Efficacy and Safety of Luspatercept for the Treatment of Anemia Due to MDS With del5q, Refractory/Resistant/Intolerant to Prior Treatments, RBC-TD

NCT05924100 | Recruiting Phase 2

• 1 other identifier: QOL-ONE Phoenix
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 23

Brief Summary

Myelodysplastic syndromes, primarily affecting older adults, are a heterogeneous group of clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis that manifest clinically as anemia, neutropenia, and/or thrombocytopenia of variable severity; these often result in RBC- transfusion dependent (TD) anemia, increased risk of infection, and/or hemorrhage, as well as a potential to progress to acute myeloid leukemia (AML). Lenalidomide is approved for red blood cell transfusion-dependent (RBC TD) anemia due to low-risk myelodysplastic syndromes (MDS) with a chromosome 5q deletion (del5q) with or without additional cytogenetic abnormalities. About one third of patients are refractory/resistant/intolerant and will require further treatment options. Luspatercept (ACE-536), an erythroid maturation agent, is a recombinant fusion protein consisting of a modified form of the extracellular domain (ECD) of the human activin receptor type IIB (ActRIIB) linked to the Fc portion of human immunoglobulin G1 (IgG1-Fc). Luspatercept acts on endogenous inhibitors of late-stage erythropoiesis (eg, growth differentiation factor 11, GDF11) to increase release of mature erythrocytes into circulation. Nonclinical data have demonstrated that luspatercept binds to negative regulators governing late-stage erythroid development to inhibit their action, thereby promoting the maturation of erythrocytes in the bone marrow. Luspatercept is indicated for the treatment of adult patients with transfusion-dependent anaemia associated with beta-thalassaemia and due to very low, low and intermediate-risk MDS with ring sideroblasts, who had an unsatisfactory response to or are ineligible for erythropoietin-based-therapy. It is not indicated for other MDS subtypes. Unfortunately, patients with MDS with del5q refractory/resistant/intolerant to lenalidomide are excluded from clinical trials that evaluate novel treatments for the anemia of RBC TD lower risk MDS. Therefore, treatment of anemia in such patients is an unmet need. QOL-ONE Phoenix is a Phase 2, multicenter, single arm, prospective study. The primary objective of the study is to evaluate the effect of luspatercept on RBC TI in subjects with MDS with del5q with IPSS-R very low, low, or intermediate risk and \< 5% bone marrow blasts, resistant/refractory/intolerant to lenalidomide and who require RBC transfusions. The study is divided into a Screening Period, a 2-year Treatment Period and a 3-year Follow-up Period. Primary objective is to evaluate the effect of luspatercept on RBC TI (lack of transfusions for 8 consecutive weeks within the first 24 weeks) in subjects with MDS with del5q with IPSS-R very low, low, or intermediate risk and \< 5% bone marrow blasts, resistant/refractory/intolerant to lenalidomide and RBC TD.

Conditions

Myelodysplastic Syndromes; Del(5Q); Anemia; Transfusion-dependent Anemia

Keywords

MDS with Del(5Q)

Outcome Measures

Primary Outcomes (1)

• RBC Transfusion Independence

  Proportion of subjects who are RBC TI for 8 weeks over the first 24 weeks from trial entry

  24 WEEKS

Secondary Outcomes (10)

• Safety and tolerability of Luspatercept measured as frequency and severity of adverse events occurred and assessed by CTCAE v. 5.0

  5 years

• RBC-TI in long term

  5 years

• Duration of RBC-TI

  2 years

• Reduction in RBC transfusions

  24 weeks

• Increase in hemoglobin

  2 years

Study Arms (1)

Luspatercept

EXPERIMENTAL

Drug: Luspatercept Injection [Reblozyl]

Interventions

Luspatercept Injection [Reblozyl] DRUG

Eligible subjects will receive luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg (with a maximum total dose of 168 mg). All subjects who have received at least one dose of luspatercept should undergo follow-up evaluations after day 169 with Assessment visits every 24 weeks (168 days) up to 2 years to evaluate evidence of clinical benefit.

Luspatercept

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• P53 mutation at screening
• 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. 5 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 7. Known history of diagnosis of AML 8. 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. 9. Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment. 10. 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) 12. 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 13. 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

Sponsors & Collaborators

• Associazione Qol-one: lead

Study Sites (23)

A.O. SS. Antonio e Biagio e Cesare Arrigo Ospedale Civile

Alessandria, Italy

NOT YET RECRUITING

A.O.U. Ospedali Riuniti

Ancona, Italy

RECRUITING

A.O. S. Giuseppe Moscati

Avellino, Italy

NOT YET RECRUITING

Ospedale degli Infermi

Biella, Italy

NOT YET RECRUITING

A.O.U. G. Rodolico San Marco

Catania, Italy

NOT YET RECRUITING

ARNAS Garibaldi, PO Nesima

Catania, Italy

NOT YET RECRUITING

ASL TO 4 - Ospedale Chivasso

Chivasso, Italy

NOT YET RECRUITING

Azienda Ospedaliera Annunziata

Cosenza, Italy

NOT YET RECRUITING

A.O.U. Careggi

Florence, Italy

NOT YET RECRUITING

A.O.U. Federico II

Napoli, Italy

NOT YET RECRUITING

A.O.U. Maggiore della Carità

Novara, Italy

NOT YET RECRUITING

A.O.U. Policlinico Paolo Giaccone

Palermo, Italy

NOT YET RECRUITING

Ospedale Civile Spirito Santo

Pescara, Italy

NOT YET RECRUITING

Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli

Reggio Calabria, 89133, Italy

RECRUITING

IRCCS di Reggio Emilia

Reggio Emilia, Italy

NOT YET RECRUITING

Ospedale S. Eugenio

Roma, Italy

NOT YET RECRUITING

Policlinico Tor Vergata

Roma, Italy

NOT YET RECRUITING

Policlinico Umberto I

Roma, Italy

NOT YET RECRUITING

A.O.U. San Giovanni di Dio e Ruggì D'Aragona

Salerno, Italy

NOT YET RECRUITING

Casa Sollievo della Sofferenza IRCCS

San Giovanni Rotondo, Italy

NOT YET RECRUITING

AO Santa Maria di Terni

Terni, Italy

NOT YET RECRUITING

A.O. Città della Salute e della Scienza

Torino, Italy

NOT YET RECRUITING

ASU Giuliano Isontina

Trieste, Italy

NOT YET RECRUITING

MeSH Terms

Conditions

Myelodysplastic Syndromes; Anemia

Interventions

luspatercept

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Central Study Contacts

Esther N Oliva, MD

CONTACT

+393298699514; trials@qol-one.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 8, 2023
• First Posted: June 29, 2023
• Study Start: November 3, 2022
• Primary Completion: December 3, 2024
• Study Completion (Estimated): December 3, 2029
• Last Updated: November 18, 2024

Record last verified: 2024-11

Locations

IT (23)