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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
90
Solution for intravenous infusion
Tablet for oral administration
Solution for subcutaneous injection or intravenous infusion
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
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
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
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.
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25Uni of Alabama at Birmingham
Birmingham, Alabama, United States
Yale University School Of Medicine
New Haven, Connecticut, United States
Uni Of Iowa Hospitals And Clinics
Iowa City, Iowa, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
Mayo Clinic Rochester
Rochester, Minnesota, United States
Memorial Sloan Kettering
New York, New York, United States
Weill Cornell Medicine NY-Presb
New York, New York, United States
Levine Cancer Insitute Carolinas Healthcare System
Charlotte, North Carolina, United States
Duke Univ Medical Center
Durham, North Carolina, United States
Chattanooga Onc And Hem Assoc PC
Chattanooga, Tennessee, United States
...and 18 more locations
Time frame: approx. 31 months
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
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
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
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
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
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
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
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
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
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
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
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