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A Study to Evaluate the Efficacy, Pharmacokinetics and Safety of Luspatercept (ACE-536) for the Treatment of Anemia Due to IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MDS) in Chinese and Japanese Subjects With Ring Sideroblasts Who Require Red Blood Cell Transfusions

  • Clinicaltrials.gov identifier

    NCT04477850

  • Recruitment Status

    Recruiting

  • First Posted

    July 20, 2020

  • Last update posted

    August 12, 2021

Study Description

Brief summary:

This is a Phase 2, multicenter, single-arm bridging study to evaluate the efficacy, pharmacokinetics, and safety of luspatercept (ACE-536) for the treatment of anemia due to IPSSR very low, low, or intermediate risk myelodysplastic syndromes (MDS) in Chinese and Japanese subjects with ring sideroblasts who require RBC transfusions. The study is divided into the Screening Period, Treatment Period (Primary Phase and Extension Phase) and a Posttreatment Follow-up Period and will enroll a total of 30 subjects.

  • Condition or Disease:Myelodysplastic Syndromes
  • Intervention/Treatment: Drug: Luspatercept
  • Phase: Phase 2

Detailed Description

N/A

Study Design

  • Study Type: Interventional
  • Estimated Enrollment: 40 participants
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: A Phase 2, Multicenter, Single-Arm Bridging Study to Evaluate the Efficacy, Pharmacokinetics, and Safety of Luspatercept (ACE-536) for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Myelodysplastic Syndromes(MDS) in Chinese and Japanese Subjects With Ring Sideroblasts Who Require Red Blood Cell Transfusions
  • Actual Study Start Date: November 2020
  • Estimated Primary Completion Date: October 2023
  • Estimated Study Completion Date: February 2026

Arms and interventions

Arm Intervention/treatment
Experimental: Luspatercept Administration
Starting dose of 1.0mg/kg subcutaneous injection every 3 weeks
Drug: Luspatercept
Luspatercept

Outcome Measures

  • Primary Outcome Measures: 1. Red Blood Cell Transfusion Independence (RBCTI) ≥ 8 weeks [ Time Frame: Week 1 through Week 24 ]
    Proportion of subjects who are RBC transfusion free over any consecutive 56-day period
  • Secondary Outcome Measures: 1. Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 weeks [ Time Frame: Week 1 through Week 24 ]
    Proportion of subjects who are RBC transfusion free over any consecutive 84-day period
  • 2. Reduction in RBC units transfused over 16 weeks compared to baseline [ Time Frame: Week 9 through Week 24 ]
    Mean change in total RBC units transfused over a fixed 16-week period compared to the total number of RBC units transfused in the 16 weeks immediately prior to first dose
  • 3. Modified hematologic improvement - erythroid (mHI-E) per IWG [ Time Frame: Week 1 through Week 24 ]
    Proportion of subjects achieving mHI-E over any consecutive 56-day period
  • 4. Mean hemoglobin increase ≥ 1.0 g/dL [ Time Frame: Week 1 through Week 24 ]
    Proportion of subjects achieving hemoglobin (Hgb) increase from baseline ≥ 1.0 g/dL over any consecutive 56-day period in absence of RBC transfusions
  • 5. Duration of RBC-TI [ Time Frame: Week 1 through Week 24 ]
    Maximum duration of RBC transfusion independence for subjects who achieve RBC-TI ≥ 8 weeks
  • 6. Mean decrease in serum ferritin compared to baseline [ Time Frame: Week 9 through Week 24 ]
    Change in mean serum ferritin over a fixed 16-week period compared to baseline value
  • 7. Mean decrease in iron chelation therapy (ICT) use compared to baseline [ Time Frame: Week 9 through Week 24 ]
    Change in mean daily dose of ICT over a fixed 16-week period compared to baseline dose
  • 8. Time to RBC-TI [ Time Frame: Week 1 through Week 24 ]
    Time from first dose to first onset of transfusion independence ≥ 8 weeks
  • 9. Progression to AML [ Time Frame: Cycle1 Day1 (each cycle is 21 days) through at least 3 years post first dose ]
    Proportion of subjects progressing to AML
  • 10. Overall survival (OS) [ Time Frame: Cycle1 Day1 (each cycle is 21 days) through at least 3 years post first dose ]
    Time from first dose to death due to any cause
  • 11. Anti-drug antibodies (ADA) [ Time Frame: Cycle1 Day1 (each cycle is 21 days) through 1-year post first dose ]
    Frequency of anti-drug antibodies
  • 12. Adverse Events (AEs) [ Time Frame: Screening through 42 days post last dose ]
    Type, frequency, severity, seriousness of AEs and relationship of AEs to luspatercept
  • 13. Pharmacokinetics - AUC [ Time Frame: Cycle1 Day1 (each cycle is 21 days) through 1-year post first dose ]
    Area under the curve
  • 14. Pharmacokinetics - Cmax [ Time Frame: Cycle1 Day1 (each cycle is 21 days) through 1-year post first dose ]
    Maximum plasma concentration of the drug
  • 15. Time to AML progression [ Time Frame: Cycle1 Day1 (each cycle is 21 days) through at least 3 years post first dose ]
    Time to progression to AML

Eligibility Criteria

  • Ages Eligible for Study: 20 Years and older (Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria: Subjects must satisfy the following criteria to be enrolled in the study: Subject is ≥ 20 years of age at the time of signing the informed consent form (ICF). Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. Subject has documented diagnosis of Myelodysplastic Syndromes (MDS) according to WHO 2016 classification that meets Revised International Prognostic Scoring System (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. Subject is refractory or intolerant to, or ineligible for, prior ESA treatment as defined by any one of the following: Refractory to prior erythropoiesis stimulating agent (ESA) 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 G-CSF); ESA regimen must have been either: recombinant human erythropoietin (rHu EPO) ≥ 40,000 IU/week for at least 8 doses or equivalent (for Japan); or ≥ 10,000 IU at least every other day for 45 days (for China) OR darbepoetin alpha ≥ 240 μg QW for at least 12 weeks or equivalent (for Japan only); 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 ESAs based on endogenous serum erythropoietin level > 200 U/L for subjects not previously treated with ESAs. If subject was previously treated with an ESA or granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), both agents must have been discontinued ≥ 4 weeks prior to date of luspatercept treatment. Subject requires Red blood cell (RBC) transfusions, as documented by the following criteria: average transfusion requirement of ≥ 2 units/8 weeks of packed RBCs (pRBCs) confirmed for a minimum of 16 weeks immediately preceding luspatercept treatment. hemoglobin levels at the time of or within 7 days prior to administration of an RBC transfusion must have been ≤ 9.0 g/dL with symptoms of anemia (or ≤ 7 g/dL in the absence of symptoms) in order for the transfusion to be counted towards meeting eligibility criteria. Red blood cell transfusions administered when Hgb levels were >9.0 (or > 7 g/dL in the absence of symptoms) and/or RBC transfusions administered for elective surgery, infections or bleeding events will not qualify as a required transfusion for the purpose of meeting eligibility criteria. no consecutive 56-day period that was RBC transfusion-free during the 16 weeks immediately preceding luspatercept treatment. Subject has Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2. Females of childbearing potential (FCBP), defined as a sexually mature woman who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy or amenorrhea due to other medical reason does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months), must: Have two negative pregnancy tests as verified by the Investigator prior to starting study therapy (unless the screening pregnancy test was done within 72 hours of C1D1). She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or if sexually active, agree to use, and be able to comply with, highly effective contraception without interruption, 5 weeks prior to starting luspatercept treatment, during the study therapy (including dose interruptions), and for 12 weeks after discontinuation of study therapy and/or by local regulations. If breastfeeding, agree to stop breastfeeding prior to the participation in the study and not to resume breastfeeding after treatment discontinuation. Male subjects must: a. Practice true abstinence (which must be reviewed prior to each luspatercept administration or on a monthly basis [eg, in the event of dose delays]) or agree to use a condom (latex or nonlatex, but NOT made out of natural [animal] membrane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks following luspatercept discontinuation, even if he has undergone a successful vasectomy. Subject is willing and able to adhere to the study visit schedule and other protocol requirements. Exclusion Criteria: The presence of any of the following will exclude a subject from enrollment: Subject has had prior therapy with disease modifying agents for underlying MDS disease (eg, immunomodulatory drugs [IMiDs such as lenalidomide], hypomethylating agents [HMAs], or immunosuppressive therapy [IST]). - Subjects who previously received HMAs or lenalidomide may be enrolled at the Investigator's discretion contingent that the subject received no more than 2 doses of HMA or no more than 1 calendar week of treatment with lenalidomide. The last dose must be ≥ 5 weeks from the date of luspatercept treatment. Subject was previously treated with either luspatercept (ACE-536) or sotatercept (ACE- 011). Subject has MDS associated with del(5q) cytogenetic abnormality. Subject has 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. Subject has known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding. a. Iron deficiency to be determined by serum ferritin ≤ 15 μg/L and additional testing if clinically indicated (eg, calculated transferrin saturation [iron/total iron binding capacity ≤ 20%] or bone marrow aspirate stain for iron). Subject had prior allogeneic or autologous stem cell transplant. Subject has known history of diagnosis of AML. Subject used any of the following within 5 weeks prior to enrollment: anticancer cytotoxic chemotherapeutic agent or treatment. corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to enrollment 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 enrollment. 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 enrollment or within 5 weeks, whichever is longer is excluded. Subject has uncontrolled hypertension, defined as repeated elevations of systolic blood pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment, or with a history of hypertensive crisis or hypertensive encephalopathy. Subject has absolute neutrophil count (ANC) < 500/μL (0.5 x 109/L). Subject has platelet count < 50,000/μL (50 x 109/L). Subject has estimated glomerular filtration rate (eGFR) or creatinine clearance < 40 mL/min. Subject has serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN). Subject has total bilirubin ≥ 2.0 x ULN. higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis) or in the presence of known history of Gilbert Syndrome. subjects are excluded if there is evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of > 2% with either a positive Coombs' test or over 50% indirect bilirubin. Subject has 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). Subject had major surgery within 8 weeks prior to enrollment. Subjects must have completely recovered from any previous surgery prior to enrollment. Subject has a history of stroke, deep venous thrombosis (DVT), pulmonary or arterial embolism within 6 months prior to enrollment. Subject is a pregnant or breastfeeding female. Subject had myocardial infarction, uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia as determined by the Investigator within 6 months prior to enrollment. Subjects with a known ejection fraction ˂ 35%, confirmed by a local echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed within 6 months prior to enrollment are excluded. Subject has uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment), known Human Immunodeficiency Virus (HIV), known evidence of active infectious hepatitis B and/or known evidence of active hepatitis C. Local testing confirming HIV, hepatitis B, and hepatitis C status should not have been performed earlier than 4 weeks from the date of ICF signature. Subject had a history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product (see luspatercept Investigator's Brochure). Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. Subject has any condition that confounds the ability to interpret data from the study.

Contacts and Locations

Contacts

Contact: Recruiting sites have contact information. Please contact the sites directly. If there is no contact information, please email: Clinical.Trials@bms.com

Contact: First line of the email MUST contain NCT # and Site #.

Locations

China
Peking Union Medical College Hospital
Beijing

China
West China Hospital
Chengdu, Sichuan

China
Sun Yat-sen University Cancer Center
Guangzhou

China
Guangdong General Hospital
Guangzhou

China
Nanfang Hospital of Southern Medical University
Guangzhou

China
The First Affiliated Hospital of Medical School of Zhejiang University
Hangzhou City

China
Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University
Nanjing

China
Shanghai 6th Hospital
Shanghai

China
The First Affiliated Hospital of Soochow University
Suzhu

China
Institution of Hematology & Hospital of Blood Disease, Chinese Academy of Medical Sciences
Tianjin

Japan
Kameda Medical Center
Kamogawa

Japan
Matsuyama Red Cross Hospital
Matsuyama

Japan
Dokkyo Medical University Hospital
Mibu-Machi

Japan
The Japanese Red Cross Nagasaki Genbaku Hospital
Nagasaki

Japan
Ogaki Municipal Hospital
Ogaki

Japan
Kindai University Hospital
Osaka-Sayama

Japan
Osaka City University Hospital
Osaka

Japan
Kitasato University Hospital
Sagamihara

Japan
Tohoku University Hospital
Sendai

Japan
NTT Medical Center Tokyo
Shinagawa-ku, Tokyo

Sponsors and Collaborators

Celgene

Investigators

Study Director: Veronika Pozharskaya, MD Celgene

More Information

  • Responsible Party: Celgene
  • ClinicalTrials.gov Identifier: NCT04477850 History of Changes
  • Other Study ID Numbers: ACE-536-MDS-004, U1111-1251-9249
  • First Posted: July 20, 2020 Key Record Dates
  • Last Update Posted: August 12, 2021
  • Last Verified: August 2021
  • Individual Participant
    Data (IPD) Sharing
    Statement:

  • Plan to Share IPD: Yes
  • Plan Description: Information relating to our policy on data sharing and the process for requesting data can be found at the following link: https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/
  • Supporting Materials: Study Protocol, Statistical Analysis Plan (SAP), Informed Consent Form (ICF), Clinical Study Report (CSR), Analytic Code
  • Time Frame: See Plan Description
  • Access Criteria: See Plan Description
  • URL: https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/
  • Studies a U.S. FDA-regulated Drug Product: No
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by Celgene: Myelodysplastic Syndromes
    MDS
    ACE-536
    Anemia
  • Additional relevant MeSH terms: Preleukemia
    Anemia
    Myelodysplastic Syndromes
    Syndrome
    Disease
    Pathologic Processes
    Hematologic Diseases
    Bone Marrow Diseases
    Precancerous Conditions
    Neoplasms