A Phase 3b, open-label, single-arm, rollover study to evaluate long-term safety in subjects who have participated in other luspatercept (ACE-536, also known as BMS 986346) clinical trials.
- Trial ID
- 2022-502498-40-00
- Protocol
- ACE-536-LTFU-001
- Sponsor
- Celgene Corp.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the long-term **safety** of **luspatercept** in subjects who have participated in other luspatercept clinical trials. This includes monitoring for progression to **acute myeloid leukemia** (AML) and/or other malignancies or pre-malignancies. The clinical relevance of this objective lies in ensuring the continued safety of luspatercept, a therapeutic agent used in conditions such as **myelodysplastic syndrome**, **beta-thalassemia**, and **myelofibrosis**, by identifying any potential long-term adverse effects that could impact patient health outcomes.
Secondary objectives include: - Following subjects for overall survival, which is crucial for understanding the long-term efficacy and impact of luspatercept on patient longevity. - Evaluating treatment-emergent **extramedullary hematopoiesis** (EMH) masses, which are important for assessing any unexpected hematological developments that may arise during treatment.
Participants
The clinical trial involves a total of **154 participants** who are being evaluated for the long-term safety of luspatercept, particularly in relation to progression to acute myeloid leukemia (AML) and other malignancies or pre-malignancies. The study population includes both **male and female subjects** aged 18 years and older, who have previously participated in other luspatercept clinical trials. Participants are required to have been assigned to either the luspatercept treatment or placebo arm in the parent protocol and must continue to fulfill all requirements of the parent study. The trial includes individuals with medical conditions such as **myelodysplastic syndrome (MDS)**, beta-thalassemia (THAL), and myelofibrosis (MF). The selection criteria ensure that participants are willing and able to adhere to the study visit schedule and other protocol requirements. The trial population is not limited by specific lifestyle considerations such as diet or physical activity, but compliance with the study protocol is essential. The study also includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants.
Plans and Procedures
The clinical trial is a **Phase 3b**, open-label, single-arm, rollover study designed to evaluate the long-term safety of **luspatercept** in subjects who have previously participated in other luspatercept clinical trials. The primary objective is to assess the safety profile, including the progression to acute myeloid leukemia (AML) and other malignancies or pre-malignancies. The trial targets individuals with conditions such as **myelodysplastic syndrome (MDS)**, **beta-thalassemia (THAL)**, and **myelofibrosis (MF)**. The study is expected to run until February 2029, with participant recruitment having commenced in July 2019.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, willingness to adhere to the study protocol, and previous participation in a luspatercept trial. The trial will include regular follow-up visits to monitor safety and efficacy outcomes, with the primary endpoints being adverse events, progression to high-risk MDS, progression to AML, and the development of other malignancies. Secondary endpoints include overall survival and treatment-emergent extramedullary hematopoiesis (EMH) masses.
The expected length of participant involvement is up to 360 days, with conditions for early termination including non-compliance with the study protocol or the occurrence of significant adverse events. Participants will be required to attend an end-of-study visit to assess final outcomes and ensure proper discontinuation of the investigational product. The study employs a subcutaneous route of administration for luspatercept, with a maximum daily dose of 1.75 mg/kg and a total dose not exceeding 152 mg. The trial is not categorized as low intervention and does not include a pediatric formulation.
Treatment
The clinical trial involves the administration of **luspatercept**, marketed under the name Reblozyl, which is provided in two formulations: 75 mg and 25 mg powder for solution for injection. The pharmaceutical form is a powder that is reconstituted into a solution for injection. The active substance, **luspatercept**, is a recombinant fusion protein consisting of a modified form of the extracellular domain of human activin receptor IIB linked to the human IgG1 Fc domain. The drug is administered via the subcutaneous route. The dosing regimen allows for a maximum daily dose of 1.75 mg/kg, with a total maximum dose of 152 mg over a treatment period of up to 360 days. The administration schedule and participant compliance are monitored throughout the study to ensure adherence to the protocol.
Reblozyl is manufactured by Bristol-Myers Squibb Pharma EEIG and is designated as an orphan drug, with the orphan drug designation number EU/3/14/1331. The product has undergone secondary packaging and labeling specific for clinical supply, and it is subject to importation and QP release. The trial is designed to evaluate the long-term safety of luspatercept, including the progression to acute myeloid leukemia (AML) and other malignancies or pre-malignancies, in subjects who have participated in previous luspatercept clinical trials. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the evaluation of adverse events (AEs), progression to high/very high-risk myelodysplastic syndrome (MDS), progression to **Acute Myeloid Leukemia (AML)**, and the development of other malignancies or premalignancies. These endpoints are critical in determining the long-term safety profile of luspatercept in subjects who have participated in previous luspatercept clinical trials.
Secondary endpoints will focus on overall survival and the occurrence of treatment-emergent extramedullary hematopoiesis (EMH) masses. The collection and analysis of these endpoints will be conducted throughout the study duration, with specific timepoints aligned with the study protocol. The trial is designed as a Phase 3b, open-label, single-arm, rollover study, ensuring that data collection is consistent and comprehensive to support the evaluation of long-term safety and efficacy outcomes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subjects must meet all the following criteria to be enrolled in this study: 1) Subject is ≥ 18 years at the time of signing the informed consent form (ICF).
- Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
- Subject has been participating in a luspatercept trial and continues to fulfill all the requirements of the parent protocol and the subject has been either: a) Assigned to luspatercept treatment, continues to receive clinical benefit in the opinion of the investigator and should continue to receive luspatercept treatment, OR b) Assigned to placebo arm in the parent protocol (at the time of unblinding or in follow-up) and should cross over to luspatercept treatment, OR c) Assigned to the Follow-up Phase of the parent protocol, previously treated with luspatercept or placebo in the parent protocol who shall continue into Long-term Posttreatment Follow-up Phase in the rollover study until the follow-up commitments are met (unless requirements are met as per parent protocol to cross over to luspatercept treatment).
- Subject understands and voluntarily signs an informed consent document prior to any studyrelated assessments or procedures being conducted.
- Subject demonstrates compliance, as assessed by the investigator, with the parent study protocol requirements.
- Applies to on treatment subjects only- 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 reasons 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) and must: a) Have two negative pregnancy tests as verified by the investigator prior to starting study therapy. A medically supervised serum pregnancy test (conducted locally) is to be obtained and verified negative in all female subjects of childbearing potential at enrollment (for details refer to Section 6.1.7). She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. 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 highly effective, contraception without interruption, 35 days prior to starting investigational product (IP), during the study therapy (including dose interruptions), and for 84 days after discontinuation of study therapy.
- Applies to on treatment subjects only- Male subjects must: a) 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 84 days following investigational product discontinuation even if he has undergone a successful vasectomy.
Exclusion Criteria
- Applies to on treatment subjects only- Concomitant use of any medications/procedures that are prohibited in the parent luspatercept protocol.
- Subject has met one or more criteria for study discontinuation as stipulated in the parent luspatercept protocol.
- Applies to on treatment subjects only- More than 26 days between last luspatercept dose in the parent protocol and first dose into ACE-536-LTFU-001 protocol unless dose delay or dose discontinuation criteria met.
- Applies to on treatment subjects only- Pregnant or breastfeeding females. If breastfeeding, agree to stop breastfeeding prior to the participation in the study and not to resume breastfeeding during treatment with luspatercept and until 3 months after the last dose.
- Subject has 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.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 01 Jul 2019 | 13 |
 France | Not Recruiting | 01 Jul 2019 | 1 |
 Germany | Not Recruiting | 01 Jul 2019 | 8 |
 Greece | Recruiting | 01 Jul 2019 | 44 |
 Italy | Recruiting | 01 Jul 2019 | 66 |
 The Netherlands | Not Recruiting | 01 Jul 2019 | — |
 Spain | Not Recruiting | 01 Jul 2019 | 2 |
 Sweden | Not Recruiting | 01 Jul 2019 | 1 |
| Netherlands | — | — | 4 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Reblozyl 75 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1.75 | 360 | PRD9757717 |
Reblozyl 25 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1.75 | 360 | PRD9757762 |