The goal of this clinical study is to compare the effectiveness of the study drugs, magrolimab in combination with azacitidine, versus venetoclax in combination with azacitidine in participants with previously untreated TP53 mutant acute myeloid leukemia (AML).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
258
Administered intravenously (IV).
Administered orally at a dose of 100 milligrams (mg) on Day 1, 200 mg on Day 2, 400 mg on Days 3-28 during Cycle 1, followed by 400 mg on Days 1-28 during every cycle (Cycle=28 days).
Administered either subcutaneously (SC) or IV, 75 milligrams per square meter (mg/m\^2) on Days 1-7 or Days 1-5, 8 and 9 during every cycle (Cycle=28 days).
Overall Survival (OS) in Participants Appropriate for Non-intensive Therapy
OS was measured from the date of randomization to the date of death from any cause. Deaths which were not observed during the study were censored at their last known alive date. Kaplan-Meier (KM) estimates were used in outcome measure analysis.
Time frame: Up to 2.1 years
Overall Survival in All Participants
OS was measured from the date of randomization to the date of death from any cause. Deaths which were not observed during the study were censored at their last known alive date. KM estimates were used in outcome measure analysis.
Time frame: Up to 2.1 years
Event-Free Survival (EFS) in All Participants
EFS: time from randomization to earliest relapse from CR (CR without minimal residual disease (CRMRD-) and CR with MRD positive/MRD unknown (CRMRD+/unk)), treatment failure (failure to achieve CR in 6 months of magrolimab/venetoclax+azacitidine; 2 months after chemotherapy), or death within the response window. CRMRD- and CRMRD+/unk: neutrophils \>1.0 ×10\^9/L, platelets \>100 ×10\^9/L, \<5% bone marrow blasts, no circulating blasts or extramedullary disease (confirmed by flow cytometry \<0.1% sensitivity for CRMRD-). Post-SCT assessments or new AML therapies were included. Date of randomization was assigned as event date for participants with treatment failure. Participants without events were censored at their last assessment. KM estimates were used for analysis.
Time frame: Up to 2.1 years
Rate of Complete Remission (CR) in All Participants
The rate of CR was the percentage of participants who achieved a CR, including CR without minimal residual disease (CR MRD-) and CR with positive or unknown minimal residual disease (CR MRD+/unk) within 6 months of treatment with magrolimab + azacitidine or venetoclax + azacitidine, or within 2 months of treatment with 7 + 3 chemotherapy, as defined by investigators based on European Leukemia Net (ELN) 2017 AML (ELN 2017 AML) with modifications, while on study prior to initiation of any new anti-AML therapy or stem cell transplant (SCT) within the response assessment window of 2.1 years. CR MRD- and CR MRD+/unk are defined in Outcome Measure#3 (EFS). Percentages were rounded-off. Clopper-Pearson method were used in outcome measure analysis.
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Induction: administered continuous infusion, 100 or 200 mg/m\^2 on Days 1-7 (7+3 induction) and if needed Days 1-5 (5+2 induction) during a cycle (Cycle=Up to 42 Days). Consolidation: administered IV, 1500 or 3000 mg/m\^2 on Days 1, 3, and 5 once every 12 hours for up to 4 cycles.
Administered IV peripherally (IVP), 60 mg/m\^2 on Days 1-3 (7+3 induction) and if needed Days 1-2 (5+2 induction) during a cycle (Cycle=Up to 42 days).
Administered IV, 12 mg/m\^2 on Days 1-3 (7+3 induction) and if needed Days 1-2 (5+2 induction) during a cycle (Cycle=Up to 42 days).
Administered per institutional standard during consolidation.
University of Alabama at Birmingham
Birmingham, Alabama, United States
City of Hope (City of Hope National Medical Center, City of Hope Medical Center)
Duarte, California, United States
USC/ Norris Comprehensive Cancer Center
Los Angeles, California, United States
Ronald Reagan UCLA Medical Center
Los Angeles, California, United States
UC Irvine Health
Orange, California, United States
Colorado Blood Cancer Institute
Denver, Colorado, United States
Mayo Clinic Florida
Jacksonville, Florida, United States
Miami Cancer Institute
Miami, Florida, United States
AdventHealth Orlando
Orlando, Florida, United States
Memorial Cancer Institute
Pembroke Pines, Florida, United States
...and 146 more locations
Time frame: Up to 2.1 years
Rate of CR Without Minimal Residual Disease (CR MRD-) in All Participants
Rate of CR MRD- was the percentage of participants who achieve a CR MRD- within 6 months treatment with magrolimab + azacitidine or venetoclax + azacitidine, or within 2 months of treatment with 7 + 3 chemotherapy, as defined by investigators based on ELN 2017 AML with modifications, while on study prior to initiation of any new anti-AML therapy or SCT within the response assessment window of 2.1 years. CR MRD- is defined in Outcome Measure #3 (EFS). Percentages were rounded-off. Clopper-Pearson method were used in outcome measure analysis.
Time frame: Up to 2.1 years
Rate of CR and CR With Partial Hematologic Recovery (CR+CRh) in All Participants
The CR+CRh rate was the percentage of participants who achieved a CR (including CR MRD- and CR MRD+/unk) or CRh as defined by CR with partial platelet and absolute neutrophil count (ANC) recovery within 6 months of treatment with magrolimab + azacitidine or venetoclax + azacitidine, or within 2 months of treatment with 7 + 3 chemotherapy while on study prior to initiation of any new anti-AML therapy or SCT up to the response assessment window of 2.1 years. CRh is defined as neutrophils \> 0.5 x 10\^9/L; platelets \> 50 x 10\^9/L; bone marrow blasts \< 5%; Absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CR MRD- and CR MRD+/unk are defined in Outcome Measure#3 (EFS). Percentages were rounded-off. Clopper-Pearson method were used in outcome measure analysis.
Time frame: Up to 2.1 years
Duration of CR (DCR)
DCR was measured from the time the assessment criteria were first met for CR (including CR MRD- and CR MRD+/unk) within 6 months of treatment with magrolimab + azacitidine or venetoclax + azacitidine, or within 2 months of treatment with 7 + 3 chemotherapy, until the first date of AML relapse or death (including assessments post SCT). Participants who were not observed to have relapsed disease or death while on study were censored at the date of their last response assessment with no evidence of relapse. Participants who started taking new anti-AML therapies (excluding post-SCT maintenance therapy) before relapse, the DCR were censored at the last response assessment before the initiation of the new anti-AML therapies. CR MRD- and CR MRD+/unk are defined in Outcome Measure#3 (EFS). KM estimates were used in outcome measure analysis.
Time frame: Up to 2.1 years
Duration of CR+CRh
Duration of CR+CRh was measured from the time the assessment criteria were first met for CR (including CR MRD- and CR MRD+/unk) or CRh within 6 months of treatment with magrolimab + azacitidine or venetoclax + azacitidine, or within 2 months of treatment with 7 + 3 chemotherapy, until the first date of AML relapse or death (including assessments post SCT). Participants who were not observed to have relapsed disease or death while on study were censored at the date of their last response assessment with no evidence of relapse. Participants who started taking new anti-AML therapies (excluding post-SCT maintenance therapy) before relapse, the duration of CR + CRh were censored at the last response assessment before the initiation of the new anti-AML therapies. CR MRD- and CR MRD+/un are defined in Outcome Measure #3. CRh is defined in Outcome Measure #6. KM estimates were used for outcome measure analysis.
Time frame: Up to 2.1 years
Percentage of Participants Experiencing Grade ≥ 3 Treatment-Emergent Adverse Events (TEAEs)
TEAEs were defined as any AE that began on or after the date of first dose of study treatment up to the date of last dose of study treatment plus 70 days or the day before initiation of new anti-AML therapy including SCT, whichever occurred first. Percentages were rounded-off.
Time frame: First dose date up to 1.3 years plus 70 days
Percentage of Participants Experiencing Grade 3 or 4 Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last dose of study treatment plus 70 days or the day before initiation of any new anti-AML therapy including SCT, whichever occurred first. Percentages were rounded-off.
Time frame: First dose date up to 1.3 years plus 70 days
Serum Concentration of Magrolimab
Time frame: Predose on Days 1, 4, 8, 11; Days 29 and 57 Predose and 1 hour Postdose; Predose on Days 113, 169, 253, 281 and 337
Percentage of Participants With Anti-Magrolimab Antibodies
Percentages were rounded-off.
Time frame: Up to 2 years