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)

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)

ClinicalTrials.gov Identifier: NCT04266301

Novartis Reference Number: CMBG453B12301

Last Update: Nov 08, 2021

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All compounds are either investigational or being studied for (a) new use(s). Efficacy and safety have not been established. There is no guarantee that they will become commercially available for the use(s) under investigation. 

Study 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) 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.

Condition 
Myelodysplastic Syndromes
Leukemia, Myelomonocytic, Chronic
Phase 
Phase 3
Overall status 
Recruiting
Enrollment count 
500 participants
Start date 
Jun 08, 2020
Completion date 
Jan 29, 2027
Gender 
All
Age(s)
18 Years and older (Adult, Older Adult)

Interventions

Drug
MBG453
A dose of MBG453 800 mg will be administered intravenously (IV) every 4 weeks (Q4W).
Drug
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.
Drug
Placebo
A dose of Placebo 800 mg will be administered intravenously every 4 weeks (Q4W).

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.

Study Locations

United States
Yuma Regional Cancer Center
Recruiting
Yuma, 85364
Arizona
United States
University of California at Los Angeles
Recruiting
Los Angeles, 90095
California
United States
Yale University School of Medicine Smilow Cancer Hospital
Recruiting
New Haven, 06520
Connecticut
United States
Mayo Clinic Jacksonville
Recruiting
Jacksonville, 32224
Florida
United States
University of Miami
Recruiting
Miami, 33136
Florida
United States
Northwestern University Div of Hematology/Oncology
Recruiting
Chicago, 60611
Illinois
United States
University of Iowa Hospitals and Clinics Univ of Iowa Hosp & Clinic
Recruiting
Iowa City, 52242
Iowa
United States
Massachusetts General Hospital
Recruiting
Boston, 02114
Massachusetts
United States
Hackensack University Medical Center SC
Recruiting
Hackensack, 07601
New Jersey
United States
New Mexico Cancer Center
Recruiting
Albuquerque, 87109
New Mexico
United States
Weill Cornell Medicine NewYork Presbyterian Hospital
Recruiting
New York, 10021
New York
United States
University of Rochester Medical Center Dept.ofUniv.Rochester/JPWilmot
Recruiting
Rochester, 14642
New York
United States
University of Virginia University of Virginia
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Charlottesville, 22903
Virginia
United States
Argentina
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Pilar, B1629AHJ
Buenos Aires
Argentina
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Buenos Aires, C1431FWO
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Argentina
Australia
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Woolloongabba, 4102
Queensland
Australia
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Clayton, 3168
Victoria
Australia
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Perth, 6000
Western Australia
Australia
Austria
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Graz, 8036
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Austria
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Innsbruck, A-6020
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Austria
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Linz, A-4010
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Austria
Belgium
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Brasschaat, 2930
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Belgium
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Roeselare, 8800
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Belgium
Brazil
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Florianopolis, 88034-000
SC
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Sao Paulo, 04014-002
SP
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Chile
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Shenzhen, 518037
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Madrid, 28009
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Spain
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Bern, 3010
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