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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
First received
Last updated
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
Health authority
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.

Study Design


Related Conditions & MeSH terms


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)
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