A study to evaluate the benefit and safety of Luspatercept (ACE-536) in adults with myeloproliferative neoplasm-associated myelofibrosis on concomitant JAK2 inhibitor therapy and who require red blood cell transfusions
- Conditions
- Anemia associated with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF)MedDRA version: 20.0Level: PTClassification code 10077161Term: Primary myelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 21.0Level: LLTClassification code 10074689Term: Post polycythemia vera myelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 21.0Level: LLTClassification code 10074690Term: Post essential thrombocythemia myelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 21.0Level: LLTClassification code 10074692Term: Post essential thrombocythaemia myelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 21.1Level: LLTClassification code 10074691Term: Post polycythaemia vera myelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 20.0Level: PTClassification code 10028537Term: MyelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]
- Registration Number
- EUCTR2020-000607-36-DE
- Lead Sponsor
- Celgene Corporation
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 309
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-ET or post-PV myelofibrosis according to the IWG-MRT 2007 criteria, confirmed by the most recent local pathology report.
3. Subject is requiring 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 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) JAK2 inhibitor therapy as approved in the country of the study site for the treatment for 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 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). 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 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.
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
* True abstinence is acceptable when it is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.]
** Agreement to use highly effective methods of contraception that alone or in combination resu
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, 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 x 10^9/L
b. White blood count (WBC): > 100 x 10^9/L
c. Platelets: the lowest allowable level as approved for the concomitant JAK2 inhibitor but not < 25 x 10^9/L or > 1000 x 10^9/L
d. Peripheral blood myeloblasts: > 5%
e. Estimated glomerular filtration rate: < 30 mL/min/1.73 m2 (via the 4variable modification of diet in renal disease [MDRD] formula) or nephrotic subjects (eg, urine albumin-tocreatinine ratio> 3500 mg/g)
f. Aspartate aminotransferase (AST) or alanine aminotransferase: (ALT) > 3.0 x upper limit of normal (ULN)
g. Direct bilirubin: = 2 x 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.
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).
12. Subject with
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To evaluate the efficacy of luspatercept compared with placebo for the treatment of anemia in subjects with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) with concomitant JAK2 inhibitor therapy and who require red blood cell transfusions.;Secondary Objective: - To evaluate additional efficacy parameters of luspatercept compared with placebo;<br>- To evaluate the the safety of luspatercept compared to placebo in subjects with MPN-associated MF as measured by the frequency and severity of adverse events (AEs), serious adverse events (SAEs), antidrug antibodies (ADA), and transformation to blast phase;<br>- To evaluate pharmacokinetics (PK) for luspatercept in MPN-associated MF.;Primary end point(s): Proportion of subjects who become RBC transfusion free during any consecutive 12-week period <br>;Timepoint(s) of evaluation of this end point: Any consecutive rolling” 12-week period starting from randomization up to and including Week 24
- Secondary Outcome Measures
Name Time Method