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出境医 / 临床实验 / A Study of MBG453 in Combination With Hypomethylating Agents in Subjects With IPSS-R Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS). (STIMULUS-MDS1)

A Study of MBG453 in Combination With Hypomethylating Agents in Subjects With IPSS-R Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS). (STIMULUS-MDS1)

Study Description
Brief Summary:
This Phase II is a multicenter, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to hypomethylating agents (azacitidine or decitabine) in adult subjects with IPSS-R intermediate, high or very high risk myelodysplastic syndrome (MDS) not eligible for Hematopoietic Stem Cell Transplant (HSCT) or intensive chemotherapy.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Drug: MBG453 Drug: Placebo Drug: Hypomethylating agents Phase 2

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 127 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Supportive Care
Official Title: A Randomized, Double-blind, Placebo-controlled Phase II Multi-center Study of Intravenous MBG453 Added to Hypomethylating Agents in Adult Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R Criteria
Actual Study Start Date : June 4, 2019
Estimated Primary Completion Date : October 27, 2023
Estimated Study Completion Date : August 10, 2024
Arms and Interventions
Arm Intervention/treatment
Experimental: MBG453 + hypomethylating agents
Patients will take MBG453 plus hypomethylating agents
 Drug: MBG453
MBG453 will be administered i.v.

Drug: Hypomethylating agents
Decitabine will be administered i.v. Azacitidine will be administered i.v or s.c.
Placebo Comparator: Placebo + hypomethylating agents
Patients will take placebo plus hypomethylating agents
 Drug: Placebo
Placebo will be administered i.v.

Drug: Hypomethylating agents
Decitabine will be administered i.v. Azacitidine will be administered i.v or s.c.
Outcome Measures
Primary Outcome Measures :
  1. Complete remission (CR) rate [ Time Frame: 7 months after last patient first visit (LPFV) ]
    Modified response criteria According to International Working Group (IWG) for Myelodysplastic syndromes (MDS) as per investigator assessment.

  2. Progression Free Survival (PFS) [ Time Frame: Up to 4 yrs after Last Patient First Visit (LPFV) ]
    Defined as time from randomization to disease progression (including transformation to acute leukemia per WHO 2016 classification), relapse from CR according to IWG-MDS or death due to any cause, whichever occurs first, as per investigator assessment


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: Up to 4 years after LPFV ]
    Time from randomization to death due to any cause

  2. Event Free Survival [ Time Frame: Up to 4 years after LPFV ]
    Time from randomization to lack of reaching CR within the first 6 months, relapse from CR or death due to any cause, whichever occurs first

  3. Leukemia-free survival [ Time Frame: Up to 4 yrs after Last Patient First Visit (LPFV) ]
    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

  4. Response Rate (CR/mCR/PR/HI) [ Time Frame: 7 months after Last Patient First Visit (LPFV) ]
    Percentage of complete remission(CR)/marrow Complete Remission (mCR)/partial remission (PR) and Hematological improvement (HI) according to IWG-MDS as per investigator assessment

  5. Duration of complete remission [ Time Frame: Up to 4 yrs after Last Patient First Visit (LPFV) ]
    Time from the date of the first documented CR to the date of first documented relapse from CR or death due to any cause, whichever occurs first

  6. Time to complete remission [ Time Frame: 7 months after Last Patient First Visit (LPFV) ]
    Time from randomization to the first documented CR

  7. Percent of subjects who are red blood cells (RBC)/platelets transfusion independent after randomization as per IWG-MDS [ Time Frame: Up to 4 years after last randomized patient ]
    Improvement in RBC/platelets transfusion independence

  8. Red blood cells (RBC)/platelets transfusion independence duration after randomization [ Time Frame: Up to 4 years after last randomized patient ]
    Duration of transfusion independence

  9. Serum concentrations for MBG453 [ Time Frame: At Day 8 of each cycle (1 cycle = 28 days) until cycle 6 and at day 8 of cycles 9, 12, 18 and 24, and up to 150 day of the safety follow up period ]
    Pharmacokinetics of MBG453 when given in combination with hypomethylating agents (HMA)

  10. Immunogenicity of MBG453 when given in combination of hypomethylating agents [ Time Frame: Up to 4 years after Last Patient First Visit (LPFV) ]
    Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed informed consent must be obtained prior to participation in the study.
  2. Age ≥ 18 years at the date of signing the informed consent form (ICF)

  3. Morphologically confirmed diagnosis of a myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) by investigator assessment with one of the following Prognostic Risk Categories, based on the International Prognostic Scoring System (IPSS-R):

    • Very high
    • High
    • Intermediate with at least ≥ 5% bone marrow blast
  4. Not eligible at the time of screening, for intensive chemotherapy according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions
  5. Not eligible at the 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.
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

Exclusion Criteria:

  1. Prior exposure to TIM-3 directed therapy at any time. Prior therapy with immune check point inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer vaccines are allowed except if the drug was administered within 4 months prior to randomization.
  2. Previous first-line treatment for higher risk MDS with chemotherapy or any other antineoplastic agents including lenalidomide and hypomethylating agent (HMAs) such as decitabine or azacitidine.
  3. History of severe hypersensitivity reactions to any ingredient of the study treatment (azacitidine, decitabine or MGB453) or their excipients, or to monoclonal antibodies (mAbs).
  4. Currently using or used within 14 days prior to randomization of systemic, steroid therapy (> 10 mg/day prednisone or equivalent) or any immunosuppressive therapy. Topical, inhaled, nasal, ophthalmic steroids are allowed. Replacement therapy, steroids given in the context of a transfusion are allowed and not considered a form of systemic treatment.
  5. Investigational treatment for MDS received within 4 weeks prior to randomization. In case of a checkpoint inhibitor: 4 months minimum prior to randomization interval is necessary to allow enrollment.
  6. Active autoimmune disease requiring systemic therapy (e.g.corticosteroids).
  7. Live vaccine administered within 30 Days prior to randomization.

Other protocol-defined Inclusion/Exclusion may apply.

Contacts and Locations

Locations
Show Show 47 study locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Layout table for investigator information
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Tracking Information
First Submitted Date  ICMJE May 8, 2019
First Posted Date  ICMJE May 13, 2019
Last Update Posted Date February 24, 2021
Actual Study Start Date  ICMJE June 4, 2019
Estimated Primary Completion Date October 27, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 15, 2020)
  • Complete remission (CR) rate [ Time Frame: 7 months after last patient first visit (LPFV) ]
    Modified response criteria According to International Working Group (IWG) for Myelodysplastic syndromes (MDS) as per investigator assessment.
  • Progression Free Survival (PFS) [ Time Frame: Up to 4 yrs after Last Patient First Visit (LPFV) ]
    Defined as time from randomization to disease progression (including transformation to acute leukemia per WHO 2016 classification), relapse from CR according to IWG-MDS or death due to any cause, whichever occurs first, as per investigator assessment
Original Primary Outcome Measures  ICMJE
 (submitted: May 9, 2019)
  • Complete remission (CR) rate [ Time Frame: 7 mo. after last patient first visit (LPFV) ]
    Modified response criteria According to International Working Group (IWG) for Myelodysplastic syndromes (MDS) as per investigator assessment.
  • Progression Free Survival (PFS) [ Time Frame: Up to 4 yrs after LPFV ]
    Defined as time from randomization to disease progression (including transformation to leukemia per WHO 2016 classification), relapse from CR according to IWG-MDS or death due to any cause, whichever occurs first, as per investigator assessment
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 15, 2020)
  • Overall Survival [ Time Frame: Up to 4 years after LPFV ]
    Time from randomization to death due to any cause
  • Event Free Survival [ Time Frame: Up to 4 years after LPFV ]
    Time from randomization to lack of reaching CR within the first 6 months, relapse from CR or death due to any cause, whichever occurs first
  • Leukemia-free survival [ Time Frame: Up to 4 yrs after Last Patient First Visit (LPFV) ]
    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
  • Response Rate (CR/mCR/PR/HI) [ Time Frame: 7 months after Last Patient First Visit (LPFV) ]
    Percentage of complete remission(CR)/marrow Complete Remission (mCR)/partial remission (PR) and Hematological improvement (HI) according to IWG-MDS as per investigator assessment
  • Duration of complete remission [ Time Frame: Up to 4 yrs after Last Patient First Visit (LPFV) ]
    Time from the date of the first documented CR to the date of first documented relapse from CR or death due to any cause, whichever occurs first
  • Time to complete remission [ Time Frame: 7 months after Last Patient First Visit (LPFV) ]
    Time from randomization to the first documented CR
  • Percent of subjects who are red blood cells (RBC)/platelets transfusion independent after randomization as per IWG-MDS [ Time Frame: Up to 4 years after last randomized patient ]
    Improvement in RBC/platelets transfusion independence
  • Red blood cells (RBC)/platelets transfusion independence duration after randomization [ Time Frame: Up to 4 years after last randomized patient ]
    Duration of transfusion independence
  • Serum concentrations for MBG453 [ Time Frame: At Day 8 of each cycle (1 cycle = 28 days) until cycle 6 and at day 8 of cycles 9, 12, 18 and 24, and up to 150 day of the safety follow up period ]
    Pharmacokinetics of MBG453 when given in combination with hypomethylating agents (HMA)
  • Immunogenicity of MBG453 when given in combination of hypomethylating agents [ Time Frame: Up to 4 years after Last Patient First Visit (LPFV) ]
    Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment
Original Secondary Outcome Measures  ICMJE
 (submitted: May 9, 2019)
  • Overall Suvival [ Time Frame: Up to 4 years after last patient randomized ]
    Time from randomization to death due to any cause
  • Leukemia-free survival [ Time Frame: Up to 4 yrs after LPFV ]
    Time from randomization to ≥ 20% blasts in bone marrow/ peripheral blood (per WHO 2016 classification) or death due to any cause
  • Response Rate (CR/mCR/PR) [ Time Frame: 7 mo. after the LPFV ]
    Percentage of complete remission(CR)/marrow Complete Remission (mCR)/partial remission (PR) according to IWG-MDS as per investigator assessment
  • Duration of complete remission [ Time Frame: Up to 4 yrs after LPFV ]
    Time from the date of the first documented CR to the date of first documented relapse from CR or death due to any cause, whichever occurs first
  • Time to complete remission [ Time Frame: 7 mo. after the LPFV ]
    Time from randomization to the first documented CR
  • Number of subjects who are RBC/platelets transfusion independent after randomization as per IWG-MDS [ Time Frame: Up to 4 years after last randomized patient ]
    Improvement in RBC/platelets transfusion independence
  • Percent of subjects who are red blood cells (RBC)/platelets transfusion independent after randomization as per IWG-MDS [ Time Frame: Up to 4 years after last randomized patient ]
    Improvement in RBC/platelets transfusion independence
  • Pharmacokinetics of MBG453 when given in combination with HMA [ Time Frame: At Day 8 of each cycle (1 cycle = 28 days) until cycle 6 and at day 8 of cycles 9, 12, 18 and 24, and up to 150 day of the safety follow up period ]
    Serum concentrations for MBG453
  • Immunogenicity of MBG453 when given in combination of hypomethylating agents [ Time Frame: Up to 4 years after LPFV ]
    Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of MBG453 in Combination With Hypomethylating Agents in Subjects With IPSS-R Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS).
Official Title  ICMJE A Randomized, Double-blind, Placebo-controlled Phase II Multi-center Study of Intravenous MBG453 Added to Hypomethylating Agents in Adult Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R Criteria
Brief Summary This Phase II is a multicenter, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to hypomethylating agents (azacitidine or decitabine) in adult subjects with IPSS-R intermediate, high or very high risk myelodysplastic syndrome (MDS) not eligible for Hematopoietic Stem Cell Transplant (HSCT) or intensive chemotherapy.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Supportive Care
Condition  ICMJE Myelodysplastic Syndromes
Intervention  ICMJE
  • Drug: MBG453
    MBG453 will be administered i.v.
  • Drug: Placebo
    Placebo will be administered i.v.
  • Drug: Hypomethylating agents
    Decitabine will be administered i.v. Azacitidine will be administered i.v or s.c.
Study Arms  ICMJE
  • Experimental: MBG453 + hypomethylating agents
    Patients will take MBG453 plus hypomethylating agents
    Interventions:
    • Drug: MBG453
    • Drug: Hypomethylating agents
  • Placebo Comparator: Placebo + hypomethylating agents
    Patients will take placebo plus hypomethylating agents
    Interventions:
    • Drug: Placebo
    • Drug: Hypomethylating agents
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: September 27, 2020) 		127
Original Estimated Enrollment  ICMJE
 (submitted: May 9, 2019) 		120
Estimated Study Completion Date  ICMJE August 10, 2024
Estimated Primary Completion Date October 27, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Signed informed consent must be obtained prior to participation in the study.
  2. Age ≥ 18 years at the date of signing the informed consent form (ICF)

  3. Morphologically confirmed diagnosis of a myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) by investigator assessment with one of the following Prognostic Risk Categories, based on the International Prognostic Scoring System (IPSS-R):

    • Very high
    • High
    • Intermediate with at least ≥ 5% bone marrow blast
  4. Not eligible at the time of screening, for intensive chemotherapy according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions
  5. Not eligible at the 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.
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

Exclusion Criteria:

  1. Prior exposure to TIM-3 directed therapy at any time. Prior therapy with immune check point inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer vaccines are allowed except if the drug was administered within 4 months prior to randomization.
  2. Previous first-line treatment for higher risk MDS with chemotherapy or any other antineoplastic agents including lenalidomide and hypomethylating agent (HMAs) such as decitabine or azacitidine.
  3. History of severe hypersensitivity reactions to any ingredient of the study treatment (azacitidine, decitabine or MGB453) or their excipients, or to monoclonal antibodies (mAbs).
  4. Currently using or used within 14 days prior to randomization of systemic, steroid therapy (> 10 mg/day prednisone or equivalent) or any immunosuppressive therapy. Topical, inhaled, nasal, ophthalmic steroids are allowed. Replacement therapy, steroids given in the context of a transfusion are allowed and not considered a form of systemic treatment.
  5. Investigational treatment for MDS received within 4 weeks prior to randomization. In case of a checkpoint inhibitor: 4 months minimum prior to randomization interval is necessary to allow enrollment.
  6. Active autoimmune disease requiring systemic therapy (e.g.corticosteroids).
  7. Live vaccine administered within 30 Days prior to randomization.

Other protocol-defined Inclusion/Exclusion may apply.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Belgium,   Canada,   Czechia,   France,   Germany,   Greece,   Hong Kong,   Hungary,   Italy,   Japan,   Korea, Republic of,   Spain,   Taiwan,   Turkey,   United Kingdom,   United States
Removed Location Countries Norway,   Sweden
 
Administrative Information
NCT Number  ICMJE NCT03946670
Other Study ID Numbers  ICMJE CMBG453B12201
2018-004479-11 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Access Criteria:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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