This Phase IIb study (BEXERA) will evaluate the safety and efficacy of bexmarilimab (FP-1305), an antibody targeting Clever-1, given in combination with azacitidine compared with azacitidine plus placebo in adults with treatment-naïve higher-risk myelodysplastic syndromes (HR-MDS). Participants will be randomized to receive bexmarilimab at one of two dose levels (1 mg/kg or 3 mg/kg) plus azacitidine, or placebo plus azacitidine. The primary aim is to select the recommended dose of bexmarilimab for subsequent development based on a predefined integration of clinical response and safety/tolerability.
Participant provides written informed consent.
Participant is ≥18 years of age.
Participant has newly diagnosed MDS with morphologically confirmed HR-MDS as defined according to 2022 World Health Organization classification (5th Edition, Annex 7).
IPSS-M classification of moderately high risk, high risk, and very high risk.
Participant has a previous diagnosis of AML, has transformed to AML, or has MDS subtypes outside the scope or overlapping myeloid neoplasms: MDS evolved from pre-existing myeloproliferative neoplasms (MPN); MDS/MPN overlap (e.g., chronic myelomonocytic leukemia, acute chronic myeloid leukemia, juvenile myelomonocytic leukemia, unclassifiable); advanced myelofibrosis (MF Grade ≥3); or severe autoimmune hemolysis.
Participants who are considered appropriate candidates for immediate allogeneic haematopoietic stem cell transplantation (HSCT) at the time of screening are excluded, irrespective of transplant timing, donor availability, or planned bridging therapy. Determination of transplant candidacy should be based on institutional standards and routine clinical practice, including assessment of individual clinical factors such as age, performance status, comorbidities, organ function, disease risk, and donor suitability.
Participants with ≥20% blasts in peripheral blood or bone marrow or evidence of myeloid sarcoma (extramedullary AML).
Participant has a lack of screening cytogenetic data or demonstrated normal karyotype per local or central analysis, should the patient have <5% blasts at screening.
Parallel
bexmarilimab (1mg/kg)
Drug1mg/kg. Administered weekly (Q1W) with the opportunity to reduce frequency to biweekly (Q2W) based on time on treatment, response and investigator's discretion Intravenous (IV) administration
azacitidine
DrugStandard of care medication, administered per institutional guidelines/label
Placebo
DrugParticipants will receive saline placebo, prepared by the local site pharmacy to match bexmarilimab at point of dispensation. Administered on a schedule to match bexmarilimab
bexmarilimab (3mg/kg)
Drug3mg/kg. Administered weekly (Q1W) with the opportunity to reduce frequency to biweekly (Q2W) based on time on treatment, response and investigator's discretion Intravenous (IV) administration
Dose selection utility score 3-months from last participant enrollment utilising efficacy and safety components.
Dose-selection utility score at the end of the primary dose-selection assessment window (3 months from last participant enrollment), calculated per dose using a pre-specified algorithm that integrates: * Efficacy component (achievement of CR + CReq per IWG2023 criteria). * Safety/tolerability component (rate of treatment-related Grade 3-5 treatment-related adverse events \[TRAEs\]). For each arm, there will be an observed efficacy rate (PE) and toxicity rate (PT) and the utility score will be defined as U = PE - ωPT where the ω is a pre-specified weight.
Complete Remission (CR) and Complete Remission Equivalent (CReq)
Proportion of responses meeting CR or CReq based on IWG 2023 criteria. Endpoints of best response 3-months on treatment, 6-months on treatments and through full treatment period.
Composite Complete Remission (cCR) defined by IWG2023
cCR as defined by the IWG2023 at any point through participant treatment
Overall Response Rate (ORR)
ORR as defined by IWG2006 response criteria and IWG2023 criteria
Overall Survival (OS)
OS is defined as the number of months measured from the date of enrollment to the date of death from any cause.
Minimal Residual Disease (MRD)-Negative Response Rate
The MRD-negative response rate is defined as the percentage of participants who achieved a CR or CReq based on Investigator-assessed IWG criteria and reached MRD-negative disease status prior to initiation of any new anticancer therapy, including HSCT.
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