Acute Myeloid Leukemia
Conditions
Keywords
MBG453, Venetoclax, Azacitidine, Phase 2, AML, Acute myeloid Leukemia, Sabatolimab
Brief summary
This trial seeked to extend the preliminary findings of efficacy by evaluating MBG453 in combination with hypomethylating agents (HMA) and also Bcl-2 inhibitor venetoclax.
Detailed description
The primary purpose of Part 1 (Safety Run-in) was to rule out excessive toxicity of MBG453, when administered in combination with azacitidine and venetoclax. The primary purpose of the combined Part 1 and Part 2 (Safety run-in and Expansion Part) was to evaluate efficacy of MBG453, when administered in combination with azacitidine and venetoclax in adult patients with newly diagnosed AML, who were not suitable for treatment with intensive chemotherapy. Originally, there was an analysis planned of the complete response (CR) rate, after all subjects had completed at least 12 cycles of treatment (each cycle = 28 Days) or discontinued earlier. As Novartis decided to end the development of this compound, this primary analysis was skipped and only the final study analysis presented here. At the final analysis timepoint, there was only 1 patient who didn't completed the 12 cycles of treatment or discontinued earlier.
Interventions
DRUGMBG453
Solution for intravenous infusion
DRUGVenetoclax
Tablet for oral administration
DRUGAzacitidine
Solution for subcutaneous injection or intravenous infusion
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
safety -run -in with escalating dose of MBG453 followed by expansion
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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) * Newly diagnosed with AML based on 2016 WHO classification (Arber et al 2016) and not suitable for intensive chemotherapy defined as: age ≥75, ECOG performance Status 2 or 3, or any of the following comomorbitities: severe cardiac comorbities (including congestive heart failure, LVEF ≤ 50%, chronic stable Angina) , pulmonary comorbidity (DLCO ≤ 65% or FEVI ≤ 65%). moderate hepatic impairment (with total Bilirubin \>1.5 to 3x ULN) , renal impairment (eGFR≥ 30 ml/min/1.73m\^2 to \<45 ml/min/1.73m\^2), or other comorbidity incompatible with intensive chemotherapy per Investigator assessement and approved by the Novartis Medical monitor) * Not planned for hematopoietic stem-cell transplantation (HSCT) * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 , 2 or 3
Exclusion criteria
* Prior exposure to TIM-3 directed therapy * History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or MGB453) or monoclonal antibodies (mAbs) and/or their excipients * 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. * Previous treatment at any time, with any of the following antineoplastic agents, approved or investigational; checkpoint inhibitors, venetoclax and hypomethylating agents (HMAs) such as decitabine or azacitidine. * Active autoimmune disease requiring systemic therapy (e.g.corticosteroids). * Live vaccine administered within 30 Days prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Dose Limiting Toxicities (DLT)(Safety run-in Patients Only) | From Cycle 1 Day 8 to end of Cycle 2; Cycle =28 Days | A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value considered by the Investigator to be at least possibily related to MBG453 as a single contributor or in combination with other component(s) of study treatment that occurs during the DLT observation period and meets any of the criteria as per protolcol. |
| Percentage of Participants Achieving Complete Remission (CR) (CR Rate) | approx. 31 months | CR rate is defined as the percentage of participants achieving a complete remission (CR) as per investigator assessment (based on IWG Cheson et al 2003, ELN 2017 Dohner et al 2017). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Complete Remission (CR) | approx. 31 months | The duration of CR is defined as the time from first achievement of CR to the first documented relapse or progressive disease or death due to any cause, whichever occurs first. The response assessment is as per investigator assessment based on IWG (Cheson et al 2003) and ELN 2017 (Dohner et al 2017). |
| Percentage of Participants Achieving a Complete Remission (CR) or Complete Remission With Incomplete Hematologic Blood Count Recovery (CRi) (CR/CRi Rate) | approx. 31 months | CR/CRi rate is defined as the percentage pf participants with best overall response of either complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) as per investigator assessment (based on IWG (Cheson et al 2003) and ELN 2017 (Dohner et al 2017)). |
| The Duration of Complete Remission (CR)/Complete Remission With Incomplete Blood Count Recovery (CRi) | approx. 31 months | The duration of CR/CRi is defined as the time from first achievement of CR or CRi to the first documented relapse or progressive disease or death due to any cause, whichever occurs first. The response assessment is as per investigator assessment based on IWG (Cheson et al 2003) and ELN 2017 (Dohner et al 2017). |
| Percentage of Participants Achieving a Complete Remission (CR) or Complete Remission With Partial Hematologic Blood Count Recovery (CRh) (CR/CRh Rate) | approx. 31 months | CR/CRh rate is defined as the percentage of participants with best overall response of either complete remission (CR) or complete remission with partial hematologic recovery (CRh) as per derivation based on ELN 2022 (Döhner et al 2022). |
| Duration of CR/CRh | approx. 31 months | The duration of CR/CRh is defined as the time from date of first documented CR or CRh to the date of first documented relapse or death due to any cause, whichever occurs first. The response assessment is as per derivation based on ELN 2022 (Döhner et al 2022). |
| Event Free Survival (EFS) | approx. 31 months | EFS is the time from start of treatment until death due to any cause, relapse from complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), or treatment failure, whichever occurs first. Treatment failure was defined as lack of reaching CR until Cycle 8 Day 1 or earlier permanent discontinuation from study without reaching CR, the time to treatment failure was then set to Day 1. |
| Measurable Residual Disease (MRD) - Negativity Rate: Full Study Population | approx. 31 months | MRD negativity rate was defined as the percentage of participants with MRD negativity, which was defined as an MRD negative sample (frequency of LAIP below 0.1%, as determined by Multi-parameter Flow Cytometry-Measurable residual disease (MFC-MRD) at Central Lab) in participant with remission (i.e., CR or CRi) as per investigator assessment (based on IWG Cheson et al 2003, ELN 2017 Dohner et al 2017). MRD-negative response was required to be observed at or after morphological remission, and prior to relapse or disease progression. |
| Peak Serum Concentration (Cmax) of MBG453 | Cycle 1 Day 8 (end of infusion) and Cycle 3 Day 8 (end of infusion), cycle = 28 days | Cmax is the maximal concentration of MBG453. |
| Trough Serum Concentration (Cmin) MBG453 | Day 8 of Cycle 1,2,3,6,9,12,18, 24 and through treatment completion, an average of 24 months | Cmin is the minimum concentration of MBG453 (i.e., prior to the next dosing). |
| Trough Plasma Concentration (Cmin) Venetoclax | 0 hr (Pre-dose) of Day 8 of Cycle 1, 3 and 6 ; Cycle =28 days | Trough concentration of venetoclax on treatment |
| Anti-drug Antibody (ADA) Prevalence at Baseline and ADA Positive Participants On-treatment | at baseline, up to 150 days after last treatment, approx. 24 months | Immunogenicity (IG) to MBG453 prior to MBG453 exposure. ADA prevalence (i.e., ADA-positive samples) is the number of ADA-positive samples among the number of participants with a non-missing sample. |
| Rate of Participants Who Achieved Transfusion Independence From Baseline and While on Treatment | approx. 31 months | Percentage of participants having received no RBC/Platelets transfusions during at least 8 consecutive weeks. |
| Overall Survival (OS) | approx. 31 months | OS is the time from start of treatment to death due to any cause. If a participant was not known to have died, then OS was censored at the latest date the participant was known to be alive (on or before the cut-off date). |
| Measurable Residual Disease (MRD) - Negativity Rate in Participants With Best Overall Response (BOR) of CR/CRi and Evaluable MRD | approx. 31 months | MRD negativity rate was defined as the percentage of participants with MRD negativity, which was defined as an MRD negative sample (frequency of LAIP below 0.1%, as determined by Multi-parameter Flow Cytometry-Measurable residual disease (MFC-MRD) at Central Lab) in participant with remission (i.e., CR or CRi) as per investigator assessment (based on IWG Cheson et al 2003, ELN 2017 Dohner et al 2017). MRD-negative response was required to be observed at or after morphological remission, and prior to relapse or disease progression. |
Countries
Australia, Canada, France, Germany, Italy, Japan, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
This study was conducted in 28 centers across 10 countries with a total of 90 participants enrolled.
Pre-assignment details
Informed consent was obtained from each participant in writing before screening before any study specific procedure was performed.
Participants by arm
| Arm | Count |
|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine Participants received 400 mg MBG453 in combination with Venetoclax (VEN) and Azacitidine (AZA). This arm was used in Part 1 (Safety Run-in phase) of the study. | 5 |
| MBG453 800 mg + Venetoclax +Azacitidine Participants received 800 mg MBG453 in combination with Venetoclax (VEN) and Azacitidine (AZA). This arm was used in Part 1 (Safety Run-in phase) and Part 2 (Expansion Part) of the study. | 85 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 11 |
| Overall Study | Death | 0 | 8 |
| Overall Study | Disease Relapse | 0 | 18 |
| Overall Study | Hemopoietic Stem Cell Transplant (HSCT) | 1 | 5 |
| Overall Study | Participant Decision | 0 | 7 |
| Overall Study | Physician Decision | 0 | 10 |
| Overall Study | Progressive Disease | 2 | 16 |
| Overall Study | Study Terminated by Sponsor | 1 | 10 |
Baseline characteristics
| Characteristic | MBG453 400 mg + Venetoclax +Azacitidine | MBG453 800 mg + Venetoclax +Azacitidine | Total |
|---|---|---|---|
| Age, Continuous | 76.8 Years STANDARD_DEVIATION 4.97 | 76.1 Years STANDARD_DEVIATION 6.33 | 76.1 Years STANDARD_DEVIATION 6.24 |
| Body surface area (BSA) | 1.88 m^2 STANDARD_DEVIATION 0.105 | 1.84 m^2 STANDARD_DEVIATION 0.252 | 1.84 m^2 STANDARD_DEVIATION 0.246 |
| ECOG performance status ECOG performance status: 0 | 1 Participants | 14 Participants | 15 Participants |
| ECOG performance status ECOG performance status: 1 | 2 Participants | 43 Participants | 45 Participants |
| ECOG performance status ECOG performance status: 2 | 2 Participants | 24 Participants | 26 Participants |
| ECOG performance status ECOG performance status: 3 | 0 Participants | 4 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 13 Participants | 13 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 69 Participants | 74 Participants |
| Sex: Female, Male Female | 1 Participants | 38 Participants | 39 Participants |
| Sex: Female, Male Male | 4 Participants | 47 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 5 | 56 / 85 |
| other Total, other adverse events | 5 / 5 | 85 / 85 |
| serious Total, serious adverse events | 4 / 5 | 67 / 85 |
Outcome results
Primary
Incidence of Dose Limiting Toxicities (DLT)(Safety run-in Patients Only)
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value considered by the Investigator to be at least possibily related to MBG453 as a single contributor or in combination with other component(s) of study treatment that occurs during the DLT observation period and meets any of the criteria as per protolcol.
Time frame: From Cycle 1 Day 8 to end of Cycle 2; Cycle =28 Days
Population: The Dose-Determining Set (DDS) included all participants from the FAS enrolled in the safety run-in part who met the minimum exposure criterion and had sufficient safety evaluations or experienced a dose limiting toxicity (DLT) starting from Cycle 1 Day 8 to the end of Cycle 2.~FAS comprised all participants who received at least one dose of any component of the study treatment (i.e. at least one dose of sabatolimab or at least one dose of azacitidine or at least one dose of venetoclax).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Incidence of Dose Limiting Toxicities (DLT)(Safety run-in Patients Only) | Participants with at least 1 event - All grades | 0 Participants |
| MBG453 400 mg + Venetoclax +Azacitidine | Incidence of Dose Limiting Toxicities (DLT)(Safety run-in Patients Only) | Cardiac disorders - All grades | 0 Participants |
| MBG453 400 mg + Venetoclax +Azacitidine | Incidence of Dose Limiting Toxicities (DLT)(Safety run-in Patients Only) | Participants with at least 1 event - Grade >= 3 | 0 Participants |
| MBG453 400 mg + Venetoclax +Azacitidine | Incidence of Dose Limiting Toxicities (DLT)(Safety run-in Patients Only) | Cardiac disorders - Grades >= 3 | 0 Participants |
| MBG453 800 mg + Venetoclax +Azacitidine | Incidence of Dose Limiting Toxicities (DLT)(Safety run-in Patients Only) | Participants with at least 1 event - Grade >= 3 | 0 Participants |
| MBG453 800 mg + Venetoclax +Azacitidine | Incidence of Dose Limiting Toxicities (DLT)(Safety run-in Patients Only) | Participants with at least 1 event - All grades | 1 Participants |
| MBG453 800 mg + Venetoclax +Azacitidine | Incidence of Dose Limiting Toxicities (DLT)(Safety run-in Patients Only) | Cardiac disorders - Grades >= 3 | 0 Participants |
| MBG453 800 mg + Venetoclax +Azacitidine | Incidence of Dose Limiting Toxicities (DLT)(Safety run-in Patients Only) | Cardiac disorders - All grades | 1 Participants |
Primary
Percentage of Participants Achieving Complete Remission (CR) (CR Rate)
CR rate is defined as the percentage of participants achieving a complete remission (CR) as per investigator assessment (based on IWG Cheson et al 2003, ELN 2017 Dohner et al 2017).
Time frame: approx. 31 months
Population: All participants in the Full Analysis Set (FAS) and assigned to MBG453 at the 800 mg Q4W dose level. FAS comprised all participants who received at least one dose of any component of the study treatment (i.e. at least one dose of sabatolimab or at least one dose of azacitidine or at least one dose of venetoclax).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Percentage of Participants Achieving Complete Remission (CR) (CR Rate) | 47.06 Percentage of participants |
Secondary
Anti-drug Antibody (ADA) Prevalence at Baseline and ADA Positive Participants On-treatment
Immunogenicity (IG) to MBG453 prior to MBG453 exposure. ADA prevalence (i.e., ADA-positive samples) is the number of ADA-positive samples among the number of participants with a non-missing sample.
Time frame: at baseline, up to 150 days after last treatment, approx. 24 months
Population: Immunogenicity Incidence Set includes all participants in the Immunogenicity prevalence set with a non-missing baseline ADA sample and at least one non-missing post-baseline ADA sample.~The Immunogenicity prevalence set includes all participants in the Safety Set with a non-missing baseline ADA sample or at least one non-missing post-baseline ADA sample.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Anti-drug Antibody (ADA) Prevalence at Baseline and ADA Positive Participants On-treatment | ADA prevalence at baseline (BL) | 0 Participants |
| MBG453 400 mg + Venetoclax +Azacitidine | Anti-drug Antibody (ADA) Prevalence at Baseline and ADA Positive Participants On-treatment | ADA-positive participants on-treatment | 1 Participants |
| MBG453 800 mg + Venetoclax +Azacitidine | Anti-drug Antibody (ADA) Prevalence at Baseline and ADA Positive Participants On-treatment | ADA prevalence at baseline (BL) | 4 Participants |
| MBG453 800 mg + Venetoclax +Azacitidine | Anti-drug Antibody (ADA) Prevalence at Baseline and ADA Positive Participants On-treatment | ADA-positive participants on-treatment | 9 Participants |
Secondary
Duration of Complete Remission (CR)
The duration of CR is defined as the time from first achievement of CR to the first documented relapse or progressive disease or death due to any cause, whichever occurs first. The response assessment is as per investigator assessment based on IWG (Cheson et al 2003) and ELN 2017 (Dohner et al 2017).
Time frame: approx. 31 months
Population: The Full Analysis Set (FAS) comprised all participants who received at least one dose of any component of the study treatment (i.e. at least one dose of sabatolimab or at least one dose of azacitidine or at least one dose of venetoclax). This was based on participants with best overall response of CR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Duration of Complete Remission (CR) | NA Months |
| MBG453 800 mg + Venetoclax +Azacitidine | Duration of Complete Remission (CR) | 10.28 Months |
Secondary
Duration of CR/CRh
The duration of CR/CRh is defined as the time from date of first documented CR or CRh to the date of first documented relapse or death due to any cause, whichever occurs first. The response assessment is as per derivation based on ELN 2022 (Döhner et al 2022).
Time frame: approx. 31 months
Population: The Full Analysis Set (FAS) comprised all participants who received at least one dose of any component of the study treatment (i.e. at least one dose of sabatolimab or at least one dose of azacitidine or at least one dose of venetoclax). This was based on participants with best overall response of CR or CRh.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Duration of CR/CRh | NA Months |
| MBG453 800 mg + Venetoclax +Azacitidine | Duration of CR/CRh | 12.45 Months |
Secondary
Event Free Survival (EFS)
EFS is the time from start of treatment until death due to any cause, relapse from complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), or treatment failure, whichever occurs first. Treatment failure was defined as lack of reaching CR until Cycle 8 Day 1 or earlier permanent discontinuation from study without reaching CR, the time to treatment failure was then set to Day 1.
Time frame: approx. 31 months
Population: The Full Analysis Set (FAS) comprised all participants who received at least one dose of any component of the study treatment (i.e. at least one dose of sabatolimab or at least one dose of azacitidine or at least one dose of venetoclax).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Event Free Survival (EFS) | 8.28 Months |
| MBG453 800 mg + Venetoclax +Azacitidine | Event Free Survival (EFS) | 0.03 Months |
Secondary
Measurable Residual Disease (MRD) - Negativity Rate: Full Study Population
MRD negativity rate was defined as the percentage of participants with MRD negativity, which was defined as an MRD negative sample (frequency of LAIP below 0.1%, as determined by Multi-parameter Flow Cytometry-Measurable residual disease (MFC-MRD) at Central Lab) in participant with remission (i.e., CR or CRi) as per investigator assessment (based on IWG Cheson et al 2003, ELN 2017 Dohner et al 2017). MRD-negative response was required to be observed at or after morphological remission, and prior to relapse or disease progression.
Time frame: approx. 31 months
Population: The Full Analysis Set (FAS) comprised all participants who received at least one dose of any component of the study treatment (i.e. at least one dose of sabatolimab or at least one dose of azacitidine or at least one dose of venetoclax).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Measurable Residual Disease (MRD) - Negativity Rate: Full Study Population | 60.0 Percentage of participants |
| MBG453 800 mg + Venetoclax +Azacitidine | Measurable Residual Disease (MRD) - Negativity Rate: Full Study Population | 42.4 Percentage of participants |
Secondary
Measurable Residual Disease (MRD) - Negativity Rate in Participants With Best Overall Response (BOR) of CR/CRi and Evaluable MRD
MRD negativity rate was defined as the percentage of participants with MRD negativity, which was defined as an MRD negative sample (frequency of LAIP below 0.1%, as determined by Multi-parameter Flow Cytometry-Measurable residual disease (MFC-MRD) at Central Lab) in participant with remission (i.e., CR or CRi) as per investigator assessment (based on IWG Cheson et al 2003, ELN 2017 Dohner et al 2017). MRD-negative response was required to be observed at or after morphological remission, and prior to relapse or disease progression.
Time frame: approx. 31 months
Population: All participants in FAS with the best overall response of CR or CRi and who are evaluable for MRD. The Full Analysis Set (FAS) comprised all participants who received at least one dose of any component of the study treatment (i.e. at least one dose of sabatolimab or at least one dose of azacitidine or at least one dose of venetoclax). A participant is considered as evaluable for MRD if he/she had at least one post-baseline sample with MRD negative or MRD positive.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Measurable Residual Disease (MRD) - Negativity Rate in Participants With Best Overall Response (BOR) of CR/CRi and Evaluable MRD | 100.0 Percentage of participants |
| MBG453 800 mg + Venetoclax +Azacitidine | Measurable Residual Disease (MRD) - Negativity Rate in Participants With Best Overall Response (BOR) of CR/CRi and Evaluable MRD | 73.5 Percentage of participants |
Secondary
Overall Survival (OS)
OS is the time from start of treatment to death due to any cause. If a participant was not known to have died, then OS was censored at the latest date the participant was known to be alive (on or before the cut-off date).
Time frame: approx. 31 months
Population: The Full Analysis Set (FAS) comprised all participants who received at least one dose of any component of the study treatment (i.e. at least one dose of sabatolimab or at least one dose of azacitidine or at least one dose of venetoclax).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Overall Survival (OS) | 11.17 Months |
| MBG453 800 mg + Venetoclax +Azacitidine | Overall Survival (OS) | 13.27 Months |
Secondary
Peak Serum Concentration (Cmax) of MBG453
Cmax is the maximal concentration of MBG453.
Time frame: Cycle 1 Day 8 (end of infusion) and Cycle 3 Day 8 (end of infusion), cycle = 28 days
Population: The sabatolimab pharmacokinetic analysis set included all participants from the Safety Set who provided at least one evaluable sabatolimab PK concentration for the two populations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Peak Serum Concentration (Cmax) of MBG453 | Cycle 1 Day 8: 2 hr (post-dose) | 84.0 ug/ml | Geometric Coefficient of Variation 20 |
| MBG453 400 mg + Venetoclax +Azacitidine | Peak Serum Concentration (Cmax) of MBG453 | Cycle 3 Day 8: 2 hr (post-dose) | 129 ug/ml | Geometric Coefficient of Variation 4.9 |
| MBG453 800 mg + Venetoclax +Azacitidine | Peak Serum Concentration (Cmax) of MBG453 | Cycle 1 Day 8: 2 hr (post-dose) | 204 ug/ml | Geometric Coefficient of Variation 35.3 |
| MBG453 800 mg + Venetoclax +Azacitidine | Peak Serum Concentration (Cmax) of MBG453 | Cycle 3 Day 8: 2 hr (post-dose) | 261 ug/ml | Geometric Coefficient of Variation 40.9 |
Secondary
Percentage of Participants Achieving a Complete Remission (CR) or Complete Remission With Incomplete Hematologic Blood Count Recovery (CRi) (CR/CRi Rate)
CR/CRi rate is defined as the percentage pf participants with best overall response of either complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) as per investigator assessment (based on IWG (Cheson et al 2003) and ELN 2017 (Dohner et al 2017)).
Time frame: approx. 31 months
Population: The Full Analysis Set (FAS) comprised all participants who received at least one dose of any component of the study treatment (i.e. at least one dose of sabatolimab or at least one dose of azacitidine or at least one dose of venetoclax).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Percentage of Participants Achieving a Complete Remission (CR) or Complete Remission With Incomplete Hematologic Blood Count Recovery (CRi) (CR/CRi Rate) | 80.0 Percentage of participants |
| MBG453 800 mg + Venetoclax +Azacitidine | Percentage of Participants Achieving a Complete Remission (CR) or Complete Remission With Incomplete Hematologic Blood Count Recovery (CRi) (CR/CRi Rate) | 69.4 Percentage of participants |
Secondary
Percentage of Participants Achieving a Complete Remission (CR) or Complete Remission With Partial Hematologic Blood Count Recovery (CRh) (CR/CRh Rate)
CR/CRh rate is defined as the percentage of participants with best overall response of either complete remission (CR) or complete remission with partial hematologic recovery (CRh) as per derivation based on ELN 2022 (Döhner et al 2022).
Time frame: approx. 31 months
Population: The Full Analysis Set (FAS) comprised all participants who received at least one dose of any component of the study treatment (i.e. at least one dose of sabatolimab or at least one dose of azacitidine or at least one dose of venetoclax).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Percentage of Participants Achieving a Complete Remission (CR) or Complete Remission With Partial Hematologic Blood Count Recovery (CRh) (CR/CRh Rate) | 80.0 Percentage of participants |
| MBG453 800 mg + Venetoclax +Azacitidine | Percentage of Participants Achieving a Complete Remission (CR) or Complete Remission With Partial Hematologic Blood Count Recovery (CRh) (CR/CRh Rate) | 50.6 Percentage of participants |
Secondary
Rate of Participants Who Achieved Transfusion Independence From Baseline and While on Treatment
Percentage of participants having received no RBC/Platelets transfusions during at least 8 consecutive weeks.
Time frame: approx. 31 months
Population: The Full Analysis Set (FAS) comprised all participants who received at least one dose of any component of the study treatment (i.e. at least one dose of sabatolimab or at least one dose of azacitidine or at least one dose of venetoclax).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Rate of Participants Who Achieved Transfusion Independence From Baseline and While on Treatment | RBC: transfusion independence at post-BL | 60.0 Percentage of participants |
| MBG453 400 mg + Venetoclax +Azacitidine | Rate of Participants Who Achieved Transfusion Independence From Baseline and While on Treatment | Platelet transfusion independence at post-baseline | 60.0 Percentage of participants |
| MBG453 800 mg + Venetoclax +Azacitidine | Rate of Participants Who Achieved Transfusion Independence From Baseline and While on Treatment | RBC: transfusion independence at post-BL | 57.6 Percentage of participants |
| MBG453 800 mg + Venetoclax +Azacitidine | Rate of Participants Who Achieved Transfusion Independence From Baseline and While on Treatment | Platelet transfusion independence at post-baseline | 65.9 Percentage of participants |
Secondary
The Duration of Complete Remission (CR)/Complete Remission With Incomplete Blood Count Recovery (CRi)
The duration of CR/CRi is defined as the time from first achievement of CR or CRi to the first documented relapse or progressive disease or death due to any cause, whichever occurs first. The response assessment is as per investigator assessment based on IWG (Cheson et al 2003) and ELN 2017 (Dohner et al 2017).
Time frame: approx. 31 months
Population: The Full Analysis Set (FAS) comprised all participants who received at least one dose of any component of the study treatment (i.e. at least one dose of sabatolimab or at least one dose of azacitidine or at least one dose of venetoclax). This was based on participants with best overall response of CR or CRi.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | The Duration of Complete Remission (CR)/Complete Remission With Incomplete Blood Count Recovery (CRi) | NA Months |
| MBG453 800 mg + Venetoclax +Azacitidine | The Duration of Complete Remission (CR)/Complete Remission With Incomplete Blood Count Recovery (CRi) | 8.54 Months |
Secondary
Trough Plasma Concentration (Cmin) Venetoclax
Trough concentration of venetoclax on treatment
Time frame: 0 hr (Pre-dose) of Day 8 of Cycle 1, 3 and 6 ; Cycle =28 days
Population: The venetoclax pharmacokinetic analysis set included all participants from the Safety Set who provided at least one evaluable venetoclax PK concentration for the two populations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Trough Plasma Concentration (Cmin) Venetoclax | Cycle 1 day 8: 0 hr pre-dose) | 378 ng/ml | Geometric Coefficient of Variation 86.4 |
| MBG453 400 mg + Venetoclax +Azacitidine | Trough Plasma Concentration (Cmin) Venetoclax | Cycle 3 day 8: 0 hr pre-dose) | 730 ng/ml | Geometric Coefficient of Variation 8.6 |
| MBG453 800 mg + Venetoclax +Azacitidine | Trough Plasma Concentration (Cmin) Venetoclax | Cycle 1 day 8: 0 hr pre-dose) | 972 ng/ml | Geometric Coefficient of Variation 97.5 |
| MBG453 800 mg + Venetoclax +Azacitidine | Trough Plasma Concentration (Cmin) Venetoclax | Cycle 3 day 8: 0 hr pre-dose) | 1010 ng/ml | Geometric Coefficient of Variation 154.8 |
| MBG453 800 mg + Venetoclax +Azacitidine | Trough Plasma Concentration (Cmin) Venetoclax | Cycle 6 day 8: 0 hr pre-dose) | 959 ng/ml | Geometric Coefficient of Variation 64.1 |
Secondary
Trough Serum Concentration (Cmin) MBG453
Cmin is the minimum concentration of MBG453 (i.e., prior to the next dosing).
Time frame: Day 8 of Cycle 1,2,3,6,9,12,18, 24 and through treatment completion, an average of 24 months
Population: The sabatolimab pharmacokinetic analysis set included all participants from the Safety Set who provided at least one evaluable sabatolimab PK concentration for the two populations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 1 Day 8: 0 hr (pre-dose) | 0 ug/ml | Geometric Coefficient of Variation 0 |
| MBG453 400 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 2 Day 8: 0 hr (pre-dose) | 8.79 ug/ml | Geometric Coefficient of Variation 70.8 |
| MBG453 400 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 3 Day 8: 0 hr (pre-dose) | 12.4 ug/ml | Geometric Coefficient of Variation 16 |
| MBG453 400 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 6 Day 8: 0 hr (pre-dose) | 17.6 ug/ml | Geometric Coefficient of Variation 0 |
| MBG453 400 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 9 Day 8: 0 hr (pre-dose) | 6.55 ug/ml | Geometric Coefficient of Variation 0 |
| MBG453 400 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 12 Day 8: 0 hr (pre-dose) | 17.4 ug/ml | Geometric Coefficient of Variation 0 |
| MBG453 400 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 18 Day 8: 0 hr (pre-dose) | 9.76 ug/ml | Geometric Coefficient of Variation 0 |
| MBG453 400 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 24 Day 8: 0 hr (pre-dose) | 30.6 ug/ml | Geometric Coefficient of Variation 0 |
| MBG453 800 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 24 Day 8: 0 hr (pre-dose) | 61.4 ug/ml | Geometric Coefficient of Variation 84.1 |
| MBG453 800 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 1 Day 8: 0 hr (pre-dose) | 0 ug/ml | Geometric Coefficient of Variation 0 |
| MBG453 800 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 9 Day 8: 0 hr (pre-dose) | 72.9 ug/ml | Geometric Coefficient of Variation 60 |
| MBG453 800 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 2 Day 8: 0 hr (pre-dose) | 18.8 ug/ml | Geometric Coefficient of Variation 68.9 |
| MBG453 800 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 18 Day 8: 0 hr (pre-dose) | 70.4 ug/ml | Geometric Coefficient of Variation 96.5 |
| MBG453 800 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 3 Day 8: 0 hr (pre-dose) | 30.7 ug/ml | Geometric Coefficient of Variation 80.9 |
| MBG453 800 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 12 Day 8: 0 hr (pre-dose) | 78.1 ug/ml | Geometric Coefficient of Variation 62.7 |
| MBG453 800 mg + Venetoclax +Azacitidine | Trough Serum Concentration (Cmin) MBG453 | Cycle 6 Day 8: 0 hr (pre-dose) | 45.1 ug/ml | Geometric Coefficient of Variation 79.5 |
Post Hoc
All Collected Deaths
Deaths were collected from treatment start until the end of the trial, approx. 31 months including post-treatment and survival follow-up period.
Time frame: from randomization until end of trial, approx. 31 months.
Population: Clinical database population: All participants: participants who died during treatment and post-treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MBG453 400 mg + Venetoclax +Azacitidine | All Collected Deaths | On-treatment deaths | 1 Participants |
| MBG453 400 mg + Venetoclax +Azacitidine | All Collected Deaths | Post-treatment deaths | 2 Participants |
| MBG453 400 mg + Venetoclax +Azacitidine | All Collected Deaths | All deaths | 3 Participants |
| MBG453 800 mg + Venetoclax +Azacitidine | All Collected Deaths | On-treatment deaths | 11 Participants |
| MBG453 800 mg + Venetoclax +Azacitidine | All Collected Deaths | Post-treatment deaths | 45 Participants |
| MBG453 800 mg + Venetoclax +Azacitidine | All Collected Deaths | All deaths | 56 Participants |