Clinical trial NCT02631070: A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes
Official title: A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Placebo for the Treatment of Anemia Due to the IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes in Subjects With Ring Sideroblasts Who Require Red Blood Cell Transfusions.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Myelodysplastic Syndromes
Keywords: Luspatercept
Transfusion dependent
Lower risk
Low risk
Myelodysplastic Syndromes
ESA refractory
ESA intolerant
ESA ineligible
ACE-536
Anemia
Ring Sideroblasts
Require Red Blood Cell Transfusions
MEDALIST
MDS
IPSS-R very low/IPSS-R low/IPSS-R intermediate
Lead sponsor: Celgene
Sponsor class: INDUSTRY
Collaborators: name: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
First posted: 2015-12-15
Enrollment: 229
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24
timeFrame: From Week 1 through Week 24 of study treatment
Secondary outcomes:
measure: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24
timeFrame: From Week 1 through Week 24 of study treatment
measure: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48
timeFrame: From Week 1 through Week 48 of study treatment
measure: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48
timeFrame: From Week 1 through Week 48 of study treatment
measure: Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period
timeFrame: At Baseline (16 weeks prior to first dose of study treatment) and Weeks 9 to 24 or Weeks 33 to 48
measure: Percentage of Participants Who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over Any Consecutive 56-Day Period
timeFrame: Week 1 through 24 or 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
timeFrame: Week 1 though Week 24 and Week 1 through 48
measure: Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24
timeFrame: From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks
measure: Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48
timeFrame: From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks
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
timeFrame: 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.
measure: Percentage of Participants Who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) Over Any Consecutive 56-day Period
timeFrame: Week 1 through Week 24 or Week 1 Through Week 48 of study treatment
measure: Percentage of Participants Who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over Any Consecutive 56-day Period
timeFrame: Week 1 through Week 24 or Week 1 Through Week 48 of study treatment
measure: Change From Baseline in Mean Serum Ferritin
timeFrame: Baseline and Week 9 through Week 24 and Week 33 through Week 48
measure: Change From Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT)
timeFrame: Baseline and Week 9 through Week 24 and Week 33 through Week 48 of study treatment
measure: Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24
timeFrame: From first dose to Week 24 of study treatment
measure: Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48
timeFrame: From first dose to Week 48 of study treatment
measure: Percentage of Participants Who Progressed to Acute Myeloid Leukemia (AML)
timeFrame: From randomization to study completion (up to approximately 57 months)
measure: Time to Acute Myeloid Leukemia (AML) Progression
timeFrame: From randomization to study completion (up to approximately 57 months)
measure: Overall Survival
timeFrame: From randomization to study completion (up to approximately 57 months)
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From date of first dose up to 42 days after the last dose (up to approximately 83 weeks)
measure: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)
timeFrame: Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.
measure: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)
timeFrame: Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.
measure: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)
timeFrame: Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.
measure: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)
timeFrame: Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.
measure: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax)
timeFrame: Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.
measure: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State
timeFrame: Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.
measure: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss)
timeFrame: Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.
measure: Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)
timeFrame: From randomization to 1 year post first dose
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: New Orleans
country: United States
facility: Ochsner Medical Institutions
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Bronx
country: United States
facility: Montefiore Medical Center Albert Einstein Cancer Center
state: New York
city: New York
country: United States
facility: Columbia-Presbyterian Medical Center
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Institute
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Brasschaat
country: Belgium
facility: Algemeen Ziekenhuis Klina
city: Brugge
country: Belgium
facility: AZ Sint-Jan AV Brugge
city: Brussel
country: Belgium
facility: UZ Brussels
city: Charleroi
country: Belgium
facility: Grand Hopital de Charleroi
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Yvoir
country: Belgium
facility: Cliniques Universitaires UCL de Mont-Godine
city: Calgary
country: Canada
facility: Tom Baker Cancer Center
state: Alberta
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Angers
country: France
facility: CHU d'Angers
city: Grenoble Cedex 09
country: France
facility: CHU Hotel
city: Lille
country: France
facility: CHRU de Lille-Hopital Claude Huriez Service des Maladies du Sang
city: Marseille cedex
country: France
facility: Institut Paoli Calmettes
city: Nice
country: France
facility: CHU de Nice Archet I
city: Paris
country: France
facility: Hopital Saint Louis
city: Pessac Cedex
country: France
facility: Hopital Haut Leveque
city: Pierre-Bénite cedex
country: France
facility: Centre hospitalier Lyon Sud Hematologie
city: Strasbourg
country: France
facility: Hopital civil
city: Toulouse Cedex 9
country: France
facility: Institut Universitaire du Cancer de Toulouse - Oncopole
city: Tours
country: France
facility: Hopital Bretonneau
city: Bonn
country: Germany
facility: Universitatsklinikum Bonn
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carus an der TU Dresden
city: Dusseldorf
country: Germany
facility: Marien Hospital
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: München
country: Germany
facility: Klinikum rechts der Isar der Technischen Universität München
city: Allessandria
country: Italy
facility: Azienda Ospedaliera Santi Antonio Biagio E Cesare Arrigo
city: Bologna
country: Italy
facility: Azienda Ospedaliero Universitaria Di Bologna Policlinico Sorsola Malpighi
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Lecce
country: Italy
facility: Azienda Sanitaria Locale Lecce
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Reggio, Calabria
country: Italy
facility: Azienda Ospedaliera Bianchi Melacrino Morelli
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario A Gemelli
city: Roma
country: Italy
facility: Fondazione PTV Policlinico Tor Vergata
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Hoofddorp
country: Netherlands
facility: Spaarne Ziekenhuis
city: Barakaldo
country: Spain
facility: Hospital Universitario Cruces
city: Barcelona
country: Spain
facility: Hospital Universitario Vall D hebron
city: Barcelona
country: Spain
facility: Instituto Catalan de Oncologia-Hospital Duran i Reynals
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Seville
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhus
city: Lund
country: Sweden
facility: Skanes Universitetssjukhus Lund
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Uppsala
country: Sweden
facility: Akademiska Sjukhuset
city: Adana
country: Turkey
facility: Cukurova University Medical Faculty Balcali Hospital
city: Ankara
country: Turkey
facility: Ankara University Medical Faculty Cebeci Hospital
city: Istanbul
country: Turkey
facility: Istanbul University Cerrahpasa Medical Faculty Hospital
city: Izmir
country: Turkey
facility: Ege Universitesi Tip Fakultesi Hastanesi
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Headington
country: United Kingdom
facility: John Radcliffe Hospital
city: Leeds
country: United Kingdom
facility: St James University Hospital
city: London
country: United Kingdom
facility: Guys Hospital
city: London
country: United Kingdom
facility: Kings College Hospital
city: Sutton in Ashfield
country: United Kingdom
facility: Kings Mill Hospital
Study officials:
affiliation: Celgene
name: Rodrigo Ito, MD
role: STUDY_DIRECTOR
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.
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.
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.
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.
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.