Myelodysplastic Syndrome Clinical Trial
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)
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 have an indication for treatment with azacitidine in first-line setting and 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.
Full 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.
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
Other protocol-defined Inclusion/Exclusion Criteria may apply.
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There are 148 Locations for this study
Yuma Arizona, 85364, United States
Los Angeles California, 90095, United States
New Haven Connecticut, 06520, United States
Jacksonville Florida, 32224, United States
Miami Florida, 33136, United States
Chicago Illinois, 60611, United States
Boston Massachusetts, 02114, United States
Hackensack New Jersey, 07601, United States
New York New York, 10021, United States
Rochester New York, 14642, United States
Charlottesville Virginia, 22903, United States
Pilar Buenos Aires, B1629, Argentina
Woolloongabba Queensland, 4102, Australia
Clayton Victoria, 3168, Australia
Perth Western Australia, 6000, Australia
Graz , 8036, Austria
Innsbruck , A-602, Austria
Linz , A-401, Austria
Brasschaat , 2930, Belgium
Roeselare , 8800, Belgium
Florianopolis SC, 88034, Brazil
Sao Paulo SP, 04014, Brazil
Sao Paulo SP, 05319, Brazil
Calgary Alberta, T2N 4, Canada
Toronto Ontario, M4N 3, Canada
Vina del Mar Valparaiso, 25403, Chile
Guangzhou Guangdong, 51000, China
Guangzhou Guangdong, 51051, China
Shenzhen Guangdong, 51803, China
Wuhan Hubei, 43002, China
Wuhan Hubei, 43003, China
Suzhou Jiangsu, 21500, China
Chang Chun Jilin, 13002, China
Tianjin Tianjin, 30002, China
Hangzhou Zhejiang, 31000, China
Beijing , 10002, China
Beijing , 10073, China
Chengdu , 61004, China
Jinan , 25001, China
Shanghai , 20002, China
Shanghai , 20023, China
Tianjin , 30005, China
Rionegro Antioquia, 05404, Colombia
Bogota , 11023, Colombia
Praha 2 Czech Republic, 128 2, Czechia
Hradec Kralove CZE, 500 0, Czechia
Brno - Bohunice , 625 0, Czechia
Praha , 12808, Czechia
Helsinki , FIN 0, Finland
Kuopio , 70211, Finland
Grenoble , 38043, France
Lille Cedex , 59037, France
Paris 10 , 75475, France
Toulouse , 31059, France
Tours , 37044, France
Vandoeuvre Les Nancy , 54511, France
Velbert North Rhine-Westphalia, 42551, Germany
Dresden Sachsen, 01307, Germany
Augsburg , 86179, Germany
Duesseldorf , 40479, Germany
Frankfurt , 60590, Germany
Greifswald , 17475, Germany
Jena , 07740, Germany
Kiel , 24116, Germany
Ulm , 89081, Germany
Alexandroupolis Evros, 681 0, Greece
Patras , 265 0, Greece
Ahmedabad Gujrat, 38000, India
Faridabad Haryana, 121 0, India
Madurai Tamil NADU, 62510, India
Kolkata West Bengal, 70001, India
Kolkata West Bengal, 70016, India
Delhi , 110 0, India
Afula , 18341, Israel
Tel Aviv , 64239, Israel
Bologna BO, 40138, Italy
Catania CT, 95123, Italy
Firenze FI, 50134, Italy
Genova GE, 16132, Italy
Milano MI, 20162, Italy
Rozzano MI, 20089, Italy
Reggio Calabria RC, 89124, Italy
Roma RM, 00133, Italy
Nagoya Aichi, 464 8, Japan
Kashiwa Chiba, 277 8, Japan
Fukuoka city Fukuoka, 812-8, Japan
Sapporo Hokkaido, 064 0, Japan
Isehara Kanagawa, 259-1, Japan
Sendai city Miyagi, 980 8, Japan
Nagasaki-city Nagasaki, 852-8, Japan
Osaka Sayama Osaka, 589 8, Japan
Bunkyo-ku Tokyo, 113-8, Japan
Osaka , 545-8, Japan
Yamagata , 990 9, Japan
Seoul Seocho Gu, 06591, Korea, Republic of
Seoul , 03080, Korea, Republic of
Seoul , 03722, Korea, Republic of
Seoul , 05505, Korea, Republic of
Seoul , 06351, Korea, Republic of
Beirut , 1107 , Lebanon
Vilnius , LT-08, Lithuania
Kuching Sarawak, 93586, Malaysia
Kuala Lumpur , 59100, Malaysia
Pulau Pinang , 10990, Malaysia
Selangor , 68000, Malaysia
Mexico Distrito Federal, 06726, Mexico
Satelite Edo Mexico, 53100, Mexico
Morelia Michoacan, 58260, Mexico
Estado de Mexico , 52787, Mexico
Groningen , 9713 , Netherlands
Muscat , 123, Oman
Lisboa , 1099 , Portugal
Porto , 4200-, Portugal
Saint Petersburg , 19702, Russian Federation
St Petersburg , 19102, Russian Federation
Riyadh , 11211, Saudi Arabia
Singapore , 11922, Singapore
Singapore , 16960, Singapore
Sevilla Andalucia, 41013, Spain
Oviedo Asturias, 33011, Spain
Salamanca Castilla Y Leon, 37007, Spain
Badalona Catalunya, 08916, Spain
Barcelona Catalunya, 08035, Spain
Valencia Comunidad Valenciana, 46010, Spain
Valencia Comunidad Valenciana, 46026, Spain
Madrid , 28009, Spain
Bern , 3010, Switzerland
Zürich , 8091, Switzerland
Hualien City Hualien, 970, Taiwan
Kaohsiung , 83301, Taiwan
Liouying Township , 73600, Taiwan
Taichung , 40447, Taiwan
Taipei , 10002, Taiwan
Taoyuan , 33305, Taiwan
Songkhla Hat Yai, 90110, Thailand
Khon Kaen THA, 40002, Thailand
Bangkok , 10330, Thailand
Bangkok , 10400, Thailand
Bangkok , 10700, Thailand
Chiang Mai , 50200, Thailand
Ankara , 06100, Turkey
Edirne , 22030, Turkey
Istanbul , 34890, Turkey
Izmir , 35040, Turkey
Samsun , 55139, Turkey
Portsmouth Hants, PO6 3, United Kingdom
Edinburgh , EH4 2, United Kingdom
Manchester , M20 4, United Kingdom
Nottingham , NG5 1, United Kingdom
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