This Phase II was 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.
The 2 primary objectives were as follows: To determine if MBG453 combined with standard HMA therapy improved complete remission in subjects with intermediate, high, or very high risk MDS. To determine if MBG453 combined with standard HMA therapy improved progression free survival (PFS) in subjects with intermediate, high or very high risk MDS. This Phase II study was 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
127
City Of Hope National Med Center
Duarte, California, United States
City of Hope National Medical Center Medical Oncology & Therapeutic
Duarte, California, United States
Yale University School Of Medicine
New Haven, Connecticut, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
The Cancer Institute of New Jersey
New Brunswick, New Jersey, United States
Ohio State Comprehensive Cancer Center James Cancer Hospital
Columbus, Ohio, United States
Mary Crowley Cancer Research
Dallas, Texas, United States
Novartis Investigative Site
Vienna, Austria
Novartis Investigative Site
Brasschaat, Belgium
Novartis Investigative Site
Leuven, Belgium
...and 38 more locations
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.
Time frame: average of 7 months
Progression Free Survival (PFS)
PFS is 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.
Time frame: approx. 32 months
Progression Free Survival (PFS) - Final PFS
PFS isdefined 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. This is an update of the Primary Outcome Measure PFS with data collected after assessment of the primary results.
Time frame: approx. 48 months
Overall Survival (OS)
Time from randomization to death due to any cause
Time frame: approx. 48 months
Event-free Survival (EFS)
EFS is defined as the time from randomization to lack of reaching complete response (CR) within the first 6 months, relapse from CR or death due to any cause, whichever occurs first. CR and relapse from CR were defined according to International Working Group (IWG) for Myelodysplastic Syndromes (MDS) as per Investigator assessment. For participants not reaching CR within the first 6 months, an EFS event at day 1 was considered.
Time frame: approx. 48 months
Leukemia-free Survival (LFS)
LFS is defined as the time from randomization to ≥ 20% blasts in bone marrow/peripheral blood (per World Health Organization (WHO) 2016 classification) or diagnosis of extramedullary acute leukemia or death due to any cause.
Time frame: approx. 48 months
Response Rate of Complete Remission (CR)/Marrow Complete Remission (mCR)/Partial Remission (PR)/Hematopoietic Improvement (HI))
Percentage of complete remission (CR)/marrow Complete Remission (mCR)/partial remission (PR) \& Hematological improvement (HI) as per investigator assessment according to IWG-MDS. 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%. mCR: where the Bone marrow ≤5% blasts and blast count decrease by ≥50% compared to baseline with or without improved blood counts or with or without transfusions. PR: All CR criteria except bone marrow: ≥50% decrease from baseline in blasts in bone marrow AND blast count in bone marrow \>5%. HI: restoration or enhancement of the function of the body's blood cell-producing system that must last as least 8 weeks. HI definition is based on modified Hematological Improvement per IWG-MDS criteria in MDS \& is the combination of Erythroid response (HI-E), Platelet response (HI-P) \& Neutrophil response (HI-N).
Time frame: approx. 32 months
Duration of Complete Remission
Duration of complete response is the 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.
Time frame: approx. 48 months
Time to Complete Remission
Time from randomization to the first documented CR
Time frame: Average of 7 months
Percent of Participants Who Are Red Blood Cells (RBC)/Platelets Transfusion Independent After Randomization as Per IWG-MDS
Improvement in RBC/platelets transfusion independence. RBC/platelets transfusion independence rate is defined as the percentage of participants having received no RBC/platelets transfusions during at least 8 consecutive weeks after randomization.
Time frame: approx. 48 months
Red Blood Cells (RBC) Transfusion Independence Duration After Randomization
The total duration of all transfusion independence periods is the sum of each period of the transfusion independence. RBC transfusions independence period is defined as the period for which participants having received no RBC transfusions during at least 8 consecutive weeks after randomization.
Time frame: approx. 48 months
Platelets Transfusion Independence Duration After Randomization
The total duration of all transfusion independence periods is the sum of each period of the transfusion independence. Platelets transfusions independence period is defined as the period for which participants having received no platelets transfusions during at least 8 consecutive weeks after randomization.
Time frame: approx. 48 months
Serum Concentrations for MBG453
Pharmacokinetics (PK) of MBG453 when given in combination with hypomethylating agents (HMA)
Time frame: 0hr pre-dose on Day 8 of each cycle until cycle 6 and on Day 8 of cycles 9, 12, 18 and 24, 2hr post-dose on Day 8 of C1 and C3, EOT (approx. 48 months) and up to 150 day of the safety follow up period; 1 cycle = 28 days
Immunogenicity (IG) of MBG453 When Given in Combination of Hypomethylating Agents: ADA Prevalence
Number of participants with at least one sample meeting the criteria at baseline. Anti-drug Antibody (ADA) prevalence equals ADA-positive at baseline.
Time frame: at baseline
Immunogenicity of MBG453 When Given in Combination of Hypomethylating Agents: ADA-positive Participants
Anti-drug Antibody (ADA) positive participants on-treatment was calculated as the number of participants with at least 1 on-treatment ADA-positive sample divided by the number of participants with a determinant baseline IG sample and at least one determinant post-baseline IG sample.
Time frame: approx. 48 months
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