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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT04266301




Registration number
NCT04266301
Ethics application status
Date submitted
21/01/2020
Date registered
12/02/2020
Date last updated
2/12/2020

Titles & IDs
Public title
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)
Scientific 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)
Secondary ID [1] 0 0
2019-002089-11
Secondary ID [2] 0 0
CMBG453B12301
Universal Trial Number (UTN)
Trial acronym
STIMULUS-MDS2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myelodysplastic Syndromes 0 0
Leukemia, Myelomonocytic, Chronic 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma
Blood 0 0 0 0
Haematological diseases
Blood 0 0 0 0
Other blood disorders
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - MBG453
Treatment: Drugs - Azacitidine
Treatment: Drugs - Placebo

Experimental: MBG453 + Azacitidine - Participants will receive MBG453 plus Azacitidine

Placebo Comparator: Placebo + Azacitidine - Participants will receive Placebo plus Azacitidine


Treatment: Drugs: MBG453
A dose of MBG453 800 mg will be administered intravenously (IV) every 4 weeks (Q4W).

Treatment: Drugs: 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.

Treatment: Drugs: Placebo
A dose of Placebo 800 mg will be administered intravenously every 4 weeks (Q4W).

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Overall Survival - Time from randomization until death due to any cause
Timepoint [1] 0 0
Up to 5 years after last patient randomized
Secondary outcome [1] 0 0
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.
Timepoint [1] 0 0
Up to 5 years after last patient randomized
Secondary outcome [2] 0 0
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
Timepoint [2] 0 0
Up to 5 years after last patient randomized
Secondary outcome [3] 0 0
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.
Timepoint [3] 0 0
Up to 5 years after last patient randomized
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
Up to 5 years after last patient randomized
Secondary outcome [5] 0 0
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.
Timepoint [5] 0 0
Up to 5 years after last patient randomized
Secondary outcome [6] 0 0
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)
Timepoint [6] 0 0
Up to 5 years after last patient randomized
Secondary outcome [7] 0 0
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)
Timepoint [7] 0 0
Up to 5 years after last patient randomized
Secondary outcome [8] 0 0
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
Timepoint [8] 0 0
Up to 5 years after last patient randomized
Secondary outcome [9] 0 0
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
Timepoint [9] 0 0
Up to 5 years after last patient randomized
Secondary outcome [10] 0 0
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
Timepoint [10] 0 0
Up to 5 years after last patient randomized as per IWG-MDS criteria
Secondary outcome [11] 0 0
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
Timepoint [11] 0 0
Up to 5 years after last patient randomized
Secondary outcome [12] 0 0
Pharmacokinetics of MBG453 (parameter Cmax) - Maximum (peak) MBG453 concentration [Cmax]
Timepoint [12] 0 0
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 outcome [13] 0 0
Pharmacokinetics of MBG453 (parameter AUC) - Area Under the Curve [AUC]
Timepoint [13] 0 0
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 outcome [14] 0 0
Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment - Immunogenicity of MBG453
Timepoint [14] 0 0
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 outcome [15] 0 0
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.
Timepoint [15] 0 0
Up to 5 years after last patient randomized
Secondary outcome [16] 0 0
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.
Timepoint [16] 0 0
Up to 5 years after last patient randomized
Secondary outcome [17] 0 0
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.
Timepoint [17] 0 0
Up to cycle 12 day 1 (C12D1)(1 cycle = 28 days)

Eligibility
Key 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) by local investigator assessment with WBC < 13 x 109/L

- 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
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC,WA
Recruitment hospital [1] 0 0
Novartis Investigative Site - Woolloongabba
Recruitment hospital [2] 0 0
Novartis Investigative Site - Clayton
Recruitment hospital [3] 0 0
Novartis Investigative Site - Perth
Recruitment postcode(s) [1] 0 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 0 0
3168 - Clayton
Recruitment postcode(s) [3] 0 0
6000 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
Austria
State/province [2] 0 0
Graz
Country [3] 0 0
Austria
State/province [3] 0 0
Innsbruck
Country [4] 0 0
Austria
State/province [4] 0 0
Linz
Country [5] 0 0
Belgium
State/province [5] 0 0
Brasschaat
Country [6] 0 0
Belgium
State/province [6] 0 0
Roeselare
Country [7] 0 0
Czechia
State/province [7] 0 0
Czech Republic
Country [8] 0 0
Czechia
State/province [8] 0 0
Brno - Bohunice
Country [9] 0 0
Czechia
State/province [9] 0 0
Praha
Country [10] 0 0
Finland
State/province [10] 0 0
Helsinki
Country [11] 0 0
Finland
State/province [11] 0 0
Kuopio
Country [12] 0 0
France
State/province [12] 0 0
Grenoble
Country [13] 0 0
France
State/province [13] 0 0
Lille Cedex
Country [14] 0 0
France
State/province [14] 0 0
Paris Cedex 10
Country [15] 0 0
France
State/province [15] 0 0
Toulouse
Country [16] 0 0
France
State/province [16] 0 0
Tours
Country [17] 0 0
France
State/province [17] 0 0
Vandoeuvre Les Nancy
Country [18] 0 0
Germany
State/province [18] 0 0
Sachsen
Country [19] 0 0
India
State/province [19] 0 0
Gujrat
Country [20] 0 0
India
State/province [20] 0 0
Tamil NADU
Country [21] 0 0
India
State/province [21] 0 0
Delhi
Country [22] 0 0
Israel
State/province [22] 0 0
Afula
Country [23] 0 0
Israel
State/province [23] 0 0
Tel Aviv
Country [24] 0 0
Italy
State/province [24] 0 0
FI
Country [25] 0 0
Italy
State/province [25] 0 0
GE
Country [26] 0 0
Italy
State/province [26] 0 0
MI
Country [27] 0 0
Japan
State/province [27] 0 0
Chiba
Country [28] 0 0
Japan
State/province [28] 0 0
Fukuoka
Country [29] 0 0
Japan
State/province [29] 0 0
Hokkaido
Country [30] 0 0
Japan
State/province [30] 0 0
Kanagawa
Country [31] 0 0
Japan
State/province [31] 0 0
Miyagi
Country [32] 0 0
Japan
State/province [32] 0 0
Nagasaki
Country [33] 0 0
Japan
State/province [33] 0 0
Osaka
Country [34] 0 0
Japan
State/province [34] 0 0
Tokyo
Country [35] 0 0
Japan
State/province [35] 0 0
Yamagata
Country [36] 0 0
Korea, Republic of
State/province [36] 0 0
Seoul
Country [37] 0 0
Lithuania
State/province [37] 0 0
Vilnius
Country [38] 0 0
Malaysia
State/province [38] 0 0
Sarawak
Country [39] 0 0
Portugal
State/province [39] 0 0
Porto
Country [40] 0 0
Singapore
State/province [40] 0 0
Singapore
Country [41] 0 0
Spain
State/province [41] 0 0
Andalucia
Country [42] 0 0
Spain
State/province [42] 0 0
Asturias
Country [43] 0 0
Spain
State/province [43] 0 0
Catalunya
Country [44] 0 0
Spain
State/province [44] 0 0
Comunidad Valenciana
Country [45] 0 0
Spain
State/province [45] 0 0
Madrid
Country [46] 0 0
Spain
State/province [46] 0 0
Salamanca
Country [47] 0 0
Switzerland
State/province [47] 0 0
Zürich
Country [48] 0 0
Taiwan
State/province [48] 0 0
Hualien
Country [49] 0 0
Taiwan
State/province [49] 0 0
Liouying Township
Country [50] 0 0
Taiwan
State/province [50] 0 0
Taichung
Country [51] 0 0
Taiwan
State/province [51] 0 0
Taipei
Country [52] 0 0
Thailand
State/province [52] 0 0
THA
Country [53] 0 0
Thailand
State/province [53] 0 0
Bangkok
Country [54] 0 0
Thailand
State/province [54] 0 0
Chiang Mai
Country [55] 0 0
Turkey
State/province [55] 0 0
Ankara
Country [56] 0 0
Turkey
State/province [56] 0 0
Edirne
Country [57] 0 0
Turkey
State/province [57] 0 0
Istanbul
Country [58] 0 0
Turkey
State/province [58] 0 0
Izmir
Country [59] 0 0
Turkey
State/province [59] 0 0
Samsun

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief 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.
Trial website
https://clinicaltrials.gov/show/NCT04266301
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Country 0 0
Phone 0 0
1-888-669-6682
Fax 0 0
Email 0 0
novartis.email@novartis.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT04266301