Acute Myeloid Leukemia
Conditions
Brief summary
The goal of this clinical study is to compare the study drugs, magrolimab + venetoclax + azacitidine, versus placebo + venetoclax + azacitidine in participants with untreated acute myeloid leukemia (AML) who are not able to have chemotherapy.
Interventions
DRUGMagrolimab
Administered intravenously (IV)
DRUGVenetoclax
Tablets administered orally
DRUGAzacitidine
Administered according to region-specific drug labeling, either subcutaneously (SC) or intravenously (IV)
DRUGPlacebo
Administered intravenously (IV)
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Previously untreated individuals with histological confirmation of acute myeloid leukemia (AML) by World Health Organization (WHO) criteria who are ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age, or comorbidity. Individuals must be considered ineligible for intensive chemotherapy, defined by the following: * ≥ 75 years of age; Or * ≥ 18 to 74 years of age with at least 1 of the following comorbidities: * Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3 * Diffusing capacity of the lung of carbon monoxide ≤ 65% or forced expiratory volume in 1 second ≤ 65% * Left ventricular ejection fraction ≤ 50% * Baseline creatinine clearance ≥ 30 mL/min to \< 45 mL/min calculated by the Cockcroft Gault formula or measured by 24-hour urine collection * Hepatic disorder with total bilirubin \> 1.5 x upper limit of normal (ULN) * Any other comorbidity that the investigator judges to be incompatible with intensive chemotherapy * ECOG performance status: * Of 0 to 2 for individuals ≥ 75 years of age Or * Of 0 to 3 for individuals ≥ 18 to 74 years of age * Individuals with white blood cell (WBC) count ≤ 20 x 10\^3/μL prior to randomization. If the individual's WBC is \> 20 x10\^3/μL prior to randomization, the individual can be enrolled, assuming all other eligibility criteria are met. However, the WBC should be ≤ 20 x 10\^3/μL prior to the first dose of study treatment and prior to each magrolimab/placebo dose during Cycle 1. * Note: Individuals can be treated with hydroxyurea and/or leukapheresis prior to randomization and throughout the study to reduce the WBC to ≤ 20 x 10\^3/μL to enable eligibility for study drug dosing * Hemoglobin must be ≥ 9 g/dL prior to initial dose of study treatment * Note: Transfusions are allowed to meet hemoglobin eligibility * Pretreatment blood cross-match completed Key
Exclusion criteria
* Prior treatment with any of the following: * cluster of differentiation 47 (CD47) or signal regulatory protein alpha (SIRPα)-targeting agents * Antileukemic therapy for the treatment of AML (eg, hypomethylating agents (HMAs), low-dose cytarabine, and/or venetoclax), excluding hydroxyurea * Note: Individuals with prior MDS who have not received prior HMAs or venetoclax or chemotherapeutic agents for MDS may be enrolled in the study. Prior treatment with myelodysplastic syndrome (MDS) therapies including, but not limited to lenalidomide, erythroid-stimulating agents, or similar red blood cell negative (RBC-), white blood cell negative (WBC-), or platelet-direct therapies or growth factors is allowed for these individuals. * Clinical suspicion of or documented active central nervous system (CNS) involvement with AML * Individuals who have acute promyelocytic leukemia * Second malignancy, except MDS, treated basal cell or localized squamous skin carcinomas, localized prostate cancer, or other malignancies for which individuals are not on active anticancer therapies and have had no evidence of active malignancy for at least 1 year Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 1.6 years | OS was measured from the date of randomization to the date of death from any cause. Participants were censored at last known alive date. Kaplan-Meier (KM) estimates were used in outcome measure analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Anti-Magrolimab Antibodies | Up to 1.6 years | Percentages were rounded off. |
| Rate of Complete Remission (CR) + Complete Remission With Partial Hematologic Recovery (CRh) | Up to 1.6 years | The CR + CRh rate was defined as the percentage of participants who achieved a CR (including CR without minimal residual disease (CRMRD-) and CR with positive or unknown MRD (CRMRD+/unk)) or CRh as defined by CR with partial platelet and absolute neutrophil count recovery within 6 cycles of treatment while on study prior to initiation of any new anti-acute myeloid leukemia (AML) therapy or stem cell transplant (SCT). 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-) within the response assessment window of 1.6 years. Percentages were rounded-off. Clopper-Pearson method were used in outcome measure analysis. Each cycle was of 28 days. |
| Rate of Complete Remission (CR) | Up to 1.6 years | CR was defined as the percentage of the participants who achieved CR (including CRMRD- and CRMRD+/unk) within 6 cycles of treatment as determined by the investigator while on study prior to initiation of any new anti-acute myeloid leukemia (AML) therapy or stem cell transplant (SCT) within the response assessment window of 1.6 years. Definitions for CRMRD- and CRMRD+/unk were mentioned in outcome measure #2. Percentages were rounded-off. Clopper-Pearson method were used in outcome measure analysis. Each cycle was of 28 days. |
| Event-Free Survival (EFS) | Up to 1.6 years | EFS was defined as time from the date of randomization to the earliest date of the documented relapse from CR, treatment failure (defined as failure to achieve CR within 6 cycles of treatment), or death from any cause within the response window. KM estimates were used in outcome measure analysis. CR is defined in outcome measure 2. |
| Duration of CR + CRh in Participants Who Achieved Complete Remission (CR) or Complete Remission With Partial Hematologic Recovery (CRh) | Up to 1.6 years | The duration of CR + CRh was measured from the time the assessment criteria were first met for CR (including CRMRD- and CRMRD+/unk) or CRh within 6 cycles of treatment until the first date of AML relapse or death (including assessments post SCT). Those 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 on or prior to the data cut off date within the response assessment window of 1.6 years. Participants started taking new anti-AML therapies (excluding post-SCT maintenance therapy) before relapse, duration of CR + CRh were censored at the last response assessment before the initiation of the new anti-AML therapies. CR and CRh are defined in Outcome Measure #2. Each cycle was of 28 days. |
| Duration of Complete Remission (DCR) in Participants Who Achieved Complete Remission (CR) | Up to 1.6 years | The DCR was measured from the time the assessment criteria were first met for CR (including CRMRD- and CRMRD+/unk) within 6 cycles of treatment until the first date of AML relapse or death (including assessments post SCT). Those 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 on or prior to the data cutoff date within the response assessment window of 1.6 years. Participants started taking new anti-AML therapies (excluding post-SCT maintenance therapy) before relapse, DCR were censored at the last response assessment before the initiation of the new anti-AML therapies. KM estimates were used in outcome measure analysis. CRMRD- and CRMRD+/unk are defined in outcome measure #2. Each cycle was of 28 days. |
| Rate of CR/CRh Without Minimal Residual Disease (CR/CRhMRD-) | Up to 1.6 years | The CR/CRhMRD- rate was the percentage of participants who achieved a CRMRD- or CRhMRD- within 6 cycles of treatment while on study prior to initiation of any new anti-AML therapy or SCT within the response assessment window of 1.6 years. Each cycle was of 28 days. KM estimates were used for outcome measure analysis. CRhMRD- : neutrophils \> 0.5 x 10\^9/L; platelets \> 50 x 10\^9/L; bone marrow blasts \< 5%; MRD negative (determined using multiparameter flow cytometry with a sensitivity of \< 0.1%). Absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. Percentages were rounded off. |
| Rate of CR Without Minimal Residual Disease (CRMRD-) | Up to 1.6 years | The CRMRD- rate was the percentage of participants who achieved a CRMRD- within 6 cycles of treatment SCT within the response assessment window of 1.6 years. Percentages were rounded-off. Clopper-Pearson method were used in outcome measure analysis. CRMRD is defined in outcome measure #2. Each cycle was of 28 days. Percentages were rounded off |
| Red Blood Cell (RBC) Transfusion Independence Conversion Rate | Up to 1.6 years | The RBC transfusion independence conversion rate was the percentage of participants who had a 56-day or longer period with no RBC or whole blood transfusions at any time between the date of the first dose of study treatment and discontinuation of study treatment among all participants who were RBC transfusion dependent at baseline. Percentages were rounded-off. Clopper-Pearson method were used in outcome measure analysis. |
| Platelet Transfusion Independence Conversion Rate | Up to 1.6 years | The platelet transfusion independence conversion rate was the percentage of participants who had a 56-day or longer period with no platelet transfusions at any time between the date of the first dose of study treatment and discontinuation of study treatment among all participants who were platelet transfusion dependent at baseline. Percentages were rounded-off. Clopper-Pearson method were used in outcome measure analysis. |
| Time to First Deterioration (TTD) on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Scale | Up to 1.6 years | The TTD on the EORTC QLQ-C30 GHS/QoL scale was defined as time from the date of randomization to the time a participant experienced at least 1 threshold value deterioration from baseline or death, whichever was earlier. Questionnaire includes 30 questions resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning), 1 GHS/QoL scale, 3 symptom scales (fatigue, nausea and vomiting, pain), and 6 single items (dyspnea, insomnia, loss of appetite, constipation, diarrhea, financial difficulties). After linear transformation, all scales and single item measures range in score from 0-100. Higher score on GHS/QoL scale meant better GHS/QoL. KM estimates were used in outcome measure analysis. |
| Time to First Deterioration (TTD) on the EORTC QLQ-C30 Physical Functioning Scale | Up to 1.6 years | The TTD on the EORTC QLQ-C30 physical functioning scale was defined as time from the date of randomization to the time a participant experienced at least 1 threshold value deterioration from baseline or death, whichever is earlier. Physical functioning scale is one of the five functional scales of the EORTC QLQ C30 questionnaire. After linear transformation, scale range in score from 0-100. A higher score on functional scales means better functioning and better quality of life. KM estimates were used in outcome measure analysis. |
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | First dose date up to 1.4 years plus 70 days | An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. TEAEs were defined as any AEs with an onset date on or after the study drug start date and no later than 70 days after the study drug last dose date or the day before initiation of new anti-AML therapy including stem cell transplantation, whichever is earlier. Percentages were rounded-off. |
| Percentage of Participants Experiencing Grade 3 or Higher Treatment-Emergent Laboratory Abnormalities | First dose date up to 1.4 years, plus 70 days | Treatment-emergent laboratory abnormalities were defined as values that increased by at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of the last dose of study drug plus 70 days or the day before the initiation of new anti-AML therapy including SCT, whichever came first, and were summarized by treatment group. Severity grades were defined by the CTCAE Version 5.0. 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Life-Threatening; 5 = Death. Percentages were rounded-off. |
| Serum Concentration of Magrolimab Over Time | Predose on Day 1, Day 8, Day 15, Day 29; Predose on Day 57 and 1 hour post-dose; Predose on Day 113, Day 169, Day 253, and Day 337. | — |
| Maximum Levels of Serum Anti-Magrolimab Antibodies | Up to 1.6 years | — |
Countries
Australia, Austria, Belgium, Canada, Czechia, France, Germany, Hong Kong, Hungary, Israel, Italy, Netherlands, Norway, Poland, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
502 participants were screened.
Pre-assignment details
Participants were enrolled at study sites in Asia, Europe, North America and Australia.
Participants by arm
| Arm | Count |
|---|---|
| Magrolimab + Venetoclax + Azacitidine Participants received magrolimab 1 mg/kg priming dose intravenously (IV) on Days 1 and 4; 15 mg/kg on Day 8; and 30 mg/kg on Days 11, 15, and then every week for 5 doses, and every 2 weeks thereafter; venetoclax 100 mg orally on Cycle 1 Day 1, 200 mg on Cycle 1 Day 2, 400 mg on Cycle 1 Day 3, and daily thereafter; azacitidine 75 mg/m² subcutaneously (SC) or IV on Days 1-7 or Days 1-5 and 8-9 of each cycle up to 1.4 years. Each cycle was of 28 days. | 189 |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine Participants received magrolimab matching placebo IV on Days 1, 4, 8, 11, and 15, then every week for 5 doses and every 2 weeks thereafter; venetoclax 100 mg orally on Cycle 1 Day 1, 200 mg on Cycle 1 Day 2, 400 mg on Cycle 1 Day 3 and daily thereafter; azacitidine 75 mg/m\^2 SC or IV on Days 1-7 or Days 1-5 and 8-9 of each cycle up to 1.4 years. Each cycle was of 28 days. | 189 |
| Total | 378 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 72 | 66 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Study Terminated by Sponsor | 101 | 102 |
| Overall Study | Withdrew Consent | 16 | 18 |
Baseline characteristics
| Characteristic | Magrolimab Matching Placebo + Venetoclax + Azacitidine | Magrolimab + Venetoclax + Azacitidine | Total |
|---|---|---|---|
| Age, Continuous | 74 years STANDARD_DEVIATION 8 | 74 years STANDARD_DEVIATION 7 | 74 years STANDARD_DEVIATION 7.5 |
| Age, Customized < 75 Years | 91 Participants | 93 Participants | 184 Participants |
| Age, Customized >= 75 Years | 98 Participants | 96 Participants | 194 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 18 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 149 Participants | 149 Participants | 298 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 28 Participants | 22 Participants | 50 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 25 Participants | 26 Participants | 51 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 30 Participants | 26 Participants | 56 Participants |
| Race (NIH/OMB) White | 130 Participants | 130 Participants | 260 Participants |
| Region of Enrollment Australia | 11 Participants | 7 Participants | 18 Participants |
| Region of Enrollment Austria | 2 Participants | 3 Participants | 5 Participants |
| Region of Enrollment Belgium | 9 Participants | 8 Participants | 17 Participants |
| Region of Enrollment Canada | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Czechia | 15 Participants | 11 Participants | 26 Participants |
| Region of Enrollment France | 24 Participants | 16 Participants | 40 Participants |
| Region of Enrollment Germany | 9 Participants | 13 Participants | 22 Participants |
| Region of Enrollment Hong Kong | 2 Participants | 7 Participants | 9 Participants |
| Region of Enrollment Hungary | 3 Participants | 1 Participants | 4 Participants |
| Region of Enrollment Israel | 3 Participants | 5 Participants | 8 Participants |
| Region of Enrollment Italy | 5 Participants | 5 Participants | 10 Participants |
| Region of Enrollment Netherlands | 9 Participants | 12 Participants | 21 Participants |
| Region of Enrollment Norway | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment Poland | 3 Participants | 3 Participants | 6 Participants |
| Region of Enrollment South Korea | 4 Participants | 8 Participants | 12 Participants |
| Region of Enrollment Spain | 25 Participants | 27 Participants | 52 Participants |
| Region of Enrollment Switzerland | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Taiwan | 12 Participants | 10 Participants | 22 Participants |
| Region of Enrollment United Kingdom | 3 Participants | 3 Participants | 6 Participants |
| Region of Enrollment United States | 47 Participants | 46 Participants | 93 Participants |
| Sex: Female, Male Female | 83 Participants | 73 Participants | 156 Participants |
| Sex: Female, Male Male | 106 Participants | 116 Participants | 222 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 84 / 189 | 70 / 189 |
| other Total, other adverse events | 180 / 189 | 179 / 184 |
| serious Total, serious adverse events | 138 / 189 | 134 / 184 |
Outcome results
Primary
Overall Survival (OS)
OS was measured from the date of randomization to the date of death from any cause. Participants were censored at last known alive date. Kaplan-Meier (KM) estimates were used in outcome measure analysis.
Time frame: Up to 1.6 years
Population: Participants in the Intent-to-Treat Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Overall Survival (OS) | 10.7 months |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine | Overall Survival (OS) | 14.1 months |
p-value: 0.327695% CI: [0.848, 1.637]stratified log-rank test
Secondary
Duration of Complete Remission (DCR) in Participants Who Achieved Complete Remission (CR)
The DCR was measured from the time the assessment criteria were first met for CR (including CRMRD- and CRMRD+/unk) within 6 cycles of treatment until the first date of AML relapse or death (including assessments post SCT). Those 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 on or prior to the data cutoff date within the response assessment window of 1.6 years. Participants started taking new anti-AML therapies (excluding post-SCT maintenance therapy) before relapse, DCR were censored at the last response assessment before the initiation of the new anti-AML therapies. KM estimates were used in outcome measure analysis. CRMRD- and CRMRD+/unk are defined in outcome measure #2. Each cycle was of 28 days.
Time frame: Up to 1.6 years
Population: Participants in the Intent-To-Treat Analysis Set who achieved CR within 6 cycle in all participants were analyzed. Each cycle was of 28 days.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Duration of Complete Remission (DCR) in Participants Who Achieved Complete Remission (CR) | 9.4 months |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine | Duration of Complete Remission (DCR) in Participants Who Achieved Complete Remission (CR) | 8.1 months |
Secondary
Duration of CR + CRh in Participants Who Achieved Complete Remission (CR) or Complete Remission With Partial Hematologic Recovery (CRh)
The duration of CR + CRh was measured from the time the assessment criteria were first met for CR (including CRMRD- and CRMRD+/unk) or CRh within 6 cycles of treatment until the first date of AML relapse or death (including assessments post SCT). Those 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 on or prior to the data cut off date within the response assessment window of 1.6 years. Participants started taking new anti-AML therapies (excluding post-SCT maintenance therapy) before relapse, duration of CR + CRh were censored at the last response assessment before the initiation of the new anti-AML therapies. CR and CRh are defined in Outcome Measure #2. Each cycle was of 28 days.
Time frame: Up to 1.6 years
Population: Participants in the Intent-To-Treat Analysis Set who achieved CR + CRh within 6 cycles were analyzed. Each cycle was of 28 days.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Duration of CR + CRh in Participants Who Achieved Complete Remission (CR) or Complete Remission With Partial Hematologic Recovery (CRh) | 9.4 months |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine | Duration of CR + CRh in Participants Who Achieved Complete Remission (CR) or Complete Remission With Partial Hematologic Recovery (CRh) | 9.2 months |
Secondary
Event-Free Survival (EFS)
EFS was defined as time from the date of randomization to the earliest date of the documented relapse from CR, treatment failure (defined as failure to achieve CR within 6 cycles of treatment), or death from any cause within the response window. KM estimates were used in outcome measure analysis. CR is defined in outcome measure 2.
Time frame: Up to 1.6 years
Population: Participants in the Intent-To-Treat Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Event-Free Survival (EFS) | 0.0 months |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine | Event-Free Survival (EFS) | 1.7 months |
p-value: 0.790395% CI: [0.73, 1.225]Stratified Log Rank
Secondary
Maximum Levels of Serum Anti-Magrolimab Antibodies
Time frame: Up to 1.6 years
Population: Data is reported for participants in the Immunogenicity Analysis Set with quantifiable measurement for ADA for magrolimab.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Maximum Levels of Serum Anti-Magrolimab Antibodies | 40 titer | Standard Deviation 67.33 |
Secondary
Percentage of Participants Experiencing Grade 3 or Higher Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities were defined as values that increased by at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of the last dose of study drug plus 70 days or the day before the initiation of new anti-AML therapy including SCT, whichever came first, and were summarized by treatment group. Severity grades were defined by the CTCAE Version 5.0. 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Life-Threatening; 5 = Death. Percentages were rounded-off.
Time frame: First dose date up to 1.4 years, plus 70 days
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Percentage of Participants Experiencing Grade 3 or Higher Treatment-Emergent Laboratory Abnormalities | 99.5 percentage of participants |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine | Percentage of Participants Experiencing Grade 3 or Higher Treatment-Emergent Laboratory Abnormalities | 100 percentage of participants |
Secondary
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. TEAEs were defined as any AEs with an onset date on or after the study drug start date and no later than 70 days after the study drug last dose date or the day before initiation of new anti-AML therapy including stem cell transplantation, whichever is earlier. Percentages were rounded-off.
Time frame: First dose date up to 1.4 years plus 70 days
Population: The Safety Analysis Set included all participants who received at least 1 dose of any study treatment, with treatment assignments designated according to the actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 99.5 percentage of participants |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 100 percentage of participants |
Secondary
Percentage of Participants With Anti-Magrolimab Antibodies
Percentages were rounded off.
Time frame: Up to 1.6 years
Population: The participants in the Immunogenicity Analysis Set with available data were analyzed. The Immunogenicity Analysis Set included all randomized participants who received at least one dose of magrolimab and had at least one evaluable anti-magrolimab antibody test result.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Percentage of Participants With Anti-Magrolimab Antibodies | 2.4 percentage of participants |
Secondary
Platelet Transfusion Independence Conversion Rate
The platelet transfusion independence conversion rate was the percentage of participants who had a 56-day or longer period with no platelet transfusions at any time between the date of the first dose of study treatment and discontinuation of study treatment among all participants who were platelet transfusion dependent at baseline. Percentages were rounded-off. Clopper-Pearson method were used in outcome measure analysis.
Time frame: Up to 1.6 years
Population: Participants in the Intent-To-Treat Analysis Set with Platelet transfusion dependence at Baseline were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Platelet Transfusion Independence Conversion Rate | 48.6 percentage of participants |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine | Platelet Transfusion Independence Conversion Rate | 47.3 percentage of participants |
p-value: 0.57995% CI: [0.62, 2.36]Cochran-Mantel-Haenszel
Secondary
Rate of Complete Remission (CR)
CR was defined as the percentage of the participants who achieved CR (including CRMRD- and CRMRD+/unk) within 6 cycles of treatment as determined by the investigator while on study prior to initiation of any new anti-acute myeloid leukemia (AML) therapy or stem cell transplant (SCT) within the response assessment window of 1.6 years. Definitions for CRMRD- and CRMRD+/unk were mentioned in outcome measure #2. Percentages were rounded-off. Clopper-Pearson method were used in outcome measure analysis. Each cycle was of 28 days.
Time frame: Up to 1.6 years
Population: Participants in the Intent-To-Treat Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Rate of Complete Remission (CR) | 41.3 percentage of participants |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine | Rate of Complete Remission (CR) | 46.0 percentage of participants |
p-value: 0.467995% CI: [0.56, 1.307]Stratum-adjusted Mantel-Haenszel
Secondary
Rate of Complete Remission (CR) + Complete Remission With Partial Hematologic Recovery (CRh)
The CR + CRh rate was defined as the percentage of participants who achieved a CR (including CR without minimal residual disease (CRMRD-) and CR with positive or unknown MRD (CRMRD+/unk)) or CRh as defined by CR with partial platelet and absolute neutrophil count recovery within 6 cycles of treatment while on study prior to initiation of any new anti-acute myeloid leukemia (AML) therapy or stem cell transplant (SCT). 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-) within the response assessment window of 1.6 years. Percentages were rounded-off. Clopper-Pearson method were used in outcome measure analysis. Each cycle was of 28 days.
Time frame: Up to 1.6 years
Population: Participants in the Intent-to-Treat analysis set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Rate of Complete Remission (CR) + Complete Remission With Partial Hematologic Recovery (CRh) | 47.6 percentage of participants |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine | Rate of Complete Remission (CR) + Complete Remission With Partial Hematologic Recovery (CRh) | 53.4 percentage of participants |
p-value: 0.361695% CI: [0.545, 1.251]Stratum-adjusted Mantel-Haenszel
Secondary
Rate of CR/CRh Without Minimal Residual Disease (CR/CRhMRD-)
The CR/CRhMRD- rate was the percentage of participants who achieved a CRMRD- or CRhMRD- within 6 cycles of treatment while on study prior to initiation of any new anti-AML therapy or SCT within the response assessment window of 1.6 years. Each cycle was of 28 days. KM estimates were used for outcome measure analysis. CRhMRD- : neutrophils \> 0.5 x 10\^9/L; platelets \> 50 x 10\^9/L; bone marrow blasts \< 5%; MRD negative (determined using multiparameter flow cytometry with a sensitivity of \< 0.1%). Absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. Percentages were rounded off.
Time frame: Up to 1.6 years
Population: Participants in the Intent-To-Treat Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Rate of CR/CRh Without Minimal Residual Disease (CR/CRhMRD-) | 24.3 percentage of participants |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine | Rate of CR/CRh Without Minimal Residual Disease (CR/CRhMRD-) | 22.2 percentage of participants |
p-value: 0.487395% CI: [0.727, 1.945]Stratum-adjusted Mantel Haenszel
Secondary
Rate of CR Without Minimal Residual Disease (CRMRD-)
The CRMRD- rate was the percentage of participants who achieved a CRMRD- within 6 cycles of treatment SCT within the response assessment window of 1.6 years. Percentages were rounded-off. Clopper-Pearson method were used in outcome measure analysis. CRMRD is defined in outcome measure #2. Each cycle was of 28 days. Percentages were rounded off
Time frame: Up to 1.6 years
Population: Participants in the Intent-To-Treat Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Rate of CR Without Minimal Residual Disease (CRMRD-) | 21.7 percentage of participants |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine | Rate of CR Without Minimal Residual Disease (CRMRD-) | 20.1 percentage of participants |
p-value: 0.584295% CI: [0.69, 1.932]Stratum-adjusted Mantel Haenszel
Secondary
Red Blood Cell (RBC) Transfusion Independence Conversion Rate
The RBC transfusion independence conversion rate was the percentage of participants who had a 56-day or longer period with no RBC or whole blood transfusions at any time between the date of the first dose of study treatment and discontinuation of study treatment among all participants who were RBC transfusion dependent at baseline. Percentages were rounded-off. Clopper-Pearson method were used in outcome measure analysis.
Time frame: Up to 1.6 years
Population: Participants in the Intent-To-Treat Analysis Set with RBC transfusion dependence at Baseline were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Red Blood Cell (RBC) Transfusion Independence Conversion Rate | 51.7 percentage of participants |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine | Red Blood Cell (RBC) Transfusion Independence Conversion Rate | 58.3 percentage of participants |
p-value: 0.300395% CI: [0.492, 1.245]Cochran-Mantel-Haenszel
Secondary
Serum Concentration of Magrolimab Over Time
Time frame: Predose on Day 1, Day 8, Day 15, Day 29; Predose on Day 57 and 1 hour post-dose; Predose on Day 113, Day 169, Day 253, and Day 337.
Population: The Pharmacokinetic (PK) Analysis Set included all randomized participants who took at least one dose of magrolimab and have at least 1 measurable (non - below the limit of quantitation (BLQ) numeric values) post-treatment serum concentration of magrolimab with data available for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Serum Concentration of Magrolimab Over Time | Day 1 Predose | 0 µg/mL | Standard Deviation 0 |
| Magrolimab + Venetoclax + Azacitidine | Serum Concentration of Magrolimab Over Time | Day 8 Predose | 0 µg/mL | Standard Deviation 0 |
| Magrolimab + Venetoclax + Azacitidine | Serum Concentration of Magrolimab Over Time | Day 15 Predose | 291 µg/mL | Standard Deviation 123 |
| Magrolimab + Venetoclax + Azacitidine | Serum Concentration of Magrolimab Over Time | Day 29 Predose | 385 µg/mL | Standard Deviation 206 |
| Magrolimab + Venetoclax + Azacitidine | Serum Concentration of Magrolimab Over Time | Day 57 Predose | 503 µg/mL | Standard Deviation 230 |
| Magrolimab + Venetoclax + Azacitidine | Serum Concentration of Magrolimab Over Time | Day 57, 1 h Postdose | 1060 µg/mL | Standard Deviation 289 |
| Magrolimab + Venetoclax + Azacitidine | Serum Concentration of Magrolimab Over Time | Day 113 Predose | 281 µg/mL | Standard Deviation 140 |
| Magrolimab + Venetoclax + Azacitidine | Serum Concentration of Magrolimab Over Time | Day 169 Predose | 274 µg/mL | Standard Deviation 120 |
| Magrolimab + Venetoclax + Azacitidine | Serum Concentration of Magrolimab Over Time | Day 253 Predose | 322 µg/mL | Standard Deviation 151 |
| Magrolimab + Venetoclax + Azacitidine | Serum Concentration of Magrolimab Over Time | Day 337 Predose | 298 µg/mL | Standard Deviation 72.9 |
Secondary
Time to First Deterioration (TTD) on the EORTC QLQ-C30 Physical Functioning Scale
The TTD on the EORTC QLQ-C30 physical functioning scale was defined as time from the date of randomization to the time a participant experienced at least 1 threshold value deterioration from baseline or death, whichever is earlier. Physical functioning scale is one of the five functional scales of the EORTC QLQ C30 questionnaire. After linear transformation, scale range in score from 0-100. A higher score on functional scales means better functioning and better quality of life. KM estimates were used in outcome measure analysis.
Time frame: Up to 1.6 years
Population: Participants in the Intent-To-Treat Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Time to First Deterioration (TTD) on the EORTC QLQ-C30 Physical Functioning Scale | 3.0 months |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine | Time to First Deterioration (TTD) on the EORTC QLQ-C30 Physical Functioning Scale | 3.9 months |
p-value: 0.102695% CI: [0.948, 1.704]Stratified Log Rank
Secondary
Time to First Deterioration (TTD) on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Scale
The TTD on the EORTC QLQ-C30 GHS/QoL scale was defined as time from the date of randomization to the time a participant experienced at least 1 threshold value deterioration from baseline or death, whichever was earlier. Questionnaire includes 30 questions resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning), 1 GHS/QoL scale, 3 symptom scales (fatigue, nausea and vomiting, pain), and 6 single items (dyspnea, insomnia, loss of appetite, constipation, diarrhea, financial difficulties). After linear transformation, all scales and single item measures range in score from 0-100. Higher score on GHS/QoL scale meant better GHS/QoL. KM estimates were used in outcome measure analysis.
Time frame: Up to 1.6 years
Population: Participants in the Intent-To-Treat Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Magrolimab + Venetoclax + Azacitidine | Time to First Deterioration (TTD) on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Scale | 4.7 months |
| Magrolimab Matching Placebo + Venetoclax + Azacitidine | Time to First Deterioration (TTD) on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Scale | 5.1 months |
p-value: 0.579695% CI: [0.799, 1.487]Stratified Log Rank