Evaluation of Luspatercept and Epoetin Alfa in Low-Risk Myelodysplastic Syndromes Without Ring Sideroblasts Post-Erythropoiesis-Stimulating Agent Failure
- Trial ID
- 2024-515354-24-00
- Protocol
- COMBOLA
Trial statistics
Objectives
The primary objective of this study is to evaluate the optimal dose level of **luspatercept** in combination with EPO for patients with lower risk myelodysplastic syndromes (MDS) without ring sideroblasts (RS) who have failed or are ineligible for erythroid stimulating agents (ESA). This is crucial for determining the balance between toxicity and efficacy, ensuring that patients receive the most effective treatment with minimal adverse effects. Additionally, the study aims to assess the superiority and efficacy of the combination therapy over luspatercept monotherapy at Week 25, focusing on transfusion independence and hematological improvement.
Secondary objectives include: - Determining the response rate, including complete response (CR), partial response (PR), and stable disease with hematological improvement (HI) according to IWG 2006 criteria in each treatment arm. - Evaluating the response duration, time to progression according to the International Prognostic Scoring System (IPSS), and loss of red blood cell (RBC) transfusion independence in responders. - Assessing the rate and interval to acute myeloid leukemia (AML) evolution. - Determining overall survival. - Identifying prognostic and predictive factors of response, including IPSS-R, IPSS-karyotype, and somatic mutations. - Evaluating safety and toxicity profiles using CTCAE version 5, with specific criteria for dose-limiting toxicities (DLT) related to non-hematological and hematological adverse events.
Participants
The clinical trial involves participants diagnosed with **low-risk myelodysplastic syndrome** (MDS) without ring sideroblasts (RS), who have either failed or are ineligible for erythroid stimulating agents (ESA). The study population includes both male and female subjects aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are ambulatory and capable of self-care. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants must have adequate renal and liver function, as defined by specific laboratory criteria, and must not be refractory to platelet transfusions. The trial includes individuals who are transfusion-dependent or have hemoglobin levels below 9 g/dL. Lifestyle considerations such as diet and physical activity are not explicitly mentioned. The selection process for the trial population involves meeting specific inclusion criteria, including the ability to adhere to the study protocol and provide written informed consent. The trial also includes a vulnerable population, although specific details are not provided.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of **luspatercept** in combination with **epoetin alfa** for patients with low-risk **myelodysplastic syndromes** (MDS) without ring sideroblasts (RS) who have failed or are ineligible for erythroid stimulating agents (ESA). The trial is divided into two parts: Part A, a dose-finding study, aims to determine the optimal dose level of luspatercept combined with epoetin alfa based on both toxicity and efficacy. Part B evaluates the superiority of the combination therapy over luspatercept monotherapy at Week 25, focusing on transfusion independence and hematological improvement.
The trial is expected to last until June 2029, with participant recruitment having commenced in May 2022. Participants will be involved in the study for a duration that includes an initial screening visit, regular follow-up visits, and an end-of-study visit. The screening visit will assess eligibility based on criteria such as age, ECOG performance status, and specific laboratory values. Follow-up visits will occur at regular intervals to monitor treatment response, adverse events, and overall health status. The end-of-study visit will conclude the participant's involvement, with final assessments of efficacy and safety.
Participants are expected to remain in the study unless they experience significant adverse events, disease progression, or withdrawal of consent. Conditions that may lead to early termination include non-compliance with the study protocol or the development of contraindications to the study medication. The primary endpoints include determining the optimal dose in Part A and assessing erythroid response in Part B. Secondary endpoints focus on the duration of response, progression-free survival, and overall survival.
Treatment
The clinical trial involves the administration of **Reblozyl**, which is available in two dosages: 25 mg and 75 mg. Both formulations are presented as a **powder for solution for injection**. The active substance in Reblozyl is **luspatercept**, 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 **subcutaneous use**. The dosing schedule for Reblozyl is determined based on the trial's protocol, with careful monitoring of participant compliance to ensure adherence to the prescribed regimen. The product is manufactured by Bristol-Myers Squibb Pharma EEIG and is designated as an orphan drug under the number EU/3/14/1331.
In addition to Reblozyl, the trial also includes the administration of **EPREX**, which contains the active substance **epoetin alfa**. EPREX is provided as a 40000 UI/ml solution for injection in a pre-filled syringe. Like Reblozyl, EPREX is administered via the subcutaneous route. Epoetin alfa is a protein-based therapeutic agent, and its administration is part of the combination therapy being evaluated in the trial. The dosing and administration schedule for EPREX is aligned with the trial's objectives, focusing on achieving optimal therapeutic outcomes. The product is manufactured by Janssen-Cilag and is not designated as an orphan drug.
The trial aims to evaluate the combination of luspatercept and epoetin alfa in patients with lower-risk myelodysplastic syndromes (MDS) who have failed or are ineligible for erythropoiesis-stimulating agents (ESA). The study is structured in two parts: a dose-finding study to determine the optimal dose level and a comparative study to assess the efficacy of the combination therapy over monotherapy. Participant compliance is monitored throughout the trial to ensure accurate assessment of the treatment's efficacy and safety.
Efficacy
The efficacy of the clinical trial will be assessed through a series of predefined primary and secondary endpoints. In Part A of the trial, the primary endpoint is to determine the optimal dose of **luspatercept** combined with EPO, focusing on both toxicity and efficacy. Efficacy will be evaluated by a treatment response, defined as an increase in hemoglobin level of 1.5 g/dl or above, measured at day 21 of cycle 1. Dose-limiting toxicity will be observed up to day 42 of cycle 1.
In Part B, the primary endpoint is the erythroid response (HI-E) according to IWG2018 criteria, assessed at week 25 following randomization. Secondary endpoints include the duration of response, progression-free survival, and overall survival. These parameters will provide a comprehensive evaluation of the therapeutic benefit of the combination therapy compared to monotherapy in patients with lower-risk myelodysplastic syndromes (MDS) without ring sideroblasts (RS) who have failed or are ineligible for erythropoiesis-stimulating agents (ESA).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Myelodysplastic syndrome according to current WHO classification
- Age ≥ 18 years
- Patients with lower risk MDS according to IPSS classification (LOW, INT-1) without RS who failed to achieved a response or who subsequently relapse after ESA (at least 60000 U EPO-a over at least 12weeks or equivalent), without disease progression (or ineligible to ESA defined by EPO > 500 UI/l)
- Hemogobin < 9 gr/dl or Transfusion dependant (at least 3 RBCs in 16 wk in at least 2 transfusion episodes)
- Non del(5q) syndrome
- Adequat renal function, defined by creatinine less than 1.5 times the upper limit of normal, creatinine clearance ≥ 40 mL/min (MDRD formula)
- Adequat liver function, defined by total bilirubin and transaminases less than 1.5 times the upper limit of normal
- Patient is not known to be refractory to platelet transfusions
- Written informed consent
- Patient must understand and voluntarily sign consent form
- Patient must be able to adhere to the visit schedule as outlined in the study and follow protocol requirements
- ECOG performance status 0-2 at the time of screening
- A FCBP (female of childbearing potential) for this study was defined as a sexually mature woman who: (1) had not undergone a hysterectomy or bilateral oophorectomy; or (2) had not been naturally postmenopausal (amenorrhea following cancer therapy did not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). A FCBP participating in the study must: a) Have had 2 negative pregnancy tests as verified by the investigator prior to starting IP (unless the screening pregnancy test was done within 72 hours of Cycle 1 Day 1). She must have had agreed to ongoing a monthly pregnancy testing during the course of the study and after EOT b) If sexually active, agreed to have used, and been able to comply with, highly effective contraception** without interruption, 5 weeks prior to starting IP, during treatment with IP (including dose interruptions), and for 12 weeks after discontinuation of IP. (** Highly effective contraception was defined in this protocol as the following (information also appeared in the ICF): Hormonal contraception (eg, birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation (tying your tubes), or a partner with a vasectomy. Male subjects must: Have agreed to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (eg, polyurethane), during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions, and for at least 12 weeks following IP discontinuation, even if he had undergone a successful vasectomy.
Exclusion Criteria
- Severe infection or any other uncontrolled severe condition
- Uncontrolled hypertension
- Significant cardiac disease - NYHA Class III or IV or having suffered a myocardial infarction in the last 6 months
- del(5q) syndrome
- Use of investigational agents within 30 days or any anticancer therapy (including IMiD) within 2 weeks before the study entry with the exception of hydroxyurea. The patient must have recovered at least a grade 1 from all acute toxicity from any previous therapy.
- Use of EPO within 4 weeks before the study entry
- Active cancer, or cancer during the year prior to trial entry other than basal cell carcinoma, or carcinoma in situ of the cervix or breast
- Patient already enrolled in another therapeutic trial of an investigational drug
- Known HIV infection or active hepatitis B or C
- Women who are or could become pregnant or who are currently breastfeeding
- Any medical or psychiatric contraindication that would prevent the patient from understanding and signing the informed consent form
- Patient eligible for allogeneic stem cell transplantation
- Known allergies to luspatercept or EPO or any of its excipients
- No affiliation to a health insurance system
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 18 May 2022 | 150 |
 Italy | Recruiting | 18 May 2022 | 10 |
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 | — | — | PRD9757717 |
EPREX 40000 UI/ml, solution injectable en seringue préremplie | Other | SOLUTION INJECTABLE EN SERINGUE PRÉREMPLIE | SUBCUTANEOUS USE | — | — | PRD715868 |
Reblozyl 25 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | — | — | PRD9757762 |