STIMULUS MDS-US : Sabatolimab Added to HMA in Higher Risk MDS

Single-arm, Open Label, Phase II Study of MBG453 (Sabatolimab) Added to FDA Approved Hypomethylating Agents of Investigator's Choice (IV/SC/Oral) for Patients With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R Criteria (US Multi-center) (STIMULUS MDS-US)

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04878432

Enrollment

Registered

2021-05-07

Start date

2022-03-17

Completion date

2024-09-01

Last updated

2025-10-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Myelodysplastic Syndrome (MDS)

Keywords

sabatolimab, phase II, MBG453, TIM-3, decitabine, azacitidine, oral decitabine, INQOVI, myelodysplastic syndrome (MDS), adult, MDS

Brief summary

The main objective of this study was to assess the safety profile of MBG453 (sabatolimab) in combination with FDA approved hypomethylating agents (HMAs) of investigator's choice (IV Decitabine or Azacitidine /SC Azacitidine /Oral Decitabine (cedazuridine combination (INQOVI))).

Detailed description

This was a single arm, nonrandomized, open label, Phase II multicenter study of i.v sabatolimab added to FDA approved HMA agents of Investigator's choice (i.v/s.c/oral) in adult patients with intermediate, high or very high risk MDS as per IPSS-R criteria. There were 4 separate periods of this study: 1. Screening period (signing of written informed consent through day of enrollment), 2. Core phase for up to 12 months, 3. Extension phase for efficacy and/or survival status (up to 12 months after the core phase), 4. Post-treatment safety follow-up period monitoring for AEs for 30 days following the last dose of azacitidine or decitabine or INQOVI (oral decitabine), or 150 days following the last dose of sabatolimab, whichever was later. During the conduct of the study there were 2 updates to the Novartis development strategy for sabatolimab. Based on the results from the Phase II STIMULUS MDS-1 study, recruitment was halted for CMBG453B1US01 (STIMULUS MDS-US) on 30-Sep-2022. Novartis confirmed the decision to halt recruitment was not based on any safety findings or safety concerns. Patients who were on study treatment or in follow-up were continued as per the protocol. Furthermore, on 11-Jan-2024, all sabatolimab investigators were notified by Novartis that, based on decision taken in Dec-2023, that the sabatolimab development program (which included study CMBG453B1US01) would be terminated. After the decision was made to discontinue the sabatolimab development program, participants already enrolled in the CMBG453B1US01 study were prepared for closure; these close out activities took approximately 9 months. The actual last patient last visit date was 1 Sep 2024.

Interventions

DRUGMBG453

Solution for intravenous infusion

DRUGAzacitidine

Solution for subcutaneous injection or intravenous administration

DRUGDecitabine

Solution for intravenous administration

DRUGINQOVI (oral decitabine)

Tablet for oral administration

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 99 Years

Healthy volunteers

Inclusion criteria

Key inclusion criteria: 1. Signed informed consent was 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) primary or secondary based on 2016 WHO classification by Investigator assessment with one of the following prognostic risk categories, based on the International Prognostic Scoring System (IPSS-R).. Note: MDS diagnosis history were recorded in the CRF: * Very high (\> 6 points) * High (\> 4.5 to ≤ 6 points) * Intermediate (\> 3 to ≤ 4.5 points) 4. Not suitable at the time of Screening for immediate myeloablative/chemotherapy or HSCT based on Investigator assessment of age, comorbidities, local guidelines, institutional practice (any or all of these). 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. 6. AST and ALT ≤ 3 × upper limit of normal (ULN). 7. Total bilirubin ≤ 2 × ULN (except in the setting of isolated Gilbert syndrome). 8. Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 (estimation based on modification of diet in renal disease formula, by local laboratory). 9. Patient was able to communicate with the Investigator and had the ability to comply with the requirements of the study procedures. Key

Exclusion criteria

1. 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 were allowed only if the last dose of the drug was administered more than 4 months prior to enrollment. 2. Previous treatment for intermediate, high or very high risk MDS (based on IPSS-R) with chemotherapy or other antineoplastic agents including lenalidomide and hypomethylating agent (HMAs) such as decitabine or INQOVI (oral decitabine) or azacitidine (patients who had up to 1 cycle of HMAs were included). However, previous treatment with hydroxyurea was permitted. 3. Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and extra-medullary acute myeloid leukemia based on WHO 2016 classification. 4. Diagnosis of Chronic myelomonocytic leukemia (CMML), or primary or secondary myelofibrosis based on 2016 WHO classification. 5. History of organ transplant or allogenic HSCT. 6. Patients with prior malignancy, except: 1. Patients with history of lower risk Myelodysplastic syndrome (MDS) treated by supportive care (e.g., growth factors, transforming growth factor- beta agents) or untreated were eligible. 2. Patients with history of lower risk MDS who were treated adequately with lenalidomide and then failed were eligible. 3. Patients with history of adequately treated malignancy for which no anticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) was ongoing or required during the course of the study. Patients who were receiving adjuvant therapy such as hormone therapy were eligible. 7. Patients with MDS based on 2016 WHO classification with revised International Prognostic Scoring System (IPSS-R) ≤ 3.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	Adverse events are reported from the first dose of study medication up to approximately 24 months plus 30 - 150 day safety follow up dependent on HMA, for a maximum timeframe of approximately 29 months.	An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product.

Secondary

Measure	Time frame	Description
Number of Participants With Progression Free Survival - Death and Disease Progression	up to Month 24	Defined as time from enrollment 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 by 12 months post last patient first treatment (LPFT).
Progression Free Survival - 50th Percentile	up to Month 24	Defined as time from enrollment 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 by 12 months post last patient first treatment (LPFT).
Progression Free Survival - Percent Probability - Kaplan-Meier Probability Estimates	Months 6 and 12	Defined as time from enrollment 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 by 12 months post last patient first treatment (LPFT).
Overall Survival - Number of Participants Who Died	up to Month 24	Overall Survival (OS) is defined as the time from the first dose of study medication to death due to any cause.
Overall Survival - 50th Percentile	up to Month 24	Overall Survival (OS) is defined as the time from the first dose of study medication to death due to any cause.
Overall Survival - Percent Probability - Kaplan-Meier Probability Estimates	up to Month 24	Overall Survival (OS) is defined as the time from the first dose of study medication to death due to any cause.
Leukemia-free Survival - Number of Participants Who Died and Number of Participants Who Progressed to Leukemia	up to Month 24	Leukemia-free survival (LFS) is the time from the date of the first dose of medication to ≥ 20% blasts in bone marrow/peripheral blood (per WHO 2016 classification) or death due to any cause.
Number of Participants With Complete Remission According to International Working Group (IWG) for MDS (2006) With MBG453 (Sabatolimab) in Combination With HMAs (IV/SC/Oral) by 12 Months.	up to Month 12	Complete remission rate was assessed according to International Working Group (IWG) for MDS (2006) with MBG453 (sabatolimab) in combination with HMAs (IV/SC/Oral) in Participants with intermediate, high, or very high risk MDS by 12 months.
Leukemia-free Survival - Percent Probability - Kaplan-Meier Probability Estimates	Months 6 and 12	Leukemia-free survival (LFS) is the time from the date of the first dose of medication to ≥ 20% blasts in bone marrow/peripheral blood (per WHO 2016 classification) or death due to any cause.
Percentage of Participants With Complete Remission, Marrow Complete Remission and/or Partial Remission	up to Month 24	Percentage of complete remission, marrow complete remission, and/or partial remission according to IWG-MDS remission criteria as per investigator assessment
Time to Complete Remission	up to Month 24	Time to Complete Remission is defined as the time from the date of the first dose of study medication to the first documented CR.
Improvement in Packed RBCs Transfusion Independence - Mean Total Duration (Weeks) of Transfusion Independence Post-baseline	up to Month 24	RBC/Platelets transfusion independence is defined as a participant having received \<0 units RBC/Platelets transfusions during at least 8 consecutive weeks after enrollment.
Number of Participants With Improvement in Packed RBCs Transfusion Independence - At Least One Period of Transfusion Independence Post Baseline	up to Month 24	RBC/Platelets transfusion independence rate is defined as the percentage of participants having received \<0 units RBC/Platelets transfusions during at least 8 consecutive weeks after enrollment.
Improvement in Platelets Transfusion Independence - Mean Total Duration (Weeks) of Transfusion Independence Post-baseline	up to Month 24	RBC/Platelets transfusion independence is defined as a participant having received \<0 units RBC/Platelets transfusions during at least 8 consecutive weeks after enrollment
Number of Participants With Improvement in Platelets Transfusion Independence - At Least One Period of Transfusion Independence Post Baseline	up to Month 24	RBC/Platelets transfusion independence rate is defined as the proportion of participants having received \<0 units RBC/Platelets transfusions during at least 8 consecutive weeks after enrollment.
Leukemia-free Survival - 50th Percentile	up to Month 24	Leukemia-free survival (LFS) is the time from the date of the first dose of medication to ≥ 20% blasts in bone marrow/peripheral blood (per WHO 2016 classification) or death due to any cause.

Countries

United States

Participant flow

Participants by arm

Arm	Count
MBG453 (Sabatolimab) + Hypomethylating Agents (HMA) MBG453 400 mg/4 ml + HMA (azacitidine 75 mg/m\^2, decitabine 20 mg/m\^2, or INQOVI (oral decitabine) 100 mg cedazuridine/35 mg)	39
Total	39

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	1
Overall Study	Death	2
Overall Study	New Therapy for Study Indication	7
Overall Study	Physician Decision	11
Overall Study	Progressive Disease	7
Overall Study	Unsatisfactory Therapeutic Effect	3
Overall Study	Withdrawal by Subject	6

Baseline characteristics

Characteristic	MBG453 (Sabatolimab) + Hypomethylating Agents (HMA)
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	25 Participants
Age, Categorical Between 18 and 65 years	14 Participants
Age, Continuous	67.8 Years STANDARD_DEVIATION 11.49
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	2 Participants
Race (NIH/OMB) Black or African American	2 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants
Race (NIH/OMB) White	31 Participants
Sex: Female, Male Female	14 Participants
Sex: Female, Male Male	25 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	20 / 39
other Total, other adverse events	35 / 39
serious Total, serious adverse events	23 / 39

Outcome results

Primary

Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events

An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product.

Time frame: Adverse events are reported from the first dose of study medication up to approximately 24 months plus 30 - 150 day safety follow up dependent on HMA, for a maximum timeframe of approximately 29 months.

Population: Safety set - The SS included all patients who received at least one dose of any component of the study medication (sabatolimab+HMA).

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
MBG453 (Sabatolimab) + Hypomethylating Agents (HMA)	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	Fatal SAEs	0 Participants
MBG453 (Sabatolimab) + Hypomethylating Agents (HMA)	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	Adverse events (AEs)	39 Participants
MBG453 (Sabatolimab) + Hypomethylating Agents (HMA)	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	Treatment-related Adverse events	30 Participants
MBG453 (Sabatolimab) + Hypomethylating Agents (HMA)	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	AEs with grade ≥ 3	35 Participants
MBG453 (Sabatolimab) + Hypomethylating Agents (HMA)	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	Treatment-related AEs with grade ≥ 3	25 Participants
MBG453 (Sabatolimab) + Hypomethylating Agents (HMA)	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	Serious Adverse Events (SAEs)	23 Participants
MBG453 (Sabatolimab) + Hypomethylating Agents (HMA)	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	Treatment-related SAEs	8 Participants
MBG453 (Sabatolimab) + Hypomethylating Agents (HMA)	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	Treatment-related Fatal SAEs	0 Participants
MBG453 (Sabatolimab) + Hypomethylating Agents (HMA)	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	AEs leading to discontinuation	3 Participants
MBG453 (Sabatolimab) + Hypomethylating Agents (HMA)	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	Treatment-related AEs leading to discontinuation	3 Participants
MBG453 (Sabatolimab) + Hypomethylating Agents (HMA)	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	AEs leading to dose adjustment/interruption	8 Participants
MBG453 (Sabatolimab) + Hypomethylating Agents (HMA)	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	AEs requiring additional therapy	32 Participants

Secondary

Improvement in Packed RBCs Transfusion Independence - Mean Total Duration (Weeks) of Transfusion Independence Post-baseline

RBC/Platelets transfusion independence is defined as a participant having received \<0 units RBC/Platelets transfusions during at least 8 consecutive weeks after enrollment.

Time frame: up to Month 24