Clinical Trials

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.
• Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) based on WHO 2016 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):
  • Very high (> 6 points);
  • High (> 4.5 - ≤ 6 points);
  • Intermediate (> 3 - ≤ 4.5 points); or
  • Morphologically confirmed diagnosis of Chronic Myelomonocytic Leukemia-2 based on WHO 2016 classification (Arber et al 2016) by local investigator assessment with WBC < 13 x 10^9/L.
• Indication for azacitidine treatment according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions.
• Not eligible at time of screening for intensive chemotherapy according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions, including assessment of individual clinical factors such as age, comorbidities and performance status.
• Not eligible at 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, including assessment of individual clinical factors such as age, comorbidities, performance status, and donor availability (de Witte et al 2017).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
• Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73m^2 (estimation based on Modification of Diet in Renal Disease (MDRD) formula, by local laboratory).
• AST and ALT ≤ 3 × upper limit of normal (ULN).
• Total bilirubin ≤ 1.5 × ULN (except in the setting of isolated Gilbert syndrome, where subjects may only be included with direct bilirubin ≤ 1.5 x ULN).
• Subject 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 is allowed except if the drug was administered within 4 months prior to randomization.
• Previous first-line treatment for intermediate, high, very high risk myelodysplastic syndromes (based on IPSS-R) or CMML with any antineoplastic agents including for example chemotherapy, lenalidomide and hypomethylating agents (HMAs) such as decitibine and azacitidine. However, previous treatment with hydroxyurea or leukopheresis to reduce WBC count is allowed prior to randomization.
• Investigational treatment received within 4 weeks prior to randomization. In case of a checkpoint inhibitor: a minimal interval of 4 months prior to randomization is necessary to allow randomization.
• Current use or use 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.
• Live vaccine administered within 30 days prior to randomization.
• History of severe hypersensitivity reaction to any ingredients of the study treatments (azacitidine or MBG453) or their excipients, or to monoclonal antibodies.
• Subjects with Myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 3.
• Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and extra-medullary acute myeloid leukemia, primary or secondary myelofibrosis based on WHO 2016 classification (Arber et al 2016).
• Diagnosis of primary or secondary myelofibrosis grade 2 or higher based on WHO 2016 classification (Arber et al 2016). Patients with myelofibrosis grade 1 must not be enrolled if they have symptoms of concurrent myeloproliferative neoplasm (e.g., splenomegaly, constitutional symptoms, proliferative features and WBC not increased).
• Diagnosis of therapy related myeloid neoplasms based on WHO 2016 classification (Arber et al 2016).
• History of organ transplant or allogeneic hematopoietic stem cell transplant.
• Subjects with prior malignancy, except:
  • subjects with history of lower risk MDS treated by supportive care (e.g., growth factors, TGF-beta agents) or untreated are eligible;
  • subjects with history of lower risk MDS who were treated adequately with lenalidomide and then failed are eligible;
  • subjects with history of adequately treated malignancy for whom no anticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during the course of the study. Subjects who are receiving adjuvant therapy such as hormone therapy are eligible. However, subjects who developed therapy related neoplams are not eligible.
• Active autoimmune disease requiring systemic therapy (e.g., 10 mg/day prednisone or equivalent or any immunosuppressive therapy).
• Any concurrent severe and/or uncontrolled medical condition including significant cardiac or cardiac repolarization abnormalities, history of QT prolongation or QTcF > 470 ms at screening. Subjects with active infection requiring parenteral antibacterial, antiviral or antifungal therapy which are controlled by adequate treatment are eligible.
• Active Hepatitis B (HBV) or Hepatitis C (HCV) infection. Subjects whose disease is controlled under antiviral therapy should not be excluded. 
• HIV infection not controlled by standard therapy and/or with known history of opportunistic infection.
• Any other co-morbidity that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol.
• Sexually active males unwilling to use a condom during intercourse while taking azacitidine and for 3 months after stopping this treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above, and female partners will be instructed to use highly effective contraception.
• Subject is pregnant or breastfeeding.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 3 months after the last dose of azacitidine (or as per the respective local label, whichever is longer) and 150 days after the last dose of MBG453 or placebo. Highly effective contraception methods include:
  • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception;
  • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment;
  • Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject;
  • Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.

Eligibility last updated 2/3/22. Questions regarding updates should be directed to the study team contact.