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

Phase 2TerminatedNCT03946670

Novartis Pharmaceuticals127 enrolled

Overview

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

Conditions

Myelodysplastic Syndromes

Interventions

MBG453DRUG

MBG453 is being administered i.v.

PlaceboDRUG

Placebo is being administered i.v.

Hypomethylating agentsDRUG

Decitabine is being administered i.v. Azacitidine is being administered i.v or s.c.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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.

Locations (48)

Outcomes

Primary Outcomes

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

Secondary Outcomes

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.

Data from ClinicalTrials.gov

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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

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