A Phase 3, Double-Blind, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Placebo in Subjects with Myeloproliferative Neoplasm-Associated Myelofibrosis on Concomitant JAK2 Inhibitor Therapy and Who Require Red Blood Cell Transfusions

JRCT ID: jRCT2071200083

Registered date:15/01/2021

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Anemia associated with myelofibrosis
• Date of first enrollment: 21/05/2021
• Target sample size: 20
• Countries of recruitment: Australia,Japan,Hong Kong,Japan,South Korea,Japan,Austria,Japan,Belgium,Japan,Czech Republic,Japan,France,Japan,Germany,Japan,Greece,Japan,Ireland,Japan,Israel,Japan,Italy,Japan,Poland,Japan,Russia,Japan,Spain,Japan,United Kingdom,Japan,Canada,Japan,United States,Japan,China,Japan,Hungary,Japan,Romania,Japan,Lebanon,Japan,Colombia,Japan,Chile,Japan,Argentina,Japan
• Study type: Interventional
• Intervention(s): Administer luspatercept subcutaneously every 3 weeks (21 days). The starting dose is 1.33 mg/kg and the dose may be increased to 1.75 mg/kg. The dose is adjusted in the range from 0.6 to 1.75 mg/kg depending on a hemoglobin level and the occurrence of adverse events.

Outcome(s)

• Primary Outcome: Red blood cell-transfusion independence (RBC-TI) >=12weeks (RBC-TI 12)

Secondary Outcome

RBC-TI>=16weeks(RBC-TI 16)
Duration of RBC-TI 12
Reduction in transfusion burden
Duration of reduction in transfusion burden
RBC-TI>=12 weeks in treatment period (RBC-TI 12/TP)
RBC-TI>=16 weeks in treatment period (RBC-TI 16/TP)
Change in RBC transfusion burden
Cumulative duration of RBC-transfusion independence
Mean Hgb increase>=1g/dL
Change in serum ferritin from baseline
Safety (type, frequency, severity, and seriousness of adverse events [AEs] and relationship of AEs to luspatercept/placebo)
Transformation to blast phase
Antidrug antibodies (ADA)
PK

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1. Subject is >= 18 years of age at the time of signing the informed consent form (ICF).
2. Subject has a diagnosis of primary myelofibrosis (PMF) according to the 2016 World Health Organization (WHO) criteria or diagnosis of post-essential thrombocythemia (post-ET) or post-polycythemia vera (post-PV) myelofibrosis (MF) according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2007 criteria, confirmed by the most recent local pathology report.
3. Subject is requiring red blood cell (RBC) transfusions as defined as:
a. Average RBC-transfusion frequency: 4 to 12 RBC units/12 weeks immediately up to randomization. There must be no interval > 6 weeks (42 days) without >= 1 RBC transfusion.
b. RBC transfusions are scored in determining eligibility when given for treatment of:
-Symptomatic (ie, fatigue or shortness of breath) anemia with a pretransfusion hemoglobin (Hgb) <= 9.5 g/dL or
-Asymptomatic anemia with a pretransfusion Hgb <= 7 g/dL
c. RBC transfusions given for worsening of anemia due to bleeding or infections are not scored in determining eligibility.
4. Subjects on continuous (eg, absent of dose interruptions lasting >= 2 consecutive weeks) Janus kinase 2 (JAK2) inhibitor therapy as approved in the country of the study site for the treatment for myeloproliferative neoplasm (MPN)-associated MF as part of their standard-of-care therapy for at least 32 weeks, on stable daily dose for at least 16 weeks immediately up to the date of randomization and anticipated to be on a stable daily dose of that JAK2 inhibitor for at least 24 weeks after randomization.
5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of <= 2.
6. A female of childbearing potential (FCBP) for this study is defined as a female 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 reasons does not rule out childbearing potential) for at least 24 consecutive months (eg, has had menses at any time in the preceding 24 consecutive months). Females of childbearing potential (FCBP) participating in the study must:
a. Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the study, and after end of investigational product (IP). This applies even if the subject practices true abstinence from heterosexual contact.
b. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting IP, during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal half-life of IP based on multiple-dose pharmacokinetics [PK] data) after discontinuation of study therapy.
c. If breastfeeding, agree to stop breastfeeding prior to the participation in the study and not to resume breastfeeding after treatment discontinuation.
7. Male subjects must:
Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom 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 (approximately 5 times the mean terminal half-life of IP based on multiple-dose PK data) following IP discontinuation, even if he has undergone a successful vasectomy.
8. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
9. Subject is willing and able to adhere to the study visit schedule and other protocol requirements including the use of the electronic patient reported outcomes device.

Exclude criteria

1. Subject with anemia from cause other than MPN-associated MF or JAK2 inhibitor therapy (eg, iron deficiency, vitamin B12 and/or folate deficiencies, autoimmune or hemolytic anemia, infection, or any type of known clinically significant bleeding or sequestration).
2. Subject use of hydroxyurea, immunomodulatory compounds such as pomalidomide, thalidomide, erythropoiesis stimulating agents (ESAs), androgenic steroids or other drugs with potential effects on hematopoiesis <= 8 weeks immediately up to the date of randomization.
a. Systemic corticosteroids are permitted for nonhematological conditions providing the subject is receiving a constant dose equivalent to <= 10 mg prednisone for the 4 weeks immediately up to randomization.
b. Iron chelation therapy (ICT) is permitted providing the subject is receiving a stable dose for the 8 weeks immediately up to randomization.
3. Subject with any of the following laboratory abnormalities at screening:
a. Neutrophils: < 1 * 10^9/L
b. White blood count (WBC): > 100 * 10^9/L
c. Platelets: the lowest allowable level as approved for the concomitant JAK2 inhibitor but not < 25 * 10^9/L or > 1000 * 10^9/L
d. Peripheral blood myeloblasts: > 5%
e. Estimated glomerular filtration rate: < 30 mL/min/1.73 m^2 (via the 4-variable modification of diet in renal disease [MDRD] formula) or nephrotic subjects (eg, urine albumin-to-creatinine ratio > 3500 mg/g)
f. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT): > 3.0 * upper limit of normal (ULN)
g. Direct bilirubin: >= 2 * ULN
-Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (eg, ineffective erythropoiesis)
4. Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood pressure >= 140 mmHg or diastolic blood pressure >= 90 mmHg, that is not resolved at the time of randomization, or with a history of hypertensive crisis or hypertensive encephalopathy.
5. Subject with prior history of malignancies, other than disease under study, unless the subject has been free of the disease for >= 3 years. However, subject with the following history/concurrent conditions is allowed:
a. Basal or squamous cell carcinoma of the skin
b. Carcinoma in situ of the cervix
c. Carcinoma in situ of the breast
d. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
6. Subject with prior hematopoietic cell transplant or subject anticipated to receive a hematopoietic cell transplant during the 24 weeks from the date of randomization.
7. Subject with stroke, myocardial infarction, deep venous thrombosis, pulmonary or arterial embolism within 6 months immediately up to the date of randomization.
8. Subject with major surgery within 2 months up to the date of randomization. Subject must have completely recovered from any previous surgery immediately up to the date of randomization.
9. Subject with a major bleeding event (defined as symptomatic bleeding in a critical area or organ and/or bleeding causing a decrease in Hgb of >= 2 g/dL or leading to transfusion of >= 2 units of packed red cells) in the last 6 months prior to the date of randomization.
10. Subject with inadequately controlled heart disease and/or have a known left ventricular ejection fraction < 35%.
11. Subject with 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).
a. History of active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 4 weeks prior to screening, unless the subject has adequately recovered from coronavirus disease 2019 (COVID-19) symptoms and related complications as per Investigators discretion and following a discussion with the Medical Monitor. Use of a live COVID-19 vaccine is prohibited within 4 weeks prior to randomization.
12. Subject with known human immunodeficiency virus (HIV), evidence of active Hepatitis B (HepB) as demonstrated by the presence of Hepatitis B surface antigen (HBsAg) and/or positive for Hepatitis B virus DNA (HBVDNA-positive), and/or evidence of active Hepatitis C (HepC) as demonstrated by a positive Hepatitis C virus RNA (HCV-RNA) test of sufficient sensitivity.
13. Subject with prior therapy of luspatercept or sotatercept.
14. Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product.
15. Pregnant or breastfeeding females.
16. Subject participation in any other clinical protocol or investigational trial that involves use of experimental therapy (including investigational agents) and/or therapeutic devices within 30 days or for investigational agents within five half-lives, whichever comes later, immediately up to the date of randomization.
17. Subject with any significant medical condition, laboratory abnormality, psychiatric illness, or is considered vulnerable by local regulations (eg, imprisoned or institutionalized) that would prevent the subject from participating in the study or places the subject at unacceptable risk if he/she were to participate in the study.
18. Subject with any condition or concomitant medication that confounds the ability to interpret data from the study.

Related Information

• Primary Sponsor: Jin Hayakawa
• Secondary ID(s): NCT04717414