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

Phase 2

Completed

• Conditions: Myelodysplastic Syndromes
• Interventions: Drug: MBG453; Drug: Placebo; Drug: Hypomethylating agents

• Registration Number: NCT03946670
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2019-05-08
• Study First Submitted QC: 2019-05-09
• Study First Posted: 2019-05-13
• Study Start: 2019-06-04
• Primary Completion: 2022-04-26
• Results First Submitted: 2023-04-24
• Results First Submitted QC: 2023-07-06
• Results First Posted: 2023-07-07
• Study Completion: 2024-07-15
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-10
• Last Update Posted: 2024-12-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 127

Inclusion Criteria

1. Signed informed consent must be obtained prior to participation in the study.

2. Age ≥ 18 years at the date of signing the informed consent form (ICF)

3. 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

4. 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

5. 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.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

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Exclusion Criteria

1. 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.
2. 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.
3. History of severe hypersensitivity reactions to any ingredient of the study treatment (azacitidine, decitabine or MGB453) or their excipients, or to monoclonal antibodies (mAbs).
4. 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.
5. 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.
6. Active autoimmune disease requiring systemic therapy (e.g.corticosteroids).
7. Live vaccine administered within 30 Days prior to randomization.

Other protocol-defined Inclusion/Exclusion may apply.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MBG453 + hypomethylating agents	MBG453	Patients are taking MBG453 plus hypomethylating agents
MBG453 + hypomethylating agents	Hypomethylating agents	Patients are taking MBG453 plus hypomethylating agents
Placebo + hypomethylating agents	Placebo	Patients are taking placebo plus hypomethylating agents
Placebo + hypomethylating agents	Hypomethylating agents	Patients are taking placebo plus hypomethylating agents

Primary Outcome Measures

Name	Time	Method
Complete Remission (CR) Rate	average of 7 months	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.
Progression Free Survival (PFS)	approximately 32 months	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

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Up to 4 years after LPFV	Time from randomization to death due to any cause
Event Free Survival	Up to 4 years after LPFV	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
Leukemia-free Survival	Up to 4 yrs after Last Patient First Visit (LPFV)	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
Response Rate (CR/mCR/PR/HI)	7 months after Last Patient First Visit (LPFV)	Percentage of complete remission(CR)/marrow Complete Remission (mCR)/partial remission (PR) and Hematological improvement (HI) according to IWG-MDS as per investigator assessment
Duration of Complete Remission	Up to 4 yrs after Last Patient First Visit (LPFV)	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 to Complete Remission	7 months after Last Patient First Visit (LPFV)	Time from randomization to the first documented CR
Immunogenicity of MBG453 When Given in Combination of Hypomethylating Agents	Up to 4 years after Last Patient First Visit (LPFV)	Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment
Percent of Subjects Who Are Red Blood Cells (RBC)/Platelets Transfusion Independent After Randomization as Per IWG-MDS	Up to 4 years after last randomized patient	Improvement in RBC/platelets transfusion independence
Red Blood Cells (RBC)/Platelets Transfusion Independence Duration After Randomization	Up to 4 years after last randomized patient	Duration of transfusion independence
Serum Concentrations for MBG453	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	Pharmacokinetics of MBG453 when given in combination with hypomethylating agents (HMA)

Trial Locations

Locations (7)

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

The Cancer Institute of New Jersey; 🇺🇸 New Brunswick, New Jersey, United States

Mary Crowley Cancer Research; 🇺🇸 Dallas, Texas, United States

Novartis Investigative Site; 🇬🇧 Manchester, United Kingdom

Ohio State Comprehensive Cancer Center James Cancer Hospital; 🇺🇸 Columbus, Ohio, 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