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

Myelodysplastic Syndromes Clinical Trial

— STIMULUS-MDS1  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03946670
• Other study ID #: CMBG453B12201
• Secondary ID: 2018-004479-11
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 4, 2019
• Est. completion date: July 18, 2024

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 127
• Est. completion date: July 18, 2024
• Est. primary completion date: April 26, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

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.

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• MBG453
MBG453 is being administered i.v.
• Placebo
Placebo is being administered i.v.
• Hypomethylating agents
Decitabine is being administered i.v. Azacitidine is being administered i.v or s.c.

Locations

Country	Name	City	State
Austria	Novartis Investigative Site	Vienna
Belgium	Novartis Investigative Site	Brasschaat
Belgium	Novartis Investigative Site	Leuven
Canada	Novartis Investigative Site	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Czechia	Novartis Investigative Site	Brno - Bohunice
Czechia	Novartis Investigative Site	Praha
France	Novartis Investigative Site	Toulouse
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Leipzig
Greece	Novartis Investigative Site	Alexandroupolis	Evros
Greece	Novartis Investigative Site	Larissa	GR
Greece	Novartis Investigative Site	Patras
Hong Kong	Novartis Investigative Site	Hong Kong
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Nyiregyhaza
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Reggio Calabria	RC
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Rozzano	MI
Japan	Novartis Investigative Site	Bunkyo ku	Tokyo
Japan	Novartis Investigative Site	Fukuoka city	Fukuoka
Japan	Novartis Investigative Site	Fukushima city	Fukushima
Japan	Novartis Investigative Site	Gifu shi	Gifu
Japan	Novartis Investigative Site	Isehara	Kanagawa
Japan	Novartis Investigative Site	Kumamoto-city	Kumamoto
Japan	Novartis Investigative Site	Nagasaki-city	Nagasaki
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Sendai-shi	Miyagi
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Spain	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Santander	Cantabria
Taiwan	Novartis Investigative Site	Kaohsiung
Taiwan	Novartis Investigative Site	Taipei
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Kocaeli
Turkey	Novartis Investigative Site	Samsun
United Kingdom	Novartis Investigative Site	Manchester
United States	Dana Farber Cancer Institute Centerfor Sarcoma&BoneOncology	Boston	Massachusetts
United States	Ohio State Comprehensive Cancer Center/James Cancer Hospital SC BCL201X2102C	Columbus	Ohio
United States	Mary Crowley Cancer Research	Dallas	Texas
United States	City of Hope National Medical Center Medical Oncology & Therapeutic	Duarte	California
United States	The Cancer Institute of New Jersey The Cancer Institute of NJ	New Brunswick	New Jersey
United States	Yale University School Of Medicine	New Haven	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  Czechia,  France,  Germany,  Greece,  Hong Kong,  Hungary,  Italy,  Japan,  Korea, Republic of,  Spain,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Overall Survival	Time from randomization to death due to any cause	Up to 4 years after LPFV
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Time to Complete Remission	Time from randomization to the first documented CR	7 months after Last Patient First Visit (LPFV)
Secondary	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
Secondary	Red Blood Cells (RBC)/Platelets Transfusion Independence Duration After Randomization	Duration of transfusion independence	Up to 4 years after last randomized patient
Secondary	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
Secondary	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)