Higher Risk Myelodysplastic Syndromes
Conditions
Keywords
higher risk myelodysplastic syndromes, HR-MDS, Bexmarilimab, Hematoligical, Malignancies, Immunotherapy, CLEVER-1, anti-CLEVER-1, MDS, azacitidine
Brief summary
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.
Interventions
DRUGbexmarilimab (1mg/kg)
1mg/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
DRUGazacitidine
Standard of care medication, administered per institutional guidelines/label
DRUGPlacebo
Participants will receive saline placebo, prepared by the local site pharmacy to match bexmarilimab at point of dispensation. Administered on a schedule to match bexmarilimab
DRUGbexmarilimab (3mg/kg)
3mg/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
Sponsors
Faron Pharmaceuticals Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
1:1:1 Randomization
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participant provides written informed consent. 2. Participant is ≥18 years of age. 3. Participant has newly diagnosed MDS with morphologically confirmed HR-MDS as defined according to 2022 World Health Organization classification (5th Edition, Annex 7). 1. IPSS-M classification of moderately high risk, high risk, and very high risk. 2. \<20% bone marrow blasts per bone marrow biopsy/aspirate at screening 4. Participant is eligible for azacitidine per local practice and willing to initiate trial therapy. 5. Participant has ECOG performance score 0 to 2. 6. Participant has life expectancy ≥3 months. 7. Participant has adequate organ function: creatinine clearance ≥30 mL/min (Cockcroft-Gault); indirect (unconjugated) bilirubin ≤1.5 times the upper limit of normal (ULN) (unless related to Gilbert's syndrome, in which case the indirect bilirubin levels must be \<3×ULN for inclusion); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤3×ULN. 8. Participant has baseline leukocyte count of \<20×109/L. Hydroxycarbamide use is permitted to meet this criterion. 9. Women of childbearing potential have a negative pregnancy test; participants of childbearing potential (and their partners) agree to use highly effective contraception during treatment and for ≥6 months after last dose. 10. Participant is willing and able to comply with protocol procedures and follow up.
Exclusion criteria
1. 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. 2. 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. 3. Participants with ≥20% blasts in peripheral blood or bone marrow or evidence of myeloid sarcoma (extramedullary AML). 4. 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. 5. Participant has received previous lines of anticancer therapy for MDS (disease-modifying therapy), including HMAs (e.g., azacitidine, decitabine), chemotherapy, or HSCT. Supportive care (e.g., transfusions, growth factors) is permitted. 6. Participant has clinically significant cardiac disease: recent myocardial infarction within 12 months; symptomatic congestive heart failure (New York Heart Association Class III or IV) or left ventricular ejection fraction (LVEF) \<40%; uncontrolled clinically significant arrhythmias; or congenital/familial long-QT syndrome or pre-excitation syndrome. 7. Participant has active, uncontrolled infection requiring IV antimicrobials; known active invasive fungal infection; uncontrolled severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection per local standards. 8. Participant has known active central nervous system (CNS) involvement by myeloid malignancy 9. All prior allo-HSCT within 6 months before Screening; ongoing clinically significant graft versus host disease (GVHD) requiring systemic immunosuppression. 10. Participant has active autoimmune disease requiring systemic therapy or requiring ≥10 mg/day prednisone (or equivalent) within 14 days prior to first dose; topical/inhaled/ophthalmic steroids permitted. (Immune conditions such as type 1 diabetes, controlled thyroid disease, vitiligo, psoriasis, alopecia are not exclusions.) 11. Participant has clinically relevant hepatic disease (e.g., Child-Pugh C) or ALT/AST \>3×ULN and bilirubin exceeding inclusion thresholds (indirect \[unconjugated\] bilirubin \>1.5×ULN \[unless related to Gilbert's syndrome, in which case the indirect bilirubin levels must be \>3×ULN\]); persistent chronic ulcers with high risk of infection per investigator's assessment. 12. Participant has received recent non-MDS related anticancer therapy or investigational agents within drug-specified washout periods (e.g., \<21 days from last IV/SC cytotoxic, \<14 days or \<5 half-lives for small-molecule therapy, \<4 weeks for other immunotherapies). 13. Participant has a history of another malignancy that is active, progressing, or has required systemic treatment within the past 2 years of screening, excluding non-melanoma skin cancer, carcinoma in situ treated with curative intent. 14. Participant has known uncontrolled human immunodeficiency virus, active hepatitis B virus, or hepatitis C virus with high-level viremia; participants with controlled viral infections on stable therapy may be eligible per local guidance. 15. Participant is pregnant or lactating. 16. Participant has prior exposure to bexmarilimab. 17. Participant has any condition, including psychiatric or substance-use disorder, that in the investigator's judgment would compromise informed consent, compliance, or interpretation of trial results. 18. Participant has a history of hypersensitivity to compounds related to immunotherapy or to any of their excipients. 19. Participant has undergone major surgery within 4 weeks of Cycle 1 Day 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose selection utility score 3-months from last participant enrollment utilising efficacy and safety components. | 3 months from last participant enrollment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission (CR) and Complete Remission Equivalent (CReq) | 36 months from enrollment | 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 | 36 months from enrollment | cCR as defined by the IWG2023 at any point through participant treatment |
| Overall Response Rate (ORR) | 36 months from enrollment | ORR as defined by IWG2006 response criteria and IWG2023 criteria |
| Overall Survival (OS) | 36 months from enrollment | OS is defined as the number of months measured from the date of enrollment to the date of death from any cause. |
| Event Free Survival (EFS) | 36 months from enrollment | EFS will be defined as the number of days from the date of enrollment to the date of earliest evidence of disease progression, transformation to AML, or death from any cause |
| Complete Remission (CR) defined by IWG2006 | 36 months from enrollment | CR as defined by the IWG2006 at any point through participant treatment |
| Reporting of frequency and severity of adverse events (AEs), serious adverse events (SAE) and laboratory abnormalities | 36 months from enrollment | Reporting of the number of participants and severity of AEs, SAEs and laboratory abnormalities using NCI-CTCAE v5.0 grading |
| Time to response | 36 months from enrollment | Time to response will be defined as the number of days from the date of enrollment to the first treatment response. |
| Duration of Response (DOR) | 36 months from enrollment | DOR will be defined as the number of days from the date of first documented response to the earliest evidence of relapse or death. |
| Percentage of Participants Achieving Transfusion Independence (TI) Who are Transfusion Dependent (TD) at Baseline | 36 months from enrollment | TD at baseline is defined as receipt of three or more RBC units or platelet transfusions within ≥56 days prior to the start of study treatment. TI is defined as the absence of RBC and platelet transfusions for ≥56 days in an observation period of 8-24 weeks with the same transfusion policy compared to within 8 weeks prior to treatment. |
| Time to transformation to AML | 36 months from enrollment | The time to transformation to AML is defined as the number of days from the date of enrollment until the date of documented AML transformation, defined as a bone marrow blast count ≥20% independent of baseline bone marrow count. Patients who do not transform to AML are censored at the date of last follow-up or date of death. |
| Rate of Allogeneic hematopoietic stem cell transplantation (allo-HSCT) | 36 months from enrollment | The rate of allogeneic HSCT will be assessed as the proportion of participants who proceed to transplant after enrollment. |
| Number of infections and hospitalizations | 36 months from enrollment | Frequency of infections and participant hospitalization |
| To characterize the pharmacokinetic (PK) profile of bexmarilimab plus azacitidine at two bexmarilimab doses | 36 months from enrollment | Bexmarilimab concentration in serum and PK parameters |
| To characterize the immunogenicity profile of bexmarilimab plus azacitidine at two bexmarilimab doses | 36 months from enrollment | Anti-bexmarilimab antibody detection levels across different treatment arms |
| To characterize the pharmacodynamic (PD) profile of bexmarilimab plus azacitidine at two bexmarilimab doses | 36 months from enrollment | Free soluble Clever-1 (PD marker) detection in bone marrow and blood. Levels compared against different treatment arms |
Contacts
CONTACTJoab Williamson, PhD
CONTACTPetri Bono, MD, PhD
Outcome results
None listed