) HI-N was defined as at least a 100% increase and an absolute increase \> 0.5 X 10\^9/L.
- measure
- Percentage of Participants Who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) Over Any Consecutive 56-day Period
- time Frame
- Week 1 through Week 24 or Week 1 Through Week 48 of study treatment
- description
- Percentage of participants who achieved a hematologic improvement platelet response (HI-P) was defined as the percentage of participants meeting the HI-P criteria per the IWG sustained over any consecutive 56-day (8-week) period (Week 1 to Week 24 and Week 1 to Week 48) during the treatment period. HI - P reponse was defined as: * Absolute increase of ≥ 30 X 10\^9/L in platelets for participants starting with \> 20 X 10\^9/L platelets * Increase in platelets from \< 20 X 10\^9/L to \> 20 X 10\^9/L and by at least 100%
- measure
- Percentage of Participants Who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over Any Consecutive 56-day Period
- time Frame
- Week 1 through Week 24 or Week 1 Through Week 48 of study treatment
- description
- Mean change from baseline in mean serum ferritin was calculated as the difference of postbaseline mean serum ferritin (averaged over the specified timepoints) and baseline mean serum ferritin.
- measure
- Change From Baseline in Mean Serum Ferritin
- time Frame
- Baseline and Week 9 through Week 24 and Week 33 through Week 48
Full study description
- brief Summary
- The study will be conducted in compliance with the International Council on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements. This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) versus placebo in participants with anemia due to the Revised International Prognostic Scoring System (IPSS-R) very low, low, or intermediate MDS with ring sideroblasts who require red blood cell (RBC) transfusions.
- detailed Description
- Anemia is considered to be one of the most prevalent cytopenias in patients who have myelodysplastic syndromes, an umbrella term used to describe disorders relating to the ineffective production of red blood cells, white blood cells, and/or platelets. Ranging in severity from mild (asymptomatic) to severe, anemia can result in patients requiring regular red blood cell (RBC) transfusions, which can lead to further complications from iron overload. The goal of this study is to assess the safety and efficacy of luspatercept versus placebo in anemic patients who are categorized as International Prognostic Scoring System-Revised (IPSS-R) very low, low, or intermediate risk Myelodysplastic syndrome (MDS), have ring sideroblasts present, and require constant RBC transfusions. The design of the study will allow a period of initial randomization of patients into either the luspatercept or placebo arm, followed by a double-blind treatment period, and then an MDS disease assessment visit. For those patients that are determined to be experiencing clinical benefit as judged from the study Investigator by this disease assessment visit, they will be permitted to enter the double-blind Extension Phase of the study. Once patients are discontinued from study treatment, they will enter a post treatment follow-up period.
Source references
- references
- citation
- Porter J. Beyond transfusion therapy: new therapies in thalassemia including drugs, alternate donor transplant, and gene therapy. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):361-370. doi: 10.1182/asheducation-2018.1.361.
- pmid
- 30504333
- type
- BACKGROUND
- citation
- Piga A, Perrotta S, Gamberini MR, Voskaridou E, Melpignano A, Filosa A, Caruso V, Pietrangelo A, Longo F, Tartaglione I, Borgna-Pignatti C, Zhang X, Laadem A, Sherman ML, Attie KM. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with beta-thalassemia. Blood. 2019 Mar 21;133(12):1279-1289. doi: 10.1182/blood-2018-10-879247. Epub 2019 Jan 7.
- pmid
- 30617198
- type
- BACKGROUND
- citation
- Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, Diez-Campelo M, Finelli C, Cazzola M, Ilhan O, Sekeres MA, Falantes JF, Arrizabalaga B, Salvi F, Giai V, Vyas P, Bowen D, Selleslag D, DeZern AE, Jurcic JG, Germing U, Gotze KS, Quesnel B, Beyne-Rauzy O, Cluzeau T, Voso MT, Mazure D, Vellenga E, Greenberg PL, Hellstrom-Lindberg E, Zeidan AM, Ades L, Verma A, Savona MR, Laadem A, Benzohra A, Zhang J, Rampersad A, Dunshee DR, Linde PG, Sherman ML, Komrokji RS, List AF. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. N Engl J Med. 2020 Jan 9;382(2):140-151. doi: 10.1056/NEJMoa1908892.
- pmid
- 31914241
- type
- RESULT
- citation
- Komrokji RS. Luspatercept in Myelodysplastic Syndromes: Who and When? Hematol Oncol Clin North Am. 2020 Apr;34(2):393-400. doi: 10.1016/j.hoc.2019.10.004. Epub 2020 Jan 21.
- pmid
- 32089218
- type
- RESULT
- citation
- Fenaux P, Kiladjian JJ, Platzbecker U. Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis. Blood. 2019 Feb 21;133(8):790-794. doi: 10.1182/blood-2018-11-876888. Epub 2019 Jan 2.
- pmid
- 30602619
- type
- RESULT
- citation
- Germing U, Fenaux P, Platzbecker U, Buckstein R, Santini V, Diez-Campelo M, Yucel A, Tang D, Fabre S, Zhang G, Zoffoli R, Ha X, Miteva D, Hughes C, Komrokji RS, Zeidan AM, Garcia-Manero G. Improved benefit of continuing luspatercept therapy: sub-analysis of patients with lower-risk MDS in the MEDALIST study. Ann Hematol. 2023 Feb;102(2):311-321. doi: 10.1007/s00277-022-05071-8. Epub 2023 Jan 13.
- pmid
- 36635381
- type
- DERIVED
Source notices and limitations
Discovery and provenance
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- Ring Sideroblasts and Thrombocytosis Associated Anemia in ESA-refractory or -intolerant Patients The efficacy of REBLOZYL was evaluated in the MEDALIST trial (NCT02631070), a multi-center, randomized, double-blind, placebo-controlled trial in patients with IPSS-R very low, low, or intermediate-risk myelodysplastic syndromes who
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Preserved source evidence · Not medical advice