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

Study Overview
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Brief Summary
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Main objective of this study is to describe and evaluate safety and efficacy of MBG453 (sabatolimab) in combination with FDA approved HMAs of investigator's choice (IV Decitabine or Azacitidine /SC Azacitidine /Oral Decitabine (cedazuridine combination (INQOVI))

Detailed Description
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This is a single-arm, non- randomized, open label, phase II multi-center study of intravenous MBG453 (sabatolimab) added to FDA approved Hypomethylating agents of investigator's choice (IV/SC/ Oral) in adult participants with intermediate, high or very high risk myelodysplastic syndrome (MDS) as per IPSS-R criteria. There are three separate periods of this study: Screening period (signing of written informed consent through Day 1); Core phase for 24 months (with post treatment safety follow-up monitoring for adverse events (AEs) for 30 days following the last dose of azacitidine or decitabine or INQOVI (oral decitabine), or 150 days following the last dose of MBG453 (sabatolimab), whichever is later); Extension phase for efficacy and/or survival status (up to 36 months from last patient enrolling) (with post treatment safety follow-up monitoring for adverse events (AEs) for 30 days following the last dose of azacitidine or decitabine or INQOVI (oral decitabine), or 150 days following the last dose of MBG453 (sabatolimab), whichever is later).

Official Title
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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)

Conditions
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Myelodysplastic Syndrome (MDS)

Intervention / Treatment
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* Drug: MBG453
* Drug: Azacitidine
* Drug: Decitabine
* Drug: INQOVI (oral decitabine)


Participation Criteria
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Eligibility Criteria
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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 a myelodysplastic syndrome (MDS) primary or secondary 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). Note: MDS diagnosis history will be recorded in the CRF: Very high (> 6 points) High (> 4.5 - ≤ 6 points) Intermediate (> 3 - ≤ 4.5 points) Not suitable at the time of screening for immediate myeloablative/ chemotherapy or hematopoietic stem cell transplantation based on investigator assessment of age, comorbidities, local guidelines, institutional practice (any or all of these). Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. AST and ALT ≤ 3 × upper limit of normal (ULN). Total bilirubin ≤ 2 × ULN (except in the setting of isolated Gilbert syndrome). Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73m2 (estimation based on Modification of Diet in Renal Disease (MDRD) formula, by local laboratory). Patient is able to communicate with the investigator and has the ability to comply with the requirements of the study procedures. 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 are allowed only if the last dose of the drug was administered more than 4 months prior to enrollment. Previous treatment for intermediate, high or very high risk myelodysplastic syndromes (based on IPSS-R) with chemotherapy or other antineoplastic agents including lenalidomide and hypomethylating agent (HMAs) such as decitabine or azacitidine or INQOVI (oral decitabine) (patients who had up to 1 cycle of HMAs can be included). However, previous treatment with hydroxyurea is permitted. Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and extra-medullary acute myeloid leukemia based on WHO 2016 classification (Arber et al 2016). Diagnosis of Chronic myelomonocytic leukemia (CMML), or primary or secondary myelofibrosis based on 2016 WHO classification (Arber et al 2016). History of organ transplant or allogenic hematopoietic stem cell transplant Participants with prior malignancy, except: Participants with history of lower risk MDS treated by supportive care (e.g. growth factors, TGF-beta agents) or untreated are eligible Participants with history of lower risk MDS who were treated adequately with lenalidomide and then failed are eligible Participants with history of adequately treated malignancy for which no anticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during the course of the study. Participants who are receiving adjuvant therapy such as hormone therapy are eligible. Participants with Myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 3

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MBG453 (sabatolimab) + HMA<br>MBG453 + HMA (azacitidine, decitabine, or INQOVI (oral decitabine)) | Drug: MBG453<br>* Solution for intravenous infusion<br>* Other names: sabatolimab;Drug: Azacitidine<br>* Solution for subcutaneous injection or intravenous infusion<br>Drug: Decitabine<br>* Solution for intravenous infusion<br>Drug: INQOVI (oral decitabine)<br>* Tablet for oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of treatment emergent adverse events and serious adverse events | Adverse events will be assessed at each visit. Any clinically significant laboratory value or vital sign determined by the investigator to meet the definition of an adverse event will be reported. | Baseline up to approximately 36 months plus 30 - 150 day safety follow up dependent on HMA | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission (CR) rate according to International Working Group (IWG) for MDS (2006) * as per investigator assessment by 12 months. | Complete remission with MBG453 (sabatolimab) in combination with HMAs (IV/SC/Oral) in participants with intermediate, high, or very high risk MDS by 12 months | Baseline, by 12 months | 
| Progression free survival in participants with intermediate, high or very high risk MDS | 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 24 months and during extension phase to 36 months post LPFV | Baseline, every 12 weeks up to approximately 36 months | 
| Overall Survival | Time from enrollment to death due to any cause | Baseline, every 12 weeks up to approximately 36 months | 
| Leukemia-free survival | Time from enrollment to > 20% blasts in bone marrow/peripheral blood (per WHO 2016 classification) or death due to any cause | Baseline, every 12 weeks up to approximately 36 months | 
| Percentage of participants with complete response, marrow complete response and/or partial response | Percentage of complete response, marrow complete response, and/or partial response according to IWG-MDS response criteria as per investigator assessment | Baseline, every 12 weeks up to approximately 36 months | 
| Duration of complete remission | 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 | Baseline, every 12 weeks up to approximately 36 months | 
| Time to complete remission | Time from first treatment to the first documented complete remission | Baseline, every 12 weeks up to approximately 36 months | 
| Percentage of participants with improvement in RBC/platelets transfusion independence | Transfusion independence is defined as less than 3 units of transfusion within any 8 consecutive weeks on study | Baseline, every 12 weeks up to approximately 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sabatolimab, phase II, MBG453, TIM-3, decitabine, azacitidine, oral decitabine, INQOVI, myelodysplastic syndrome (MDS), adult, MDS