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)

Myelodysplastic Syndromes Clinical Trial

— STIMULUS-MDS2  

Official title:

A Randomized, Double-blind, Placebo-controlled Phase III Multi-center Study of Azacitidine With or Without MBG453 for the Treatment of Patients With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04266301
• Other study ID #: CMBG453B12301
• Secondary ID: 2019-002089-11
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: April 14, 2013
• Est. completion date: September 17, 2024

Study information

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

Clinical Trial Summary

This is a Phase III multi-center, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to azacitidine in adult subjects 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 is to assess clinical effects of MBG453 in combination with azacitidine in adult subjects with IPSS-R intermediate, high, very high risk MDS and CMML-2.

Description:

This is a Phase III multi-center, randomized, two-arm parallel-group, double-blind, placebo controlled study of MBG453 or placebo added to azacitidine in adult subjects 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 is to compare overall survival (OS) in the MBG453 plus azacitidine arm versus placebo plus azacitidine arm where OS is the time from randomization until death due to any cause.

Subjects will be randomized in a 1:1 ratio to treatment arms as follow: MBG453 800 mg IV Q4W plus azacytidine, Placebo IV Q4W plus azacitidine The randomization will be stratified into 4 groups: intermediate risk MDS, high risk MDS, very high risk MDS and CMML-2.

All subjects who discontinue both study treatments will enter 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 subject was randomized.

Subjects will be treated until they experience progression of disease (including transformation to acute leukemia per WHO 2016 classification), experience unacceptable toxicity or discontinue the study treatment for other reasons.

Continuation of study treatment beyond progression (excluding transformation to acute leukemia: continuation in this case is not possible) may be possible in selected subjects.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 530
• Est. completion date: September 17, 2024
• Est. primary completion date: September 17, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Other protocol-defined Inclusion/Exclusion Criteria may apply.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Sabatolimab
A dose of MBG453 800 mg will be administered intravenously (IV) every 4 weeks (Q4W).
• Azacitidine
A dose of Azacitidine 75 mg/m2 will be administered IV or subcutaneously (SC) on Day 1-7, or Day 1-5, 8 and 9.
• Placebo
A dose of Placebo 800 mg will be administered intravenously every 4 weeks (Q4W).

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Pilar	Buenos Aires
Australia	Novartis Investigative Site	Clayton	Victoria
Australia	Novartis Investigative Site	Perth	Western Australia
Australia	Novartis Investigative Site	Woolloongabba	Queensland
Austria	Novartis Investigative Site	Graz
Austria	Novartis Investigative Site	Innsbruck
Austria	Novartis Investigative Site	Linz
Belgium	Novartis Investigative Site	Brasschaat
Belgium	Novartis Investigative Site	Roeselare
Brazil	Novartis Investigative Site	Florianopolis	SC
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	Sao Paulo	SP
Canada	Novartis Investigative Site	Calgary	Alberta
Canada	Novartis Investigative Site	Toronto	Ontario
Chile	Novartis Investigative Site	Vina del Mar	Valparaiso
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Chang Chun	Jilin
China	Novartis Investigative Site	Chengdu
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Hangzhou	Zhejiang
China	Novartis Investigative Site	Jinan
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Shenzhen	Guangdong
China	Novartis Investigative Site	Suzhou	Jiangsu
China	Novartis Investigative Site	Tianjin
China	Novartis Investigative Site	Tianjin
China	Novartis Investigative Site	Wuhan	Hubei
China	Novartis Investigative Site	Wuhan	Hubei
Colombia	Novartis Investigative Site	Bogota
Colombia	Novartis Investigative Site	Rionegro	Antioquia
Czechia	Novartis Investigative Site	Brno - Bohunice
Czechia	Novartis Investigative Site	Hradec Kralove	CZE
Czechia	Novartis Investigative Site	Praha
Czechia	Novartis Investigative Site	Praha 2	Czech Republic
Finland	Novartis Investigative Site	Helsinki
Finland	Novartis Investigative Site	Kuopio
France	Novartis Investigative Site	Grenoble
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Paris 10
France	Novartis Investigative Site	Toulouse
France	Novartis Investigative Site	Tours
France	Novartis Investigative Site	Vandoeuvre Les Nancy
Germany	Novartis Investigative Site	Augsburg
Germany	Novartis Investigative Site	Dresden	Sachsen
Germany	Novartis Investigative Site	Duesseldorf
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Greifswald
Germany	Novartis Investigative Site	Jena
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Ulm
Germany	Novartis Investigative Site	Velbert	North Rhine-Westphalia
Greece	Novartis Investigative Site	Alexandroupolis	Evros
Greece	Novartis Investigative Site	Patras
India	Novartis Investigative Site	Ahmedabad	Gujrat
India	Novartis Investigative Site	Delhi
India	Novartis Investigative Site	Faridabad	Haryana
India	Novartis Investigative Site	Kolkata	West Bengal
India	Novartis Investigative Site	Kolkata	West Bengal
India	Novartis Investigative Site	Madurai	Tamil NADU
Israel	Novartis Investigative Site	Afula
Israel	Novartis Investigative Site	Tel Aviv
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Catania	CT
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Genova	GE
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	Isehara	Kanagawa
Japan	Novartis Investigative Site	Kashiwa	Chiba
Japan	Novartis Investigative Site	Nagasaki-city	Nagasaki
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Osaka Sayama	Osaka
Japan	Novartis Investigative Site	Sapporo	Hokkaido
Japan	Novartis Investigative Site	Sendai city	Miyagi
Japan	Novartis Investigative Site	Yamagata
Korea, Republic of	Novartis Investigative Site	Seoul	Seocho Gu
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Lebanon	Novartis Investigative Site	Beirut
Lithuania	Novartis Investigative Site	Vilnius
Malaysia	Novartis Investigative Site	Kuala Lumpur
Malaysia	Novartis Investigative Site	Kuching	Sarawak
Malaysia	Novartis Investigative Site	Pulau Pinang
Malaysia	Novartis Investigative Site	Selangor
Mexico	Novartis Investigative Site	Estado de Mexico
Mexico	Novartis Investigative Site	Mexico	Distrito Federal
Mexico	Novartis Investigative Site	Morelia	Michoacan
Mexico	Novartis Investigative Site	Satelite	Edo Mexico
Netherlands	Novartis Investigative Site	Groningen
Oman	Novartis Investigative Site	Muscat
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Porto
Russian Federation	Novartis Investigative Site	Saint Petersburg
Russian Federation	Novartis Investigative Site	St Petersburg
Saudi Arabia	Novartis Investigative Site	Riyadh
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Badalona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Oviedo	Asturias
Spain	Novartis Investigative Site	Salamanca	Castilla Y Leon
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Spain	Novartis Investigative Site	Valencia
Switzerland	Novartis Investigative Site	Bern
Switzerland	Novartis Investigative Site	Zürich
Taiwan	Novartis Investigative Site	Hualien City	Hualien
Taiwan	Novartis Investigative Site	Kaohsiung
Taiwan	Novartis Investigative Site	Liouying Township
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taoyuan
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Chiang Mai
Thailand	Novartis Investigative Site	Khon Kaen	THA
Thailand	Novartis Investigative Site	Songkhla	Hat Yai
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Edirne
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Samsun
United Kingdom	Novartis Investigative Site	Edinburgh
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Nottingham
United Kingdom	Novartis Investigative Site	Portsmouth	Hants
United States	Massachusetts General Hospital .	Boston	Massachusetts
United States	University of Virginia University of Virginia	Charlottesville	Virginia
United States	Northwestern University Div of Hematology Oncology	Chicago	Illinois
United States	Hackensack University Medical Ctr SC	Hackensack	New Jersey
United States	Mayo Clinic Jacksonville .	Jacksonville	Florida
United States	University Of California LA .	Los Angeles	California
United States	University Of Miami .	Miami	Florida
United States	Yale University School Of Medicine Smilow Cancer Hospital	New Haven	Connecticut
United States	Weill Cornell Medicine NY-Presb .	New York	New York
United States	University of Rochester Medical Ctr Univ Rochester JP Wilmot	Rochester	New York
United States	Yuma Regional Cancer Center	Yuma	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Chile,  China,  Colombia,  Czechia,  Finland,  France,  Germany,  Greece,  India,  Israel,  Italy,  Japan,  Korea, Republic of,  Lebanon,  Lithuania,  Malaysia,  Mexico,  Netherlands,  Oman,  Portugal,  Russian Federation,  Saudi Arabia,  Singapore,  Spain,  Switzerland,  Taiwan,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival	Time from randomization until death due to any cause	Up to 5 years after last patient randomized
Secondary	Key secondary endpoint 1: Time to definitive deterioration of fatigue using Functional Assessment of Cancer Therapy (FACIT)-Fatigue score	FACIT-Fatigue score is a 13-item questionnaire designed to assess fatigue in cancer patients. All items use a 5-point scale ranging from 0 to 4 (0=Not at All to 4=Very Much). The total score ranges from 0 to 52 with higher values representing better quality of life. Time from randomization to at least 3 points worsening from baseline will be presented.	Up to 5 years after last patient randomized
Secondary	Key secondary endpoint 2: Red Blood Cell transfusion-free intervals	Cumulative times of intervals with no evidence of Red Blood Cell (RBC) transfusion for at least 8 weeks after randomization	Up to 5 years after last patient randomized
Secondary	Key secondary endpoint: Percent of subjects with at least 3 point confirmed improvement from baseline in FACIT-fatigue scoresscore	FACIT-Fatigue score is a 13-item questionnaire designed to assess fatigue in cancer patients. All items use a 5-point scale ranging from 0 to 4 (0=Not at All to 4=Very Much). The total score ranges from 0 to 52 with higher values representing better quality of life. Percentage of subjects with at least 3 point confirmed improvement from baseline will be presented.	Up to 5 years after last patient randomized
Secondary	Key secondary endpoint 4: Percent of subjects with at least 10 point confirmed improvement from baseline in physical functioning using European Or ganization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30)	EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Subject's responses to 5 questions about their physical functioning (Items 1-5) are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A high score indicates a high / healthy level of functioning. Percentage of subjects with at least 10 point confirmed improvement from baseline in physical functioning will be presented.	Up to 5 years after last patient randomized
Secondary	Key secondary endpoint 5: Percent of subjects with at least 10 point confirmed improvement from baseline in emotional functioning using EORTC-QLQ-C30	EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Subject's responses to 4 questions about their emotional functioning (Items 21-24) are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A high score indicates a high / healthy level of functioning. Percentage of subjects with at least 10 point confirmed improvement from baseline in emotional functioning will be presented.	Up to 5 years after last patient randomized
Secondary	Percentage of subjects with either CR, or mCR, or PR, or HI in each treatment arm according to International Working Group for MDS (IWG-MDS) as per investigator assessment	Response rate of subjects with complete remission (CR), or marrow remission (mCR), or partial remission (PR), or hematologic improvement (HI)	Up to 5 years after last patient randomized
Secondary	Percentage of subjects with SD in each treatment arm according to International Working Group for MDS (IWG-MDS) as per investigator assessment	Response rate of subjects with stable disease (SD)	Up to 5 years after last patient randomized
Secondary	Progression Free Survival (PFS)	Time from randomization to disease progression (including transformation to acute leukemia per WHO 2016 classification), relapse from CR according to International Working Group for MDS (IWG-MDS), or death due to any cause, whichever occurs first, as per investigator assessment	Up to 5 years after last patient randomized
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 5 years after last patient randomized
Secondary	Number of transfusion dependent subjects at baseline who become Red Blood Cells/platelets transfusion independent after randomization	Improvement in RBC/Platelets transfusion independence as per International Working Group for MDS (IWG-MDS) criteria	Up to 5 years after last patient randomized as per IWG-MDS criteria
Secondary	Percentage of transfusion dependent subjects at baseline who become Red Blood Cells/platelets transfusion independent after randomization	Improvement in RBC/Platelets transfusion Independence as per International Working Group for MDS (IWG-MDS) criteria	Up to 5 years after last patient randomized
Secondary	Pharmacokinetics of MBG453 (parameter Cmax)	Maximum (peak) MBG453 concentration [Cmax]	At Day 8 of each cycle (1 cycle = 28 days) until cycle 9, at day 8 of cycle 12 and every 6 cycles thereafter up to 150 day after end of study drug
Secondary	Pharmacokinetics of MBG453 (parameter AUC)	Area Under the Curve [AUC]	At Day 8 of each cycle (1 cycle = 28 days) until cycle 9, at day 8 of cycle 12 and every 6 cycles thereafter up to 150 day after end of study drug
Secondary	Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment	Immunogenicity of MBG453	At Day 8 of each cycle (1 cycle = 28 days) until cycle 9, at day 8 of cycle 12 and every 6 cycles thereafter up to 150 day after end of study drug
Secondary	Change from baseline in the European Quality of Life (EuroQol) - 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) score over time	The EQ-5D-5L comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. For each of the 5 dimensions, subject's responses are scored on a 5-point scale (1=no problem to 5=extreme problems). Change from baseline will be presented.	Up to 5 years after last patient randomized
Secondary	Change from baseline in the European Quality of Life (EuroQoL) - 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) Visual Analogue Scale over time	The EQ-5D-5L VAS records the subject's self-rated health on a visual analogue scale numbered from 0 to 100, with 0 being "the worst health you can imagine" and 100 being "the best health you can imagine". Change from baseline will be presented.	Up to 5 years after last patient randomized
Secondary	Change from baseline to C12D1 of Global Health Status/Quality of Life scores using European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQ-C30)	EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Subject's responses to 2 questions (Items 29+30: "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?") are scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall outcome. Change from baseline to Cycle 12 Day 1 will be presented.	Up to cycle 12 day 1 (C12D1)(1 cycle = 28 days)