Evaluation of Luspatercept in Anemia Management for Myelodysplastic Syndromes with del(5q) Refractory to Lenalidomide and ESA Therapy Requiring RBC Transfusion
- Trial ID
- 2024-519310-31-00
- Protocol
- QOL-ONE Phoenix
- Sponsor
- Associazione Qol-One
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **luspatercept** on achieving red blood cell transfusion independence (RBC-TI) for 8 consecutive weeks within the first 24 weeks in subjects with anemia due to myelodysplastic syndromes (MDS) with del5q. These subjects are characterized by very low, low, or intermediate risk according to the Revised International Prognostic Scoring System (IPSS-R) and have a bone marrow blast count of less than 5%. They are resistant, refractory, or intolerant to lenalidomide and require red blood cell transfusions. This objective is clinically relevant as achieving RBC-TI can significantly reduce the burden of transfusions and improve patient outcomes.
Secondary objectives include:
- Evaluating the safety and tolerability of luspatercept.
- Assessing RBC-TI at 48 weeks and at the end of the study.
- Determining the duration of RBC-TI.
- Measuring the reduction in RBC transfusions.
- Observing the increase in hemoglobin levels.
- Evaluating changes in quality of life scores (QOL-E and HM-PRO).
- Monitoring changes in serum ferritin levels.
- Assessing changes in iron chelation therapy use.
- Determining the time to achieve RBC-TI.
Participants
The clinical trial involves participants diagnosed with **anemia** due to myelodysplastic syndromes (MDS) with del5q, classified as very low, low, or intermediate risk according to the IPSS-R, and with a bone marrow blast count of less than 5%. The study population includes both male and female subjects aged 18 years and older. Participants are required to be refractory or intolerant to, or ineligible for, prior erythropoiesis-stimulating agent (ESA) and lenalidomide treatments, and they must require regular red blood cell (RBC) transfusions. The trial population was selected based on specific inclusion criteria, including the ability to adhere to the study protocol and an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** and safety of **luspatercept** for the treatment of anemia due to myelodysplastic syndromes (MDS) with del5q, specifically in patients who are refractory, resistant, or intolerant to prior treatments and require red blood cell (RBC) transfusions. This is a Phase IV, randomized, double-blind, controlled trial. The trial aims to assess the primary endpoint of achieving RBC transfusion independence for 8 consecutive weeks within the first 24 weeks of treatment. Secondary endpoints include safety and tolerability, duration of RBC transfusion independence, reduction in RBC transfusions, increase in hemoglobin levels, and changes in quality of life scores, among others.
The trial will span an estimated duration from December 28, 2022, to December 31, 2029. Participants will be involved in the study for a maximum treatment period of 24 weeks. The study visits are structured as follows: an initial screening visit to confirm eligibility based on inclusion criteria such as age, diagnosis, and prior treatment history; regular follow-up visits to monitor treatment response and safety; and an end-of-study visit to assess final outcomes and collect data on long-term effects. Participants are expected to adhere to the study visit schedule and protocol requirements. Conditions that may lead to early termination from the study include non-compliance with the protocol, adverse events, or withdrawal of consent.
Inclusion criteria require participants to be 18 years or older, with a documented diagnosis of MDS with del5q, classified as very low, low, or intermediate risk according to the IPSS-R, and a bone marrow blast count of less than 5%. Participants must be refractory or intolerant to, or ineligible for, prior erythropoiesis-stimulating agent (ESA) and lenalidomide treatments. Exclusion criteria are not explicitly detailed in the provided data. The investigational product, luspatercept, will be administered via subcutaneous injection, with a maximum daily dose of 1.75 mg/kg and a total dose not exceeding 168 mg. The trial is not categorized as low intervention, and it is not a pediatric formulation. The study is sponsored by Bristol-Myers Squibb Pharma EEIG, and the investigational product is marketed under the name Reblozyl.
Treatment
The clinical trial involves the administration of **Reblozyl**, a pharmaceutical product containing the active substance **luspatercept**. Reblozyl is available in two dosages: 75 mg and 25 mg, both formulated as a **powder for 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 pharmaceutical form is a solution for injection, and the route of administration is via **subcutaneous injection**. The maximum daily dose is 1.75 mg/kg, with a total maximum dose of 168 mg. The treatment period is up to 24 weeks. The product is manufactured by Bristol-Myers Squibb Pharma EEIG and is authorized for use in the European Union under marketing authorization numbers EU/1/20/1452/002 and EU/1/20/1452/001.
In this study, Reblozyl is used to evaluate its efficacy and safety for the treatment of anemia due to **myelodysplastic syndromes** with del5q, particularly in patients who are refractory, resistant, or intolerant to prior treatments and require red blood cell transfusion. The primary objective is to assess the effect of luspatercept on red blood cell transfusion independence (RBC TI) over an 8-week period within the first 24 weeks of treatment. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
The efficacy of **Luspatercept** in the treatment of anemia due to Myelodysplastic Syndromes (MDS) with del5q will be assessed through several primary and secondary endpoints. The primary endpoint is the achievement of Red Blood Cell Transfusion Independence (RBC-TI) for 8 consecutive weeks within the first 24 weeks of treatment. Secondary endpoints include the safety and tolerability of Luspatercept, RBC-TI at 48 weeks and at the end of the study, duration of RBC-TI, reduction in RBC transfusions, increase in hemoglobin levels, changes in quality of life scores (QOL-E and HM-PRO), changes in serum ferritin levels, changes in iron chelation therapy use, and time to achieve RBC-TI.
These efficacy parameters will be measured and collected at specified timepoints throughout the trial, including at week 24, week 48, and at the end of the study. The assessments will utilize validated scales and laboratory tests to ensure accuracy and reliability. The data collected will be analyzed to determine the effect of Luspatercept on the specified endpoints, providing insights into its efficacy in the target patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject is ≥ 18 years of age 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.
- Documented diagnosis of MDS with del5q according to 2018 WHO classification.
- IPSS-R classification (Greenberg, 2012) of very low, low, or intermediate risk disease, and: • < 5% blasts in bone marrow • Peripheral blood WBC count <13,000/μL
- Refractory or intolerant to, or ineligible for, prior ESA treatment.
- If previously treated with ESAs or granulocyte colony-stimulating factor (G-CSF), both agents must have been discontinued ≥ 4 weeks prior to date of screening.
- Refractory or intolerant to, or ineligible for, prior lenalidomide treatment, as defined by any one of the following: • Refractory to prior lenalidomide treatment for at least 4 cycles; - documentation of non-response or response that is no longer maintained (HI-E) • Intolerant to prior lenalidomide treatment - documentation of discontinuation of lenalidomide at any time after introduction due to intolerance or an adverse event • lenalidomide ineligible –platelet counts below 50000/mmc or absolute neutrophil count below 500/mmc at the start of treatment • lenalidomide must have been discontinued ≥ 4 weeks prior to date of screening. Requires RBC transfusions, as documented by the following criteria: • average transfusion requirement of ≥ 2 units/8 weeks of pRBCs confirmed for a minimum of 16 weeks immediately preceding enrolment. • Hb levels at the time of or within 7 days prior to administration of a RBC transfusion must have been ≤ 10.0 g/dL in order for the transfusion to be counted towards meeting eligibility criteria. RBC transfusions administered when Hb levels were > 10.0 g/dL and/or RBC transfusions administered for elective surgery 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 screening
- Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2.
- Females of childbearing potential, defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy 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). Refer to Section 6.1 for additional details. She must agree to ongoing pregnancy testing during the course of the study, and after the end of study treatment. • If sexually active, agree to use, and be able to comply with, highly effective contraception without interruption, 5 weeks prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks after discontinuation of study therapy.
- Male subjects must: • Agree to use a condom, defined as a male latex condom or non latex condom not made out of natural (animal) membrane (for example, polyurethane), 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 investigational product 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
- Prior therapy with disease modifying agents for underlying MDS disease (hypomethylating agents) • subjects who previously received HMA may be enrolled at the investigator’s discretion contingent that the subject received no more than 1 dose of HMA). The last dose must be ≥ 5 weeks from the date of screening.
- Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011)
- 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.
- Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding
- Prior allogeneic or autologous stem cell transplant.
- Known history of diagnosis of AML
- Use of any of the following within 5 weeks prior to study entry: • anticancer cytotoxic chemotherapeutic agent or treatment • corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to study entry 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 screening • other RBC hematopoietic growth factors • 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 screening or within 5 weeks, whichever is longer is excluded
- Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment
- Estimated glomerular filtration rate (eGFR) or creatinine clearance < 40 mL/min.
- Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase or alanine aminotransferase/serum glutamic pyruvic transaminase ≥ 3.0 x upper limit of normal (ULN)
- 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
- 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)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 28 Dec 2022 | 22 |
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 25 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 1.75 | 24 | PRD9257430 |
Reblozyl 75 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 1.75 | 24 | PRD9257437 |