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

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))

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:

1. Screening period (signing of written informed consent through Day 1);
2. Core phase for 12 months;
3. Extension phase for efficacy and/or survival status (up to 12 months after core phase)
4. 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).

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 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:

  1. Participants with history of lower risk MDS treated by supportive care (e.g. growth factors, TGF-beta agents) or untreated are eligible
  2. Participants with history of lower risk MDS who were treated adequately with lenalidomide and then failed are eligible
  3. 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