Detailed Description:
Permitted Concomitant Medications and Procedures
- Subjects are receiving a JAK2 inhibitor for the treatment of MPN-associated MF that is
approved in the country where the study is being conducted. JAK2 inhibitors are to be
used according to their respective label and as prescribed as part of the subject's
standard-of-care therapy as prescribed by their physician prior to study entry.
- Best supportive care (BSC) includes, but is not limited to, treatment with transfusions
(eg, RBC, platelet, whole blood), ICTs, antibiotic, antiviral and/or antifungal therapy,
and nutritional support as needed.
- Granulocyte colony-stimulating factors (ie, G-CSF, granulocyte macrophage
colony-stimulating factor [GM-CSF]) are allowed only in cases of neutropenic fever or as
clinically indicated per product label.
- Prophylactic antithrombotic therapy is permitted.
- Thrombopoietin and platelet transfusions are permitted.
- Treatment with systemic corticosteroids is permitted for nonhematological conditions
providing the subject is receiving a constant dose equivalent to ≤ 10 mg prednisone
during the study.
- Administration of attenuated vaccines (eg, influenza vaccine) is allowed if clinically
indicated per Investigator discretion.
- Iron chelation therapy (ICT) is to be used according to the product label. If the label
permits, the ICT dose should be stable during at least the first 24 weeks of IP.
Initiation of ICT while within the first 24 weeks of IP should be clinically indicated
to treat an AE.
Prohibited Concomitant Medications
The following concomitant medications are specifically excluded during the course of study
treatment:
- Cytotoxic, chemotherapeutic, targeted, or investigational agents/therapies (excluding
JAK2 inhibitor therapy)
- Azacitidine, decitabine, or other hypomethylating agents
- Lenalidomide, thalidomide, and pomalidomide
- Erythropoietin stimulating agents (ESAs) and other RBC hematopoietic growth factors (eg,
IL-3)
- Hydroxyurea or other alkylating agents
- Androgens (unless given to treat hypogonadism)
- Oral retinoids (topical retinoids are permitted)
- Arsenic trioxide
- Interferon
- Anagrelide
- Systemic corticosteroids at a dose equivalent to > 10 mg prednisone
- Investigational products for the treatment of MPN-associated MF
Subjects must satisfy the following criteria to be randomized in the study:
Inclusion Criteria
- Subject is ≥18 years of age at the time of signing the ICF.
- Subject has a diagnosis of PMF according to the 2016 World Health Organization (WHO)
criteria or diagnosis of post-ET or post-PV MF according to the IWG-MRT 2007 criteria,
confirmed by the most recent local pathology report.
- Subject is requiring RBC transfusions as defined as:.
i) 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.
ii) RBC transfusions are scored in determining eligibility when given for treatment of:.
A. Symptomatic (ie, fatigue or shortness of breath) anemia with a pretransfusion Hgb ≤ 9.5
g/dL or.
B. Asymptomatic anemia with a pretransfusion Hgb ≤ 7 g/dL.
iii) RBC transfusions given for worsening of anemia due to bleeding or infections are not
scored in determining eligibility.
- 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.
- Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
- 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). Females of childbearing potential (FCBP)participating in the study must:.
i) 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.
ii) 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 PK data) after discontinuation of
study therapy.
- 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.
i) 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.].
ii) Agreement to use highly effective methods of contraception that alone or in combination
result in a failure rate of a Pearl index of less than 1% per year when used consistently
and correctly throughout the course of the study. Such methods include: Combined (estrogen
and progestogen containing) hormonal contraception: Oral, Intravaginal, Transdermal;
Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral,
Injectable hormonal contraception, Implantable hormonal contraception; Placement of an
intrauterine device (IUD); Placement of an intrauterine hormone-releasing system (IUS);
Bilateral tubal occlusion; Vasectomized partner; Sexual Abstinence.
- Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted.
- 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.
Exclusion Criteria
- The presence of any of the following will exclude a subject from randomization:.
- Subject with anemia from cause other than MPN-associated MForJAK2 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).
- 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.
i) 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.
ii) Iron chelation therapy (ICT) is permitted providing the subject is receiving a stable
dose for the 8 weeks immediately up to randomization.
- Subject with any of the following laboratory abnormalities at screening:.
i) Neutrophils: < 1 x 10^9/L.
ii) White blood count (WBC): > 100 x 10^9/L.
iii) 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.
iv) Peripheral blood myeloblasts:> 5%.
v) Estimated glomerular filtration rate:< 30 mL/min/1.73 m2 (via the 4-variable
modification of diet in renal disease [MDRD] formula) or nephrotic subjects (eg, urine
albumin-to-creatinine ratio > 3500 mg/g).
vi) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT):> 3.0 x upper limit
of normal (ULN).
vii) Direct bilirubin: ≥ 2 x ULN.
A. Higher levels are acceptable if these can be attributed to active red blood cell
precursor destruction within the bone marrow (eg, ineffective erythropoiesis).
- 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.
- 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:.
i) Basal or squamous cell carcinoma of the skin.
ii) Carcinoma in situ of the cervix.
iii) Carcinoma in situ of the breast.
iv) Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes,
metastasis [TNM] clinical staging system).
- 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.
- 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.
- 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.
- Subject with inadequately controlled heart disease and/or have a known left
ventricular ejection fraction < 35%.
- 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).
- 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.
- Subject with prior therapy of luspatercept or sotatercept.
- Subject with history of severe allergic or anaphylactic reactions or hypersensitivity
to recombinant proteins or excipients in the investigational product.
- Pregnant or breastfeeding females.
- 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.
- 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.
- Other protocol-defined Inclusion/Exclusion criteria apply.
Primary outcome:
1. Red blood cell-transfusion independence (RBC-TI) ≥ 12 weeks (RBC-TI 12) (Time Frame - Up to 24 weeks):
Proportion of subjects who become RBC-transfusion free over any consecutive 12-week period starting within the first 24 weeks.
Secondary outcome:
1. Red blood cell-transfusion independence ≥ 16 weeks (RBC-TI 16) (Time Frame - Up to 24 weeks):
Proportion of subjects who become RBC-transfusion free over any consecutive 16-week period
2. Duration of Red blood cell-transfusion independence (RBC-TI 12) (Time Frame - Up to end of treatment, approximately 3 years):
Maximum duration of RBC-TI response
3. Reduction of transfusion burden by ≥ 50% and by ≥ 4 units/12 weeks from baseline over any consecutive 12-week period (Time Frame - Up to 24 weeks):
Proportion of subjects who reduce their transfusion burden by ≥ 50% and by ≥ 4 units/12 weeks from baseline over any consecutive 12-week period
4. Duration of reduction in transfusion burden (Time Frame - Up to end of treatment, approximately 3 years):
Maximum duration of when RBC-transfusion dependent subjects who reduce their transfusion burden by ≥ 50% and by ≥ 4 units/12 weeks from baseline over any consecutive 12 week period
5. Red blood cell-transfusion independence ≥ 12 weeks in the treatment period (RBC-TI 12/TP) (Time Frame - Up to end of treatment, approximately 3 years):
Proportion of subjects who become RBC-transfusion free over any consecutive 12-week period
6. Red blood cell-transfusion independence ≥ 16 weeks in the treatment period (RBC-TI 16/TP) (Time Frame - Up to end of treatment, approximately 3 years):
Proportion of subjects who become RBC-transfusion free over any consecutive 16-week period
7. Change in RBC transfusion burden (Time Frame - Up to 24 weeks):
Mean change in transfusion burden (RBC units) from baseline
8. Cumulative duration of RBC-transfusion independence (Time Frame - Up to end of treatment, approximately 3 years):
Cumulative response duration for subjects achieving multiple episodes of RBC-TI 12
9. Mean Hgb increase ≥ 1 g/dL from baseline over any consecutive 12-week period in absence of RBC transfusions (Time Frame - Up to end of treatment, approximately 3 years):
Proportion of subjects achieving a mean Hgb increase ≥ 1 g/dL from baseline over any consecutive 12-week period in absence of RBC transfusions
10. Change in serum ferritin from baseline (Time Frame - Up to end of treatment, approximately 3 years):
Change in serum ferritin
11. Incidence of Adverse Events (AEs) (Time Frame - From screening up to 42 days post last dose):
Number of participants with adverse events
12. Transformation to blast phase: Number of subjects who transform into AML (Time Frame - Up to approximately 5 years):
AML = acute myeloid leukemia
13. Frequency of Antidrug antibodies (ADA) (Time Frame - From randomization and up to including 48 weeks post first dose):
Will be collected for assessment of anti-drug antibodies (ADA) against Luspatercept in serum in all subjects
14. Pharmacokinetics - Area Under the Concentration-Time Curve (AUC) (Time Frame - From randomization and up to including 48 weeks post first dose):
Measures of luspatercept exposure area under the curve
15. Pharmacokinetics - Maximum plasma concentration of drug (Cmax) (Time Frame - From randomization and up to including 48 weeks post first dose):
Maximum plasma concentration of drug
- Experimental: Experimental Arm: Luspatercept (ACE-536)
Luspatercept will be given to participants via subcutaneous injection (administered on Day 1 of each 21-day treatment cycle) - Placebo Comparator: Control Arm: Placebo
Placebo starting dose with volume equivalent to experimental arm subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle)
- ACE-536 (Luspatercept / BMS-986346 / ):
Subcutaneous Injection - Placebo:
Subcutaneous Injection
Quelle: ClinicalTrials.gov
