Study of efficacy and safety of MBG453 in combination with azacitidine in subjects with intermediate, high or very high risk myelodysplastic syndrome (MDS) as per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2)

JRCT ID: jRCT2080225135

Registered date:19/03/2020

Basic Information

• Recruitment status: completed
• Health condition(s) or Problem(s) studied: MDS, CMML-2
• Date of first enrollment: 31/05/2020
• Target sample size: 49
• Countries of recruitment: Japan,Asia except Japan,North America,South America,Europe
• Study type: Interventional

Intervention(s)

Active agent arm: MBG453 800 mg Q4W i.v. plus Aza 75 mg/m2 i.v. or s.c.
Pracebo arm: Placebo 800 mg Q4W i.v. plus Aza 75 mg/m2 i.v. or s.c.

Outcome(s)

Primary Outcome

efficacy
To compare overall survival (OS) in the MBG453 plus azacitidine arm versus placebo plus azacitidine arm

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1. Signed informed consent must be 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 myelodysplastic syndrome (MDS) based on WHO 2016 classification by local investigator assessment with one of the following Prognostic Risk Categories, based on the revised International Prognostic Scoring System (IPSS-R) as per Greenberg et al 2012:
-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 by local investigator assessment with WBC < 13 x 109/L at time of initial diagnosis
4. Indication for azacitidine treatment according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions
5. 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 including assessment of individual clinical factors such as age, comorbidities and performance status.
6. 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 including assessment of individual clinical factors such as age, comorbidities, performance status, and donor availability.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
8. Estimated Glomerular Filtration Rate (eGFR) >= 30 mL/min/1.73m2 (estimation based on Modification of Diet in Renal Disease (MDRD) formula, by local laboratory)
9. AST and ALT =< 3 x upper limit of normal (ULN)
10. Total bilirubin =< 1.5 x ULN (except in the setting of isolated Gilbert syndrome, where subjects may only be included with direct bilirubin =< 1.5 x ULN)
11. Subject is able to communicate with the investigator, and has the ability to comply with the requirements of the study procedures

Exclude 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 is allowed except if the drug was administered within 4 months prior to randomization.
2. 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 decitabine or azacitidine. However, previous treatment with hydroxyurea or leukapheresis to reduce WBC count is allowed prior to randomization.
3. Investigational treatment received within 4 weeks or 5 half-lives of this investigational treatment, whatever is longer, prior to randomization.
In case of a checkpoint inhibitor: a minimal interval of 4 months prior to randomization is necessary to allow randomization.
4. 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.
5. Live vaccine administered within 30 days prior to randomization.
6. History of severe hypersensitivity reaction to any ingredients of the study treatments (azacitidine or MBG453) or their excipients, or to monoclonal antibodies.
7. Subjects with Myelodysplastic syndrome (MDS) based on 2016 WHO classification with revised International Prognostic Scoring System (IPSS-R) <= 3.
8. Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and extra-medullary acute myeloid leukemia based on WHO 2016 classification.
9. Diagnosis of primary or secondary myelofibrosis grade 2 or higher based on WHO 2016 classification.
10. Diagnosis of therapy related myeloid neoplasms based on WHO 2016 classification.
11. History of organ transplant or allogeneic hematopoietic stem cell transplant.
12. Subjects with prior malignancy, except:
a) subjects with history of lower risk MDS treated by supportive care (e.g. growth factors, TGF-beta agents) or untreated are eligible
b) subjects with history of lower risk MDS who were treated adequately with lenalidomide and then failed are eligible
c) 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 neoplasm are not eligible
13. Active autoimmune disease requiring systemic therapy (e.g. 10 mg/day prednisone or equivalent or any immunosuppressive therapy)
14. 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.
15. Active Hepatitis B (HBV) or Hepatitis C (HCV) infection. Subjects whose disease is controlled under antiviral therapy should not be excluded.
16. HIV infection not controlled by standard therapy and/or with known history of opportunistic infection.
17. Any other co-morbidity that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol.

Related Information

• Primary Sponsor: Novartis Pharma. K.K.
• Source(s) of Monetary Support: -
• Secondary ID(s): NCT04266301,JapicCTI-205231