A Study of MBG453 in Combination With Hypomethylating Agents in Subjects With IPSS-R Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS).

Study Overview
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Brief Summary
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This Phase II is a multicenter, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to hypomethylating agents (azacitidine or decitabine) in adult subjects with IPSS-R intermediate, high or very high risk myelodysplastic syndrome (MDS) not eligible for Hematopoietic Stem Cell Transplant (HSCT) or intensive chemotherapy.

Detailed Description
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The 2 primary objectives are as follows: To determine if MBG453 combined with standard HMA therapy improves complete remission in subjects with intermediate, high, or very high risk MDS. To determine if MBG453 combined with standard HMA therapy improves progression free survival (PFS) in subjects with intermediate, high or very high risk MDS. This Phase II is a multicenter, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to hypomethylating agents (azacitidine or decitabine, as per investigators' choice based on local standard of care (SOC)) in adult subjects with IPSS-R intermediate, high or very high risk MDS not eligible for HSCT or intensive chemotherapy. A total of 127 subjects were randomized in a 1:1 ratio to treatment arms as follows: MBG453 400 mg IV Q2W and decitabine or azacitidine Placebo IV Q2W and decitabine or azacitidine The randomization was stratified by 2 stratification factors: a) HMA (decitabine or azacitidine) selected by the investigator as per the local SOC and b) IPSS-R prognostic risk categories (intermediate, high or very high) at randomization. Crossover between treatment arms was not permitted at any time during the study.

Official Title
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A Randomized, Double-blind, Placebo-controlled Phase II Multi-center Study of Intravenous MBG453 Added to Hypomethylating Agents in Adult Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R Criteria

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: MBG453
* Drug: Placebo
* Drug: Hypomethylating agents


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. Age ≥ 18 years at the date of signing the informed consent form (ICF) Morphologically confirmed diagnosis of a myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) by investigator assessment with one of the following Prognostic Risk Categories, based on the International Prognostic Scoring System (IPSS-R): Very high High Intermediate with at least ≥ 5% bone marrow blast Not eligible at the time of screening, for intensive chemotherapy according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions Not eligible at the time of screening, for hematopoietic stem-cell transplantation (HSCT) according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 Exclusion Criteria: Prior exposure to TIM-3 directed therapy at any time. Prior therapy with immune check point inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer vaccines are allowed except if the drug was administered within 4 months prior to randomization. Previous first-line treatment for higher risk MDS with chemotherapy or any other antineoplastic agents including lenalidomide and hypomethylating agent (HMAs) such as decitabine or azacitidine. History of severe hypersensitivity reactions to any ingredient of the study treatment (azacitidine, decitabine or MGB453) or their excipients, or to monoclonal antibodies (mAbs). Currently using or used within 14 days prior to randomization of systemic, steroid therapy (> 10 mg/day prednisone or equivalent) or any immunosuppressive therapy. Topical, inhaled, nasal, ophthalmic steroids are allowed. Replacement therapy, steroids given in the context of a transfusion are allowed and not considered a form of systemic treatment. Investigational treatment for MDS received within 4 weeks prior to randomization. In case of a checkpoint inhibitor: 4 months minimum prior to randomization interval is necessary to allow enrollment. Active autoimmune disease requiring systemic therapy (e.g.corticosteroids). Live vaccine administered within 30 Days prior to randomization. Other protocol-defined Inclusion/Exclusion may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MBG453 + hypomethylating agents<br>Patients are taking MBG453 plus hypomethylating agents | Drug: MBG453<br>* MBG453 is being administered i.v.<br>* Other names: Sabatolimab;Drug: Hypomethylating agents<br>* Decitabine is being administered i.v. Azacitidine is being administered i.v or s.c.<br>|
| Placebo Comparator: Placebo + hypomethylating agents<br>Patients are taking placebo plus hypomethylating agents | Drug: Placebo<br>* Placebo is being administered i.v.<br>Drug: Hypomethylating agents<br>* Decitabine is being administered i.v. Azacitidine is being administered i.v or s.c.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Remission (CR) Rate | CR: where the Bone marrow: ≤ 5% blasts with normal maturation of all cell lineages and Peripheral blood: where Hgb ≥ 10 g/dL AND Platelets ≥ 100*109/L AND Neutrophils ≥ 1.0*109/L AND Peripheral blasts 0%. Modified response criteria According to International Working Group (IWG) and as per World Health Organization (WHO) criteria for Myelodysplastic syndromes (MDS) as per investigator assessment. | average of 7 months | 
| Progression Free Survival (PFS) | Defined as time from randomization to disease progression (including transformation to acute leukemia per WHO 2016 classification), relapse from CR according to IWG-MDS or death due to any cause, whichever occurs first, as per investigator assessment | approximately 32 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from randomization to death due to any cause | Up to 4 years after LPFV | 
| Event Free Survival | Time from randomization to lack of reaching CR within the first 6 months, relapse from CR or death due to any cause, whichever occurs first | Up to 4 years after LPFV | 
| Leukemia-free Survival | Time from randomization to ≥ 20% blasts in bone marrow/peripheral blood (per WHO 2016 classification) or diagnosis of extramedullary acute leukemia or death due to any cause | Up to 4 yrs after Last Patient First Visit (LPFV) | 
| Response Rate (CR/mCR/PR/HI) | Percentage of complete remission(CR)/marrow Complete Remission (mCR)/partial remission (PR) and Hematological improvement (HI) according to IWG-MDS as per investigator assessment | 7 months after Last Patient First Visit (LPFV) | 
| Duration of Complete Remission | Time from the date of the first documented CR to the date of first documented relapse from CR or death due to any cause, whichever occurs first | Up to 4 yrs after Last Patient First Visit (LPFV) | 
| Time to Complete Remission | Time from randomization to the first documented CR | 7 months after Last Patient First Visit (LPFV) | 
| Percent of Subjects Who Are Red Blood Cells (RBC)/Platelets Transfusion Independent After Randomization as Per IWG-MDS | Improvement in RBC/platelets transfusion independence | Up to 4 years after last randomized patient | 
| Red Blood Cells (RBC)/Platelets Transfusion Independence Duration After Randomization | Duration of transfusion independence | Up to 4 years after last randomized patient | 
| Serum Concentrations for MBG453 | Pharmacokinetics of MBG453 when given in combination with hypomethylating agents (HMA) | At Day 8 of each cycle (1 cycle = 28 days) until cycle 6 and at day 8 of cycles 9, 12, 18 and 24, and up to 150 day of the safety follow up period | 
| Immunogenicity of MBG453 When Given in Combination of Hypomethylating Agents | Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment | Up to 4 years after Last Patient First Visit (LPFV) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sabatolimab, Placebo, Phase II, MBG453, TIM-3, decitabine, azacitidine, myelodysplastic syndrome (MDS)