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 (per IPSS-R prognostic risk categories) myelodysplastic syndrome or with Chronic Myelomonocytic Leukemia - 2 (CMML-2) |
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E.1.1.1 | Medical condition in easily understood language |
intermediate, high or very high risk myelodysplastic syndrome or with Chronic Myelomonocytic Leukemia - 2 |
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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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009018 |
E.1.2 | Term | Chronic myelomonocytic leukaemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 compare overall survival (OS) in the MBG453 plus azacitidine arm versus placebo plus azacitidine arm |
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E.2.2 | Secondary objectives of the trial |
Key Secondary:
1:compare time to definitive deterioration of fatigue in the MBG453 plus azacitidine arm versus placebo plus azacitidine arm
2: compare RBC transfusion-free intervals in the MBG453 plus azacitidine arm vs placebo plus azacitidine arm
3: compare improvement of fatigue in the MBG453 plus azacitidine arm vs placebo plus azacitidine arm
4: compare improvement of physical functioning in the MBG453 plus azacitidine arm vs placebo plus azacitidine arm
5: compare improvement of emotional functioning in the MBG453 plus azacitidine arm vs placebo plus azacitidine arm
Other:
•assess response rate in each treatment arm
•assess PFS in each treatment arm
•assess leukemia-free survival in each treatment arm
•assess safety profile of MBG453 when given in combination with azacitidine
•assess improvement in RBC/Platelets transfusion independence in each treatment arm
•characterize the PK of MBG453
•evaluate immunogenicity of MBG453
•assess overall QoL in each treatment arm |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Actigraphy substudy:
Activity monitoring sensors (Actigraphy) will be used in the study to record daily physical activity and sleep quality and will be offered to a subset of subjects as an additional, optional assessment. |
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E.3 | Principal inclusion criteria |
Key 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 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 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
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
Please refer to protocol for further details and any additional inclusion criteria. |
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E.4 | Principal exclusion criteria |
Key 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-2 with any antineoplastic agents including for example chemotherapy, lenalidomide and hypomethylating agents (HMAs) such as decitabine or azacitidine. However, previous treatment with hydroxyurea or leukopheresis to reduce WBC count is allowed prior to randomization.
• 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.
• 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 therapy related myeloid neoplasms based on WHO 2016 classification
(Arber et al 2016)
• History of organ or allogeneic hematopoietic stem cell transplant
Please refer to protocol for further details and any additional exclusion criteria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
OS is the time from randomization until death due to any cause. If the subject is not known to have died, then OS will be censored at the latest date the subject was known to be alive (on or before cut-off date).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Estimated at 28 months and 33 months after first patient randomized and up to 5 years after the first patient randomized |
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E.5.2 | Secondary end point(s) |
Key secondary endpoints:
1. Time from randomization to at least 3 points worsening from baseline in FACIT-fatigue scores with no subsequent improvement above this threshold or death due to any cause, whichever occurs first
2. Cumulative time of intervals with no evidence of RBC transfusion for at least 8 weeks at any point after randomization
3. Percent of subjects with at least 3 point confirmed improvement from baseline in FACIT-fatigue scores
4. Percent of subjects with at least 10 point confirmed improvement from baseline in physical functioning using EORTC QLQ-C30
5. Percent of subjects with at least 10 point confirmed improvement from baseline in emotional functioning using EORTC QLQ-C30
Other endpoints:
a) Percentage of CR/mCR/PR/HI according to IWG-MDS as per investigator assessment; Percentage of SD according to IWG-MDS as per investigator assessment
b) Time from randomization to disease progression (including transformation to acute leukemia per WHO 2016 classification), relapse from complete remission (CR) according to IWG-MDS or death due to any cause, whichever occurs first, as per investigator assessment
c) Time from randomization to ≥ 20% blasts in bone marrow/peripheral blood (per WHO 2016 classification) or diagnosis of extramedullary acute leukemia, or death due to any cause
d) Incidence and severity of AEs and SAEs, changes in laboratory values and vital signs (per CTCAE version 5)
e) Number and percent of transfusion dependent subjects at baseline who become RBC/platelets transfusion independent after randomization as per IWG-MDS criteria
f) Serum concentrations and pharmacokinetic parameters for MBG453
g) Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment
h) Change from baseline in EQ-5D-5L scores and VAS scores over time; Change from baseline to C12D1 of Global Health Status/QoL scores using EORTC QLQ-C30 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1&3 C3D1 & every 2 cycles, EOT & every 12wks. Estimated at 33mths & up to 5yrs after first patient (FP) rando. 2 Throughout trial. Est at 28 & 33mths and up to 5yrs after FP rando. 4&5 C3/C6/C9D1, after C15 every 3 cycles, EOT & every 12wks. Est at 33mths & up to 5yrs after FP rando.
a/b/c C7/C13D1 & every 12 cycles up to 5yrs after FP rando. d AEs, throughout trial. Hematology, D1+D8 of each cycle until EOT & every 12wks. Chemistry, D1 of each cycle until C7 & C9 & every 2 cycles after until EOT. Vital signs, D1+D8 of each cycle until EOT. e Throughout trial up to 5yrs after FP rando. f/g PK & IG, D8 of each cycle until C6, C9, C12 & every 6 cycles after, EOT, 30 & 150 days after EOT. Soluble Tim-3, D8 of C1/C3/C6. h C3D1, after every 3 cycles, EOT & every 12wks. Analysis at C12D1. |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 47 |
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 |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Chile |
China |
Colombia |
Czech Republic |
Finland |
France |
Germany |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Lebanon |
Lithuania |
Malaysia |
Mexico |
Netherlands |
Oman |
Portugal |
Russian Federation |
Saudi Arabia |
Singapore |
Spain |
Switzerland |
Taiwan |
Thailand |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 4 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 3 |