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)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic

Intervention / Treatment
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* Drug: MBG453
* Drug: Azacitidine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MBG453 + Azacitidine<br>Participants will receive MBG453 plus Azacitidine | Drug: MBG453<br>* A dose of MBG453 800 mg will be administered intravenously (IV) every 4 weeks (Q4W).<br>Drug: Azacitidine<br>* 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.<br>|
| Placebo Comparator: Placebo + Azacitidine<br>Participants will receive Placebo plus Azacitidine | Drug: MBG453<br>* A dose of MBG453 800 mg will be administered intravenously (IV) every 4 weeks (Q4W).<br>Drug: Azacitidine<br>* 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.<br>Drug: Placebo<br>* A dose of Placebo 800 mg will be administered intravenously every 4 weeks (Q4W).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from randomization until death due to any cause | Up to 5 years after last patient randomized | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MBG453, MDS, Phase III, TIM-3, azacitidine, myelodysplastic syndrome, chronic myelomonocytic leukemia, CMML-2, Sabatolimab