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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)

NCT04266301

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.

Related Conditions:
  • Chronic Myelomonocytic Leukemia-2
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief 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)
  • Official 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)

Clinical Trial IDs

  • ORG STUDY ID: CMBG453B12301
  • SECONDARY ID: 2019-002089-11
  • NCT ID: NCT04266301

Conditions

  • Myelodysplastic Syndromes
  • Leukemia, Myelomonocytic, Chronic

Interventions

DrugSynonymsArms
MBG453MBG453 + Azacitidine
AzacitidineMBG453 + Azacitidine
PlaceboPlacebo + Azacitidine

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
MBG453 + AzacitidineExperimentalParticipants will receive MBG453 plus Azacitidine
  • MBG453
  • Azacitidine
Placebo + AzacitidinePlacebo ComparatorParticipants will receive Placebo plus Azacitidine
  • MBG453
  • Azacitidine
  • Placebo

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) 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

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival
Time Frame:Up to 5 years after last patient randomized
Safety Issue:
Description:Time from randomization until death due to any cause

Secondary Outcome Measures

Measure:Key secondary objective 1: Time to definitive deterioration of fatigue using Functional Assessment of Cancer Therapy (FACIT)-Fatigue score
Time Frame:Up to 5 years after last patient randomized
Safety Issue:
Description: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.
Measure:Key secondary objective 2: Red Blood Cell transfusion-free intervals
Time Frame:Up to 5 years after last patient randomized
Safety Issue:
Description:Cumulative times of intervals with no evidence of Red Blood Cell (RBC) transfusion for at least 8 weeks after randomization
Measure:Key secondary objective 3: Improvement of fatigue using Functional Assessment of Cancer Therapy (FACIT)-Fatigue score
Time Frame:Up to 5 years after last patient randomized
Safety Issue:
Description: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.
Measure:Key secondary objective 4: Improvement from baseline in physical functioning using European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQ-C30)
Time Frame:Up to 5 years after last patient randomized
Safety Issue:
Description: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.
Measure:Key secondary objective 5: Improvement in emotional functioning using European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQ-C30)
Time Frame:Up to 5 years after last patient randomized
Safety Issue:
Description: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.
Measure:Response rate of subjects with complete remission (CR), or marrow remission (mCR), or partial remission (PR), or hematologic improvement (HI)
Time Frame:Up to 5 years after last patient randomized
Safety Issue:
Description: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
Measure:Response rate of subjects with stable disease (SD)
Time Frame:Up to 5 years after last patient randomized
Safety Issue:
Description:Percentage of subjects with SD in each treatment arm according to International Working Group for MDS (IWG-MDS) as per investigator assessment
Measure:Progression Free Survival (PFS)
Time Frame:Up to 5 years after last patient randomized
Safety Issue:
Description: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
Measure:Leukemia-free survival
Time Frame:Up to 5 years after last patient randomized
Safety Issue:
Description: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
Measure:Number of transfusion dependent subjects at baseline who become Red Blood Cells/platelets transfusion independent after randomization
Time Frame:Up to 5 years after last patient randomized
Safety Issue:
Description:Improvement in RBC/Platelets transfusion independence as per International Working Group for MDS (IWG-MDS) criteria
Measure:Percentage of transfusion dependent subjects at baseline who become Red Blood Cells/platelets transfusion independent after randomization
Time Frame:Up to 5 years after last patient randomized
Safety Issue:
Description:Improvement in RBC/Platelets transfusion Independence as per International Working Group for MDS (IWG-MDS) criteria
Measure:Pharmacokinetics of MBG453 (parameter Cmax)
Time Frame: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
Safety Issue:
Description:Maximum (peak) MBG453 concentration [Cmax]
Measure:Pharmacokinetics of MBG453 (parameter AUC)
Time Frame: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
Safety Issue:
Description:Area Under the Curve [AUC]
Measure:Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment
Time Frame: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
Safety Issue:
Description:Immunogenicity of MBG453
Measure:Change from baseline in the European Quality of Life (EuroQol) - 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) score over time
Time Frame:Up to 5 years after last patient randomized
Safety Issue:
Description: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.
Measure:Change from baseline in the European Quality of Life (EuroQoL) - 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) Visual Analogue Scale over time
Time Frame:Up to 5 years after last patient randomized
Safety Issue:
Description: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.
Measure: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)
Time Frame:Up to cycle 12 day 1 (C12D1)(1 cycle = 28 days)
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • MBG453
  • Phase III
  • TIM-3
  • azacitidine
  • myelodysplastic syndrome
  • MDS
  • chronic myelomonocytic leukemia
  • CMML-2
  • Sabatolimab

Last Updated

September 3, 2020