E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult subjects with intermediate, high or very high risk myelodysplastic syndrome (MDS) as per IPSS-R criteria |
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E.1.1.1 | Medical condition in easily understood language |
intermediate, high or very high risk myelodysplastic syndrome |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10028536 |
E.1.2 | Term | Myelodysplastic syndromes |
E.1.2 | System Organ Class | 100000004851 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• 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
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E.2.2 | Secondary objectives of the trial |
• To assess Overall Survival in each treatment arm • To assess EFS 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
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 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. 5. 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. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. Refer to protocol for complete list of inclusion criteria. |
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E.4 | Principal 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 except if the drug was administered within 4 months prior to randomization. 2. Previous first-line treatment for intermediate, high or very high risk myelodysplastic syndromes (based on IPSS-R) with chemotherapy or any other antineoplastic agents including lenalidomide and hypomethylating agent (HMAs) such as decitabine or azacitidine. 3. History of severe hypersensitivity reactions to any ingredient of the study treatment (azacitidine, decitabine or MGB453) or their excipients, or to monoclonal antibodies (mAbs). 4. Currently using or used 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. 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. Refer to protocol for complete list of exclusion criteria. |
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E.5 End points |
E.5.1 | 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 acute 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)
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E.5.1.1 | 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. If clinically indicated done at any time during the study. CR rate analysis at 18 months after first patient randomized. PFS Interim analysis at 28 months and final analysis at the latest 4 years after the first patient randomized. |
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E.5.2 | Secondary end point(s) |
1. Overall survival: Time from randomization to death due to any cause 2. EFS: Time from randomization to lack of reaching CR within the first 6 months, relapse from CR or death due to any cause, whichever occurs first. CR and relapse from CR are defined according to International Working Group (IWG) for MDS as per investigator assessment. 3. Leukemia-free survival: Time from randomization to ≥ 20% myeloblasts in bone-marrow/peripheral blood (per WHO 2016 classification) or diagnosis of extramedullary acute leukemia or death due to any cause 4. Percentage of CR/mCR/PR according to IWG-MDS as per investigator assessment and HI according to IWG-MDS 5. 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 6. Time from randomization to the first documented CR 7. Number and percent of subjects who are transfusion independent (Section 8.3) after randomization as per IWG-MDS 8. Incidence and severity of AEs and SAEs, changes in laboratory values and vital signs, incidence of notable ECG abnormalities 9. Serum concentrations and pharmacokinetic parameters for MBG453 10. Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on treatment
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E.5.2.1 | 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. Same timepoints as for the primary endpoints 3. 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 4., 5. and 6. Same timepoints as for the primary endpoints 7. and 8. 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) 9. and 10. 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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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 |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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When the last subject finishes End of Treatment or Follow-up visits and any repeat assessments associated with these visits have been documented and followed-up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |