Adult subjects with intermediate, high or very high risk myelodysplastic syndrome (MDS) as per IPSS-R criteria MedDRA version: 20.0 Level: HLT Classification code 10028536 Term: Myelodysplastic syndromes System Organ Class: 100000004851
Conditions
Interventions
Product Code: MBG453
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Not yet defined
Current Sponsor code: MBG453
Sponsors
Novartis Farmacéutica, S.A.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion 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 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 (> 6 points) • High (> 4.5-6 points) • Intermediate (> 3-4.5 points): a subject determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of >/= 5% bone marrow blast 4. Not suitable for intensive chemotherapy based on investigator assessment of age, comorbidities, local guidelines, institutional practice (any or all of these). 5. No planned hematopoietic stem-cell transplantation (HSCT). 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 36 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 84
Exclusion criteria
Exclusion criteria: 1. 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 only if the last dose of the drug was administered more than 4 months prior to randomization. 2. 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 . However, previous treatment is permitted with hydroxyurea or leukopheresis. 3. History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, decitabine or MGB453) or monoclonal antibodies (mAbs) and/or their excipients. 4. Current use or use within 14 days prior to randomization of systemic, steroid therapy (>10mg/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. 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. 6. Active autoimmune disease requiring systemic therapy (e.g. corticosteroids). 7. Live vaccine administered within 30 days prior to randomization.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - 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 ; Secondary Objective: - To assess Overall Survival in each treatment arm - To assess Leukemia-free survival in each treatment - To assess responses rate in each treatment arm - To assess duration of complete remission in each treatment arm - To assess time to complete remission in each treatment arm. - To assess the improvement in RBC/platelets transfusion independence in each treatment arm. - To assess the safety profile of MBG453 when given in combination with HMA - To characterize the pharmacokinetics of MBG453 when given in combination with HMA - To evaluate immunogenicity of MBG453 when given in combination of HMA ; Primary end point(s): - Complete remission(CR) rate according to International Working Group (IWG) for MDS (protocol section 8.3) as per investigator assessment (protocol section 12.4.1.1) - PFS is defined as time from randomization to disease progression (including transformation to leukemia per WHO 2016 classification), relapse from CR according to IWG-MDS (protocol section 8.3) or death due to any cause, whichever occurs first, as per investigator assessment (protocol section 12.4.1.2) ; Timepoint(s) of evaluation of this end point: Response assessments based on bone marrow asssessments at C4D1, C7D1, C10D1, and C13D1 and hematology assessments at D1, D8 and D22 of each cycle until end of treatment. After C13D1, bone marrow assessments done every 6 cycles (C19D1, C25D1, etc.) and hematology assessments every 2 months. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Overall survival: Time from randomization to death due to any cause 2. Leukemia-free survival: Time from randomization to = 20% myeloblasts in bone-marrow/peripheral blood (per WHO 2016 classification) or death due to any cause 3. Percentage of CR/mCR/PR according to IWG-MDS as per investigator assessment 4. Duration of CR: Time from the date of the first documented CR to the date of relapse from CR or death due to any cause, whichever occurs first 5. Time from randomization to the first documented CR 6. Number and percent of subjects who are transfusion independent (Section 8.3) after randomization as per IWG-MDS 7. Incidence and severity of AEs and SAEs, changes in laboratory values and vital signs, incidence of notable ECG abnormalities 8. Serum concentrations and pharmacokinetic parameters for MBG453 9. Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on treatment ; Timepoint(s) of evaluation of this end point: 1. At 28 months after first patient randomized or at the latest 4 years after the first patient randomized 2. Based on bone marrow asssessments at C4D1, C7D1, C10D1, and C13D1 and after C13D1, every 6 cycles (C19D1, C25D1, etc.) and if clinically indicated at any time during the study 3., 4. and 5. Same timepoints as for the primary endpoints 6. and 7. For AEs and transfusions throughout the trial. For laboratory values, vital signs and ECG at various points throughout the duration of the trial (see protocol for details) 8. and 9. PK and IG at D8 of each cycle until cycle 6 (only PK at C2) and at day 8 of cycles 9, 12, 18 and 24, end of treatment, and after EOT. Soluble TIM-3 at Cycle 1 Day 1 and Day 8, at day 8 of cycles 3 and 6. | — |
Countries
Argentina, Austria, Belgium, Canada, Czech Republic, France, Germany, Greece, Hong Kong, Hungary, Italy, Japan, Korea, Republic of, Norway, Spain, Sweden, Taiwan, Turkey, United Kingdom, United States
Contacts
Public ContactTrial Monitoring Organization (TMo)
Novartis Farmacéutica, S.A.
Outcome results
None listed