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)
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| ClinicalTrials.gov Identifier: NCT03946670 |
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Recruitment Status :
Active, not recruiting
First Posted : May 13, 2019
Last Update Posted : March 27, 2023
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Myelodysplastic Syndromes | Drug: MBG453 Drug: Placebo Drug: Hypomethylating agents | Phase 2 |
The 2 primary objectives are as follows:
To determine if MBG453 combined with standard HMA therapy improves complete remission in subjects with intermediate, high, or very high risk MDS.
To determine if MBG453 combined with standard HMA therapy improves PFS in subjects with intermediate, high or very high risk MDS.
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, as per investigators' choice based on local standard of care (SOC)) in adult subjects with IPSS-R intermediate, high or very high risk myelodysplastic syndrome (MDS) not eligible for HSCT or intensive chemotherapy. Approximately 120 subjects were randomized in a 1:1 ratio to treatment arms as follows:
MBG453 400 mg IV Q2W and decitabine or azacitidine Placebo IV Q2W and decitabine or azacitidine
The randomization was stratified by 2 stratification factors: a) HMA (decitabine or azacitidine) selected by the investigator as per the local standard of care (SOC) and b) IPSS-R prognostic risk categories (intermediate, high or very high) at randomization. Crossover between treatment arms was not permitted at any time during the study.
| 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 |
| Actual Primary Completion Date : | April 26, 2022 |
| Estimated Study Completion Date : | August 10, 2024 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: MBG453 + hypomethylating agents
Patients are taking MBG453 plus hypomethylating agents
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Drug: MBG453
MBG453 is being administered i.v.
Other Name: Sabatolimab Drug: Hypomethylating agents Decitabine is being administered i.v. Azacitidine is being administered i.v or s.c. |
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Placebo Comparator: Placebo + hypomethylating agents
Patients are taking placebo plus hypomethylating agents
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Drug: Placebo
Placebo is being administered i.v. Drug: Hypomethylating agents Decitabine is being administered i.v. Azacitidine is being administered i.v or s.c. |
- Complete remission (CR) rate [ Time Frame: up to 7 months after last patient first visit (LPFV) ]
CR: where the Bone marrow: ≤ 5% blasts with normal maturation of all cell lineages and Peripheral blood: where Hgb ≥ 10 g/dL AND Platelets ≥ 100*109/L AND Neutrophils ≥ 1.0*109/L AND Nlasts 0%.
Modified response criteria According to International Working Group (IWG) and as per World Health Organization (WHO) criteria for Myelodysplastic syndromes (MDS) as per investigator assessment. Response criteria in MDS are described as Complete remission (CR), marrow Complete remission (mCR), Partial Remission (PR), Stable Disease (SD), Relapse from CR, Disease Progression including transformation to acute leukemia.
- Progression Free Survival (PFS) [ Time Frame: Up to 20 months 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
- 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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)
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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
- 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
- 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.
- 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 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.
- 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.
- History of severe hypersensitivity reactions to any ingredient of the study treatment (azacitidine, decitabine or MGB453) or their excipients, or to monoclonal antibodies (mAbs).
- 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.
- 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.
- Active autoimmune disease requiring systemic therapy (e.g.corticosteroids).
- Live vaccine administered within 30 Days prior to randomization.
Other protocol-defined Inclusion/Exclusion may apply.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03946670
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| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT03946670 |
| Other Study ID Numbers: |
CMBG453B12201 2018-004479-11 ( EudraCT Number ) |
| First Posted: | May 13, 2019 Key Record Dates |
| Last Update Posted: | March 27, 2023 |
| Last Verified: | March 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| 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. |
| URL: | https://www.clinicalstudydatarequest.com |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Sabatolimab Phase II MBG453 TIM-3 |
decitabine azacitidine myelodysplastic syndrome (MDS) |
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Preleukemia Myelodysplastic Syndromes Syndrome Disease Pathologic Processes |
Bone Marrow Diseases Hematologic Diseases Precancerous Conditions Neoplasms |