Back to resultsA Study of Sabatolimab in Combination With Azacitidine and Venetoclax in High or Very High Risk MDS Participants (STIMULUS-MDS3)
Primary Purpose
Myelodysplastic Syndrome (MDS)
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
sabatolimab
azacitidine
venetoclax
Sponsored by
About this trial
This is an interventional treatment trial for Myelodysplastic Syndrome (MDS) focused on measuring MGM453, Phase II, sabatolimab, TIM-3, venetoclax, azacitidine, Myelodysplastic syndrome (MDS), MDS
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 (ICF)
Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) based on 2016 WHO 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) (Greenberg et al 2012):
- Very high (> 6 points)
- High (> 4.5-6 points)
- Not immediately eligible for hematopoietic stem-cell transplantation (HSCT) or intensive chemotherapy at the time of screening due to individual clinical factors such as age, comorbidities and performance status, donor availability (de Witte et al 2017)
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
Exclusion Criteria:
- Prior exposure to TIM-3 directed therapy or any BCL-2 inhibitor (including venetoclax) at any time
- Prior therapy with immune check point inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2) or cancer vaccines is not allowed if the last dose of the drug was administered within 4 months prior to start of treatment
- Previous first-line treatment for very high risk or high risk myelodysplastic syndromes (based on IPSS-R,Greenberg et al 2012 and Arber et al, 2016) with any antineoplastic agents, approved or investigational, including for example chemotherapy, lenalidomide and hypomethylating agents (HMAs) such as decitabine or azacitidine However, a one single cycle of HMAs treatment only started prior to enrollment is allowed.
- Live vaccine administered within 30 days prior to start of treatment
- Current use or use within 14 days prior to start of treatment 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
- History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or sabatolimab) or monoclonal antibodies (mAbs) and/or their excipients
- Participants with Myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al, 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 4.5
Other protocol-defined Inclusion/Exclusion may apply.
Sites / Locations
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
sabatolimab + azacitidine + venetoclax
Arm Description
Part 1: Safety run-in consists of 2 subsequent cohorts of a lower dose (cohort 1) and s higher dose (cohort 2) of sabatolimab in combination with fixed dose of venetoclax and azacitidine. Cohort 2 will be open only after the review of safety data from cohort 1 indicates the regimen is safe. If the regimen using sabatolimab at the lower dose is not safe, the study will be stopped. Subsequently, if the review of safety data from participants enrolled in cohort 2 indicates that the regimen is safe, then Part 2 will be opened. Otherwise, if the regimen at the higher dose is not safe, the study will be also stopped. Part 2: Expansion will enroll additional participants to further investigate the regimen including sabatolimab at the higher dose, azacitidine and venetoclax. Participants data from Part 1 and Part 2 treated with the higher dose will be combined to determine the complete remission rate.
Outcomes
Primary Outcome Measures
Incidence of dose limiting toxicities (DLTs) (Safety run-in patients only)
Assessment of tolerability of MBG in combination with venetoclax and azacitidine
Percentage of participants (receiving 800mg sabatolimab) achieving complete remission (CR) per investigator assessment
This endpoint will assess Complete Remission (CR) Rate of participants from Cohort 2 of Part 1 and Part 2 according to Investigator assessment per modified IWG-MDS - Cheson 2006 criteria. CR is defined as follows: bone marrow blasts <=5%, hemoglobin level ≥ 10 g/dL, platelets count ≥ 100*10^9/L, neutrophils count ≥ 1.0*10^9/L, absence of blasts in peripheral blood.
Secondary Outcome Measures
Percentage of subjects achieving a complete remission (CR) + morphologic complete remission (mCR): Safety run-in (Part 1) and Expansion (Part 2)
Assessing the durability of complete remission (CR) or morphologic complete remission (mCR) rate (defined as the proportion of participants with best overall response of either CR or mCR)
Overall Response Rate (ORR) of participants who achieved hematologic improvement (HI) or better as best response
The percentage of participants achieving [CR + mCR + partial remission (PR) + hematologic improvement (HI)], per modified IWG-MDS Cheson 2006 criteria
Percentage of participants who are RBC/platelets transfusion independent
Improvement in red blood cells (RBC)/platelets transfusion independence as per IWG-MDS by dose level
Duration of transfusion independence
Transfusion independence as per IWG-MDS by dose level
Peak Serum Concentration (Cmax) MBG453
Maximal concentration of MBG453
Trough Serum Concentration (Cmin) MBG453
Concentration of sabatolimab prior to next dosing or after end of treatment
Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment by dose level
Immunogenicity of sabatolimab prior to sabatolimab exposure and during treatment
Duration of complete remission (CR)
Duration of CR is defined as time from first occurrence of CR to relapse from CR, progression or death due to any cause whichever occurs first
Time to complete remission(CR)/marrow complete remission (mCR)
Time to CR/mCR is defined as time from start of treatment to first occurrence of CR or mCR as per investigator assessment
Duration of CR/mCR
Duration of CR/mCR is defined as time from first occurrence of CR/mCR to relapse from CR, progression or death due to any cause whichever occurs first
Duration of response for participants who achieved hematologic improvement (HI) or better
The duration of response will be derived for participants treated with sabatolimab at the higher dose who achieve HI or better as per investigator assessment and is defined from the first occurrence of CR, mCR, PR or HI until relapse, progression or death due to any reason
Progression-Free Survival (PFS)
Time from start of treatment to disease progression (including transformation to acute leukemia per WHO 2016 classification), relapse from CR or death due to any cause, whichever occurs first
Leukemia-Free Survival (LFS)
Time from start of treatment to transformation to acute leukemia [as defined as ≥ 20% blasts in bone marrow/ peripheral blood (per WHO 2016 classification) or diagnosis of extramedullary acute leukemia or death due to any cause, whichever occurs first]
Event-Free Survival (EFS)
Time from start of treatment to lack of reaching CR within the first 6 cycles, relapse from CR or death due to any cause, whichever occurs first
Overall Survival (OS)
Time from start of treatment to death due to any cause
Changes in fatigue (Part 2 - Expansion)
Changes in fatigue as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue for participants treated with sabatolimab at the higher dose of the expansion part only. Measurements are taken via scores from 0 (not at all) to 4 (very much). The higher the score, the better the Quality of Life.
Full Information
NCT ID
NCT04812548
First Posted
February 23, 2021
Last Updated
May 26, 2023
Sponsor
Novartis Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT04812548
Brief Title
A Study of Sabatolimab in Combination With Azacitidine and Venetoclax in High or Very High Risk MDS Participants
Acronym
STIMULUS-MDS3
Official Title
A Single-arm, Open-label, Phase II Study of Sabatolimab in Combination With Azacitidine and Venetoclax in Adult Participants With High or Very High Risk Myelodysplastic Syndromes (MDS) as Per IPSS-R Criteria
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
May 31, 2021 (Actual)
Primary Completion Date
May 8, 2023 (Actual)
Study Completion Date
May 8, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of the study is to find out if the new drug sabatolimab when given in combination with azacitidine and venetoclax, is safe and has beneficial effects in participants with high or very high risk myelodysplastic syndrome (MDS) who are not suitable for treatment with intensive chemotherapy or a stem-cell transplant (HSCT).
Detailed Description
Approximately 76 people with high or very high risk myelodysplastic syndrome (MDS) and age ≥ 18 years are being asked to join this study.
The primary purpose of Part 1 (Safety run-in) is to rule out excessive toxicity of sabatolimab, when administered in combination with azacitidine and venetoclax. The primary purpose of the combined cohort 2 of the Safety run-in (Part 1) and Expansion (Part 2) is to evaluate efficacy of sabatolimab, when administered in combination with azacitidine and venetoclax in adult participants with high or very high risk MDS.
This study will consist of two parts:
Safety Run-in Part:
The first approximately 18 participants to join the study will be a part of the safety run-in. The first approximately 6 participants will be enrolled to the lower dose given every four weeks sabatolimab safety run-in cohort.
After these participants have completed 2 cycles of treatment a decision will be made to confirm whether the chosen combination of sabatolimab with azacitidine and venetoclax is considered safe to continue with approximately 12 participants, will be enrolled to the higher dose given every four weeks safety run-in cohort. After these participants have completed 2 cycles of treatment a decision will be made to confirm whether the chosen combination of sabatolimab with azacitidine and venetoclax is considered safe to continue with expansion part of the study.
Expansion Part:
After the safety run-in part confirms that the study treatment (higher dose of sabatolimab given every four weeks with azacitidine and venetoclax) is safe, about 58 more participants will be enrolled in the expansion part to better investigate the efficacy of the study treatment.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndrome (MDS)
Keywords
MGM453, Phase II, sabatolimab, TIM-3, venetoclax, azacitidine, Myelodysplastic syndrome (MDS), MDS
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)
8. Arms, Groups, and Interventions
Arm Title
sabatolimab + azacitidine + venetoclax
Arm Type
Experimental
Arm Description
Part 1: Safety run-in consists of 2 subsequent cohorts of a lower dose (cohort 1) and s higher dose (cohort 2) of sabatolimab in combination with fixed dose of venetoclax and azacitidine. Cohort 2 will be open only after the review of safety data from cohort 1 indicates the regimen is safe. If the regimen using sabatolimab at the lower dose is not safe, the study will be stopped. Subsequently, if the review of safety data from participants enrolled in cohort 2 indicates that the regimen is safe, then Part 2 will be opened. Otherwise, if the regimen at the higher dose is not safe, the study will be also stopped.
Part 2: Expansion will enroll additional participants to further investigate the regimen including sabatolimab at the higher dose, azacitidine and venetoclax. Participants data from Part 1 and Part 2 treated with the higher dose will be combined to determine the complete remission rate.
Intervention Type
Drug
Intervention Name(s)
sabatolimab
Intervention Description
Sabatolimab will be administered at a low dose (Safety run-in (Part 1) cohort 1) or a high dose (Safety run-in (Part 1) cohort 2 and Expansion (Part 2)) via i.v. infusion over 30 minutes on Day 8 of every treatment cycle.
Intervention Type
Drug
Intervention Name(s)
azacitidine
Intervention Description
A standard dose of azacitidine will be given subcutaneously or intravenously every day for seven consecutive days on days 1-7 of a confirmed treatment cycle. In keeping with standard clinical practice, the alternative schedules for five consecutive days on days 1-5, followed by a two day break, then two consecutive days on days 8-9 will be permitted (alternative schedule).
Intervention Type
Drug
Intervention Name(s)
venetoclax
Intervention Description
Venetoclax film-coated tablets will be administered at a dose of 400 mg orally or corresponding reduced dose for concomitant use with P-gp inhibitors or moderate or strong CYP3A4 inhibitors, once a day, from C1D1 to C1D14 during the treatment cycle. No ramp-up for venetoclax is necessary.
Primary Outcome Measure Information:
Title
Incidence of dose limiting toxicities (DLTs) (Safety run-in patients only)
Description
Assessment of tolerability of MBG in combination with venetoclax and azacitidine
Time Frame
From Cycle 1 Day 8 to end of Cycle 2 (Cycle = 28 Days)
Title
Percentage of participants (receiving 800mg sabatolimab) achieving complete remission (CR) per investigator assessment
Description
This endpoint will assess Complete Remission (CR) Rate of participants from Cohort 2 of Part 1 and Part 2 according to Investigator assessment per modified IWG-MDS - Cheson 2006 criteria. CR is defined as follows: bone marrow blasts <=5%, hemoglobin level ≥ 10 g/dL, platelets count ≥ 100*10^9/L, neutrophils count ≥ 1.0*10^9/L, absence of blasts in peripheral blood.
Time Frame
Throughout study completion, up to 3 years
Secondary Outcome Measure Information:
Title
Percentage of subjects achieving a complete remission (CR) + morphologic complete remission (mCR): Safety run-in (Part 1) and Expansion (Part 2)
Description
Assessing the durability of complete remission (CR) or morphologic complete remission (mCR) rate (defined as the proportion of participants with best overall response of either CR or mCR)
Time Frame
Throughout study completion, an average of 3 years
Title
Overall Response Rate (ORR) of participants who achieved hematologic improvement (HI) or better as best response
Description
The percentage of participants achieving [CR + mCR + partial remission (PR) + hematologic improvement (HI)], per modified IWG-MDS Cheson 2006 criteria
Time Frame
Throughout study completion, an average of 3 years
Title
Percentage of participants who are RBC/platelets transfusion independent
Description
Improvement in red blood cells (RBC)/platelets transfusion independence as per IWG-MDS by dose level
Time Frame
Continuously collected from start of treatment up to 3 years from last patient first treatment
Title
Duration of transfusion independence
Description
Transfusion independence as per IWG-MDS by dose level
Time Frame
Continuously collected from start of treatment up to 3 years from last patient first treatment
Title
Peak Serum Concentration (Cmax) MBG453
Description
Maximal concentration of MBG453
Time Frame
Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment
Title
Trough Serum Concentration (Cmin) MBG453
Description
Concentration of sabatolimab prior to next dosing or after end of treatment
Time Frame
Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment
Title
Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment by dose level
Description
Immunogenicity of sabatolimab prior to sabatolimab exposure and during treatment
Time Frame
Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment
Title
Duration of complete remission (CR)
Description
Duration of CR is defined as time from first occurrence of CR to relapse from CR, progression or death due to any cause whichever occurs first
Time Frame
Throughout study completion, an average of 3 years
Title
Time to complete remission(CR)/marrow complete remission (mCR)
Description
Time to CR/mCR is defined as time from start of treatment to first occurrence of CR or mCR as per investigator assessment
Time Frame
Throughout study completion, an average of 3 years
Title
Duration of CR/mCR
Description
Duration of CR/mCR is defined as time from first occurrence of CR/mCR to relapse from CR, progression or death due to any cause whichever occurs first
Time Frame
Throughout study completion, an average of 3 years
Title
Duration of response for participants who achieved hematologic improvement (HI) or better
Description
The duration of response will be derived for participants treated with sabatolimab at the higher dose who achieve HI or better as per investigator assessment and is defined from the first occurrence of CR, mCR, PR or HI until relapse, progression or death due to any reason
Time Frame
Throughout study completion, an average of 3 years
Title
Progression-Free Survival (PFS)
Description
Time from start of treatment to disease progression (including transformation to acute leukemia per WHO 2016 classification), relapse from CR or death due to any cause, whichever occurs first
Time Frame
Throughout study completion, an average of 3 years
Title
Leukemia-Free Survival (LFS)
Description
Time from start of treatment to transformation to acute leukemia [as defined as ≥ 20% blasts in bone marrow/ peripheral blood (per WHO 2016 classification) or diagnosis of extramedullary acute leukemia or death due to any cause, whichever occurs first]
Time Frame
Throughout study completion, an average of 3 years
Title
Event-Free Survival (EFS)
Description
Time from start of treatment to lack of reaching CR within the first 6 cycles, relapse from CR or death due to any cause, whichever occurs first
Time Frame
Throughout study completion, an average of 3 years
Title
Overall Survival (OS)
Description
Time from start of treatment to death due to any cause
Time Frame
Date of start of treatment to date of death due to any reason (for up to 3 years from last patient first treatment)
Title
Changes in fatigue (Part 2 - Expansion)
Description
Changes in fatigue as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue for participants treated with sabatolimab at the higher dose of the expansion part only. Measurements are taken via scores from 0 (not at all) to 4 (very much). The higher the score, the better the Quality of Life.
Time Frame
Throughout the Expansion Phase, an average of 3 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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 (ICF)
Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) based on 2016 WHO 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) (Greenberg et al 2012):
Very high (> 6 points)
High (> 4.5-6 points)
Not immediately eligible for hematopoietic stem-cell transplantation (HSCT) or intensive chemotherapy at the time of screening due to individual clinical factors such as age, comorbidities and performance status, donor availability (de Witte et al 2017)
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
Exclusion Criteria:
Prior exposure to TIM-3 directed therapy or any BCL-2 inhibitor (including venetoclax) at any time
Prior therapy with immune check point inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2) or cancer vaccines is not allowed if the last dose of the drug was administered within 4 months prior to start of treatment
Previous first-line treatment for very high risk or high risk myelodysplastic syndromes (based on IPSS-R,Greenberg et al 2012 and Arber et al, 2016) with any antineoplastic agents, approved or investigational, including for example chemotherapy, lenalidomide and hypomethylating agents (HMAs) such as decitabine or azacitidine However, a one single cycle of HMAs treatment only started prior to enrollment is allowed.
Live vaccine administered within 30 days prior to start of treatment
Current use or use within 14 days prior to start of treatment 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
History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or sabatolimab) or monoclonal antibodies (mAbs) and/or their excipients
Participants with Myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al, 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 4.5
Other protocol-defined Inclusion/Exclusion may apply.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Brasschaat
ZIP/Postal Code
2930
Country
Belgium
Facility Name
Novartis Investigative Site
City
Marseille
ZIP/Postal Code
13273
Country
France
Facility Name
Novartis Investigative Site
City
Nice Cedex
ZIP/Postal Code
06202
Country
France
Facility Name
Novartis Investigative Site
City
Duesseldorf
ZIP/Postal Code
40479
Country
Germany
Facility Name
Novartis Investigative Site
City
Stuttgart
ZIP/Postal Code
70376
Country
Germany
Facility Name
Novartis Investigative Site
City
Alexandroupolis
State/Province
Evros
ZIP/Postal Code
681 00
Country
Greece
Facility Name
Novartis Investigative Site
City
Patras
ZIP/Postal Code
265 00
Country
Greece
Facility Name
Novartis Investigative Site
City
Nyiregyhaza
ZIP/Postal Code
4400
Country
Hungary
Facility Name
Novartis Investigative Site
City
Genova
State/Province
GE
ZIP/Postal Code
16132
Country
Italy
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08036
Country
Spain
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
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.
IPD Sharing URL
https://www.clinicalstudydatarequest.com
Learn more about this trial
A Study of Sabatolimab in Combination With Azacitidine and Venetoclax in High or Very High Risk MDS Participants
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