Study of Efficacy and Safety of MBG453 in Combination With Azacitidine in Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2)

NCT ID: NCT04266301

Last Updated: 2026-01-13

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 530 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-06-08
• Study Completion Date: 2024-10-02

Brief Summary

This was a Phase III multi-center, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to azacitidine in adult participants with intermediate, high or very high-risk myelodysplastic syndrome (MDS) as per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2) who are not eligible for intensive chemotherapy or hematopoietic stem cell transplantation (HSCT) according to medical judgment by the investigator.

The purpose of the current study was to assess clinical effects of MBG453 in combination with azacytidine in adult participants with IPSS-R intermediate, high, very high risk MDS and CMML-2.

Detailed Description

This was a Phase III multi-center, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to azacitidine in adult participants with intermediate, high or very high-risk myelodysplastic syndrome (MDS) as per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2).

The primary objective of this study was to compare overall survival (OS) in the MBG453 plus azacitidine arm versus placebo plus azacitidine arm where OS was the time from randomization until death due to any cause.

Participants were randomized in a 1:1 ratio to treatment arms as follow: MBG453 800 mg IV Q4W plus azacitidine, Placebo IV Q4W plus azacitidine.

The randomization was stratified into 4 groups: intermediate risk MDS, high risk MDS, very high risk MDS and CMML-2.

All participants who discontinued both study treatments were to have entered a long-term post-treatment follow-up including response and PRO assessments, and/or survival follow-up for up to 5 years after the last participant was randomized.

Participants were receiving treatment until they experienced progression of disease (including transformation to acute leukemia per WHO 2016 classification), experienced unacceptable toxicity or discontinued the study treatment for other reasons.

Continuation of study treatment beyond progression (excluding transformation to acute leukemia: continuation in this case was not possible) could have been possible in selected participants.

Conditions

Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Sabatolimab (MBG453) + Azacitidine

Participants received sabatolimab plus Azacitidine

Group Type: EXPERIMENTAL

Sabatolimab

Intervention Type: DRUG

A dose of MBG453 800 mg was administered intravenously (IV) every 4 weeks (Q4W).

Azacitidine

Intervention Type: DRUG

A dose of Azacitidine 75 mg/m2 was administered IV or subcutaneously (SC) on Day 1-7, or Day 1-5, 8 and 9.

Placebo + Azacitidine

Participants received placebo plus Azacitidine.

Group Type: PLACEBO_COMPARATOR

Azacitidine

Intervention Type: DRUG

A dose of Azacitidine 75 mg/m2 was administered IV or subcutaneously (SC) on Day 1-7, or Day 1-5, 8 and 9.

Placebo

Intervention Type: DRUG

A dose of placebo 800 mg was administered intravenously every 4 weeks (Q4W).

Interventions

Sabatolimab

A dose of MBG453 800 mg was administered intravenously (IV) every 4 weeks (Q4W).

Intervention Type: DRUG

Azacitidine

A dose of Azacitidine 75 mg/m2 was administered IV or subcutaneously (SC) on Day 1-7, or Day 1-5, 8 and 9.

Intervention Type: DRUG

Placebo

A dose of placebo 800 mg was administered intravenously every 4 weeks (Q4W).

Intervention Type: DRUG

Other Intervention Names

MBG453

Eligibility Criteria

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
• Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) based on WHO 2016 classification (Arber et al 2016) by local investigator assessment with one of the following Prognostic Risk Categories, based on the revised International Prognostic Scoring System (IPSS-R):

• Very high (> 6 points)
• High (> 4.5 - ≤ 6 points)
• Intermediate (> 3 - ≤ 4.5 points) Or Morphologically confirmed diagnosis of Chronic Myelomonocytic Leukemia -2 based on WHO 2016 classification (Arber et al 2016, including persistent monocytosis) by local investigator assessment with WBC < 13 x 109/L at time of initial diagnosis
• Indication for azacitidine treatment according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions
• Not eligible at time of screening for intensive chemotherapy according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions, including assessment of individual clinical factors such as age, comorbidities and performance status
• Not eligible at 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, including assessment of individual clinical factors such as age, comorbidities, performance status, and donor availability
• 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 checkpoint inhibitors (e.g, anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer vaccines is allowed except if the drug was administered within 4 months prior to randomization
• Previous first-line treatment for intermediate, high, very high risk myelodysplastic syndromes (based on IPSS-R) or CMML with any antineoplastic agents including for example chemotherapy, lenalidomide and hypomethylating agents (HMAs) such as decitibine and azacitidine. However, previous treatment with hydroxyurea or leukopheresis to reduce WBC count is allowed prior to randomization.
• Investigational treatment received within 4 weeks or 5 half-lives of this investigational treatment, whatever is longer, prior to randomization. In case of a checkpoint inhibitor: a minimal interval of 4 months prior to randomization is necessary to allow randomization.
• Subjects with Myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 3
• Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and extra-medullary acute myeloid leukemia, primary or secondary myelofibrosis based on WHO 2016 classification (Arber et al 2016)
• Diagnosis of therapy related myeloid neoplasms based on WHO 2016 classification (Arber et al 2016)
• History of organ or allogeneic hematopoietic stem cell transplant

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Yuma Regional Cancer Center

Yuma, Arizona, United States

University of California LA

Los Angeles, California, United States

Yale University School Of Medicine

New Haven, Connecticut, United States

Mayo Clinic Jacksonville

Jacksonville, Florida, United States

University Of Miami

Miami, Florida, United States

Northwestern University

Chicago, Illinois, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Hackensack University Medical Ctr

Hackensack, New Jersey, United States

Weill Cornell Medicine NY-Presb

New York, New York, United States

University of Rochester Medical Ctr

Rochester, New York, United States

University of Virginia

Charlottesville, Virginia, United States

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Pilar, Buenos Aires, Argentina

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Wooloongabba, Queensland, Australia

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Clayton, Victoria, Australia

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Perth, Western Australia, Australia

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Innsbruck, Tyrol, Austria

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Graz, , Austria

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Linz, , Austria

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Roeselare, West-Vlaanderen, Belgium

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Brasschaat, , Belgium

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Florianópolis, Santa Catarina, Brazil

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São Paulo, São Paulo, Brazil

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São Paulo, São Paulo, Brazil

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Calgary, Alberta, Canada

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Toronto, Ontario, Canada

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Viña del Mar, Región de Valparaíso, Chile

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Guangzhou, Guangdong, China

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Guangzhou, Guangdong, China

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Shenzhen, Guangdong, China

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Wuhan, Hubei, China

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Wuhan, Hubei, China

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Suzhou, Jiangsu, China

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Changchun, Jilin, China

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Chengdu, Sichuan, China

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Hangzhou, Zhejiang, China

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Beijing, , China

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Beijing, , China

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Jinan, , China

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Shanghai, , China

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Shanghai, , China

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Tianjin, , China

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Tianjin, , China

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Rionegro, Antioquia, Colombia

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Bogotá, , Colombia

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Brno, , Czechia

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Hradec Králové, , Czechia

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Prague, , Czechia

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Prague, , Czechia

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Helsinki, , Finland

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Kuopio, , Finland

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Grenoble, , France

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Lille, , France

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Paris, , France

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Toulouse, , France

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Tours, , France

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Vandœuvre-lès-Nancy, , France

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Frankfurt am Main, Hesse, Germany

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Velbert, North Rhine-Westphalia, Germany

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Dresden, Saxony, Germany

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Jena, Thuringia, Germany

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Augsburg, , Germany

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Düsseldorf, , Germany

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Greifswald, , Germany

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Kiel, , Germany

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Ulm, , Germany

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Alexandroupoli, , Greece

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Pátrai, , Greece

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Ahmedabad, Gujarat, India

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Faridabad, Haryana, India

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Madurai, Tamil Nadu, India

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Kolkata, West Bengal, India

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Kolkata, West Bengal, India

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Delhi, , India

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Afula, , Israel

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Tel Aviv, , Israel

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Bologna, BO, Italy

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Catania, CT, Italy

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Florence, FI, Italy

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Genova, GE, Italy

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Milan, MI, Italy

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Rozzano, MI, Italy

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Reggio Calabria, RC, Italy

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Roma, RM, Italy

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Nagoya, Aichi-ken, Japan

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Kashiwa, Chiba, Japan

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Fukuoka, Fukuoka, Japan

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Sapporo, Hokkaido, Japan

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Isehara, Kanagawa, Japan

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Sendai, Miyagi, Japan

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Nagasaki, Nagasaki, Japan

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Sakai, Osaka, Japan

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Bunkyo-ku, Tokyo, Japan

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Yamagata, Yamagata, Japan

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Osaka, , Japan

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Beirut, , Lebanon

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Vilnius, , Lithuania

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George Town, Pulau Pinang, Malaysia

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Kuching, Sarawak, Malaysia

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Kuala Lumpur, , Malaysia

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Kuala Selangor, , Malaysia

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Satélite, Edo Mexico, Mexico

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Mexico City, Mexico City, Mexico

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Morelia, Michoacán, Mexico

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Estado de México, , Mexico

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Groningen, Provincie Groningen, Netherlands

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Khoudh, , Oman

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Lisbon, , Portugal

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Porto, , Portugal

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Saint Petersburg, , Russia

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Saint Petersburg, , Russia

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Riyadh, , Saudi Arabia

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Singapore, , Singapore

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Singapore, , Singapore

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Seoul, Korea, South Korea

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Seoul, Seoul, South Korea

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Seoul, , South Korea

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Seoul, , South Korea

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Seoul, , South Korea

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Badalona, Barcelona, Spain

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Salamanca, Castille and León, Spain

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Barcelona, Catalonia, Spain

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Oviedo, Principality of Asturias, Spain

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Madrid, , Spain

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Seville, , Spain

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Valencia, , Spain

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Valencia, , Spain

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Bern, , Switzerland

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Zurich, , Switzerland

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Hualien City, , Taiwan

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Kaohsiung City, , Taiwan

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Liouying Township, , Taiwan

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Taichung, , Taiwan

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Taipei, , Taiwan

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Taoyuan District, , Taiwan

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Songkhla, Hat Yai, Thailand

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Khon Kaen, THA, Thailand

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Bangkok, , Thailand

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Chiang Mai, , Thailand

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Samsun, Atakum, Turkey (Türkiye)

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Edirne, Merkez, Turkey (Türkiye)

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Istanbul, Pendik, Turkey (Türkiye)

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Ankara, , Turkey (Türkiye)

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Izmir, , Turkey (Türkiye)

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Portsmouth, Hants, United Kingdom

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Edinburgh, Scotland, United Kingdom

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Manchester, , United Kingdom

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Nottingham, , United Kingdom

Countries

United States; Argentina; Australia; Austria; Belgium; Brazil; Canada; Chile; China; Colombia; Czechia; Finland; France; Germany; Greece; India; Israel; Italy; Japan; Lebanon; Lithuania; Malaysia; Mexico; Netherlands; Oman; Portugal; Russia; Saudi Arabia; Singapore; South Korea; Spain; Switzerland; Taiwan; Thailand; Turkey (Türkiye); United Kingdom

References

Zeidan AM, Giagounidis A, Sekeres MA, Xiao Z, Sanz GF, Hoef MV, Ma F, Hertle S, Santini V. STIMULUS-MDS2 design and rationale: a phase III trial with the anti-TIM-3 sabatolimab (MBG453) + azacitidine in higher risk MDS and CMML-2. Future Oncol. 2023 Mar;19(9):631-642. doi: 10.2217/fon-2022-1237. Epub 2023 Apr 21.

Reference Type: DERIVED

PMID: 37083373 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=2874

A Plain Language Trial Summary is available on www.novctrd.com

Other Identifiers

2019-002089-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CMBG453B12301

Identifier Type: -

Identifier Source: org_study_id