Acute Myeloid Leukemia
Conditions
Brief summary
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).
Interventions
DRUGMagrolimab
Administered intravenously (IV).
DRUGVenetoclax
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).
DRUGAzacitidine
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).
DRUGCytarabine
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.
DRUGDaunorubicin
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).
DRUGIdarubicin
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).
DRUGSteroidal Eye Drops
Administered per institutional standard during consolidation.
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Individuals with confirmation of acute myeloid leukemia (AML) by World Health Organization criteria, previously untreated for AML, and who have presence of at least 1 TP53 gene mutation that is not benign or likely benign based on evaluation by either central laboratory or an approved local laboratory (after central review of the bone marrow TP53 mitigation next-generation sequencing test results) (individuals with biallelic 17p deletions, loss of both 17p alleles, are eligible based on locally evaluated cytogenetics/karyotype/fluorescence in situ hybridization (FISH) report). * Individuals with white blood cell (WBC) count ≤ 20×10\^3/microliter (μL) prior to randomization. If the individual's WBC is \> 20×10\^3/μL prior to randomization, the individual can be enrolled, assuming all other eligibility criteria are met. However, the WBC should be ≤ 20×10\^3/μL prior to the first dose of study treatment and prior to each magrolimab dose the first 4 weeks (if the individual is randomized to the experimental arm) Note: Individuals can be treated with hydroxyurea and/or leukapheresis throughout the study or prior to randomization to reduce the WBC to ≤ 20×10\^3/μL to enable eligibility for study drug dosing. * The hemoglobin must be ≥ 9 grams per deciliter (g/dL) prior to initial dose of study treatment. Notes: Transfusions are allowed to meet hemoglobin eligibility. * Individual has provided informed consent. * Individual is willing and able to comply with clinic visits and procedure outlined in the study protocol. * Individuals must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, except for individuals less than 75 years of age and appropriate for non-intensive treatment. For these individuals, the ECOG performance status score may be 0 to 3. * Individuals must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 milliliters per minute calculated by the Cockcroft Gault formula. * Adequate cardiac function as demonstrated by: * Lack of symptomatic congestive heart failure and clinically significant cardiac arrhythmias and ischemic heart disease. * Left ventricular ejection fraction (LVEF) \> 50% for individuals appropriate for intensive therapy. * Adequate liver function as demonstrated by: * Aspartate aminotransferase ≤ 3.0 × upper limit of normal (ULN). * Alanine aminotransferase ≤ 3.0 × ULN. * Total bilirubin ≤ 1.5 × ULN, or primary unconjugated bilirubin ≤ 3.0 × ULN if individual has a documented history of Gilbert's syndrome or genetic equivalent. * Pretreatment blood cross-match completed. * Males and females of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception. * Individuals must be willing to consent to mandatory pretreatment and on-treatment bone marrow biopsies (aspirate and trephines). Key
Exclusion criteria
* Positive serum pregnancy test. * Breastfeeding female. * Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient. * 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 (excluding hydroxyurea), hypomethylating agent (HMA), low dose cytarabine and/or venetoclax. Note: Individuals with prior myelodysplastic syndrome (MDS) who have not received prior HMAs or chemotherapeutic agents for MDS are allowed on study. Other prior MDS therapies including, but not limited to, lenalidomide, erythroid stimulating agents, or similar red blood cell (RBC)-direct therapies, were allowed. Localized non-central nervous system (CNS) radiotherapy, erythroid and/or myeloid growth factors, hormonal therapy with luteinizing hormone-releasing hormone agonists for prostate cancer, hormonal therapy or maintenance for breast cancer, and treatment with bisphosphonates and receptor activator of nuclear factor kappa-B ligand inhibitors are also not criteria for exclusion. * Individuals who are appropriate for intensive treatment but who have been previously treated with maximum cumulative doses of idarubicin and/or other anthracyclines and anthracenediones will be excluded. * Individuals receiving any live vaccine within 4 weeks prior to initiation of study treatments. * For individuals appropriate for intensive therapy, individuals treated with trastuzumab within 7 months prior to initiation of study treatments. * Current participation in another interventional clinical study. * Known inherited or acquired bleeding disorders. * Individuals appropriate for non-intensive therapy, who have received treatment with strong and/or moderate cytochrome P450 enzyme 3A (CYP3A) inducers within 7 days prior to the initiation of study treatments. * Individuals appropriate for non-intensive therapy who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days prior to the initiation of study treatment. * Individuals appropriate for non-intensive therapy who have malabsorption syndrome or other conditions that preclude enteral route of administration. * Clinical suspicion of active CNS involvement with AML. * Individuals who have acute promyelocytic leukemia. * Significant disease or medical conditions, as assessed by the investigator and sponsor, that would substantially increase the risk-benefit ratio of participating in the study. This includes, but is not limited to, acute myocardial infarction within the last 6 months, unstable angina, uncontrolled diabetes mellitus, significant active infections, and congestive heart failure New York Heart Association Class III-IV. * 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 anti-cancer therapies and have had no evidence of active malignancy for at least ≥ 1 year Note: Individuals on maintenance therapy alone who have no evidence of active malignancy for at least ≥ 1 year are eligible. * Known active or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or human immunodeficiency virus (HIV) infection in medical history. * Active HBV, and/or active HCV, and/or HIV following testing at screening: * Individuals who test positive for hepatitis B surface antigen (HBsAg). Individuals who test positive for hepatitis B core antibody (anti-HBc) will require HBV deoxyribose nucleic acid (DNA) by quantitative polymerase chain reaction (PCR) for confirmation of active disease. * Individuals who test positive for HCV antibody. These individuals will require HCV ribose nucleic acid (RNA) quantitative PCR for confirmation of active disease. * Individuals who test positive for HIV antibody. * Individuals not currently receiving antiviral therapy and who have an undetectable viral load in the prior 3 months may be eligible for the study. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) in Participants Appropriate for Non-intensive Therapy | Up to 2.1 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival (EFS) in All Participants | Up to 2.1 years | 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. |
| Rate of Complete Remission (CR) in All Participants | Up to 2.1 years | 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. |
| Rate of CR Without Minimal Residual Disease (CR MRD-) in All Participants | Up to 2.1 years | 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. |
| Rate of CR and CR With Partial Hematologic Recovery (CR+CRh) in All Participants | Up to 2.1 years | 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. |
| Duration of CR (DCR) | Up to 2.1 years | 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. |
| Overall Survival in All Participants | Up to 2.1 years | 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. |
| Percentage of Participants Experiencing Grade ≥ 3 Treatment-Emergent Adverse Events (TEAEs) | First dose date up to 1.3 years plus 70 days | 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. |
| Percentage of Participants Experiencing Grade 3 or 4 Treatment-Emergent Laboratory Abnormalities | First dose date up to 1.3 years plus 70 days | 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. |
| Serum Concentration of Magrolimab | 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 | Up to 2 years | Percentages were rounded-off. |
| Duration of CR+CRh | Up to 2.1 years | 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. |
Countries
Australia, Austria, Belgium, Canada, Denmark, France, Germany, Hong Kong, Italy, Japan, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
841 participants were screened.
Pre-assignment details
Participants were enrolled at study sites in North America, the United Kingdom, Europe, Asia, and, Australia. 1 participant was enrolled but was not randomized.
Participants by arm
| Arm | Count |
|---|---|
| Magrolimab + Azacitidine (Non-Intensive Therapy) Participants who were appropriate for non-intensive therapy received 1 mg/kg magrolimab intravenously (IV) on Days 1, 4; 15 mg/kg on Day 8; 30 mg/kg on Days 11, 15, and then QW x 5 weekly 30 mg/kg dose; 30 mg/kg Q2W beginning 1 week after the 5 weekly 30 mg/kg dose. Participants received azacitidine subcutaneously (SC) or IV, 75 mg/m\^2 on Days 1-7 or Days 1-5, 8 and 9 during every cycle of 28 days. The treatment duration was up to a maximum of 1.3 years. | 101 |
| Control Arm: Venetoclax + Azacitidine (Non-Intensive Therapy) Participants who were appropriate for non-intensive therapy received Venetoclax 100 mg orally on Cycle 1 Day 1; 200 mg orally on Cycle 1 Day 2; 400 mg orally on Cycle 1 Day 3 everyday and throughout all the cycles. Participants received azacitidine SC or IV, 75 mg/m\^2 on Days 1-7 or Days 1-5, 8 and 9 during every cycle of 28 days. The treatment duration was up to a maximum of 1.3 years. | 104 |
| Magrolimab + Azacitidine (Intensive Therapy) Participants who were appropriate for intensive therapy received 1 mg/kg magrolimab IV on Days 1, 4; 15 mg/kg on Day 8; 30 mg/kg on Days 11, 15, and then QW x 5 weekly 30 mg/kg dose; 30 mg/kg Q2W beginning 1 week after the 5 weekly 30 mg/kg dose. Participants received azacitidine SC or IV, 75 mg/m\^2 on Days 1-7 or Days 1-5, 8 and 9 during every cycle of 28 days. The treatment duration was up to a maximum of 1.3 years. | 27 |
| Control Arm: 7+3 Chemotherapy (Intensive Therapy) Participants who were appropriate for intensive therapy received 7+3 chemotherapy: 7 day treatment with cytarabine 100 or 200 mg/m\^2 continuous infusion and 3 day treatment with daunorubicin 60 mg/m\^2 IV push or idarubicin 60 mg/m\^2 IV during induction and high-dose cytarabine 1500 or 3000 mg/m\^2 IV every 12 hours on Days 1, 3, and 5 up to 4 cycles and steroidal eye drops during consolidation up to 32 months. Each cycle was 28 days. | 25 |
| Total | 257 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 59 | 54 | 11 | 9 |
| Overall Study | Lost to Follow-up | 2 | 1 | 0 | 1 |
| Overall Study | Reason Not Specified | 1 | 3 | 0 | 2 |
| Overall Study | Study Terminated by Sponsor | 34 | 42 | 15 | 12 |
| Overall Study | Withdrew Consent | 5 | 4 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Magrolimab + Azacitidine (Non-Intensive Therapy) | Control Arm: Venetoclax + Azacitidine (Non-Intensive Therapy) | Magrolimab + Azacitidine (Intensive Therapy) | Control Arm: 7+3 Chemotherapy (Intensive Therapy) |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 179 Participants | 82 Participants | 81 Participants | 6 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 78 Participants | 19 Participants | 23 Participants | 21 Participants | 15 Participants |
| Age, Continuous | 68 years STANDARD_DEVIATION 10 | 70 years STANDARD_DEVIATION 9.6 | 71 years STANDARD_DEVIATION 8 | 57 years STANDARD_DEVIATION 9.6 | 61 years STANDARD_DEVIATION 8.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 9 Participants | 13 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 195 Participants | 82 Participants | 74 Participants | 19 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 37 Participants | 10 Participants | 17 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 30 Participants | 12 Participants | 11 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 2 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 9 Participants | 4 Participants | 2 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 37 Participants | 8 Participants | 17 Participants | 8 Participants | 4 Participants |
| Race (NIH/OMB) White | 174 Participants | 75 Participants | 72 Participants | 12 Participants | 15 Participants |
| Region of Enrollment Australia | 20 Participants | 5 Participants | 7 Participants | 4 Participants | 4 Participants |
| Region of Enrollment Austria | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Belgium | 4 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants |
| Region of Enrollment Canada | 4 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment France | 32 Participants | 6 Participants | 13 Participants | 7 Participants | 6 Participants |
| Region of Enrollment Germany | 16 Participants | 9 Participants | 5 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Hong Kong | 5 Participants | 4 Participants | 1 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Italy | 18 Participants | 7 Participants | 10 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Japan | 21 Participants | 8 Participants | 9 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Spain | 35 Participants | 10 Participants | 10 Participants | 6 Participants | 9 Participants |
| Region of Enrollment Sweden | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Switzerland | 8 Participants | 5 Participants | 2 Participants | 1 Participants | 0 Participants |
| Region of Enrollment United Kingdom | 26 Participants | 12 Participants | 11 Participants | 2 Participants | 1 Participants |
| Region of Enrollment United States | 65 Participants | 31 Participants | 33 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 102 Participants | 43 Participants | 43 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 155 Participants | 58 Participants | 61 Participants | 22 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 61 / 101 | 57 / 104 | 14 / 27 | 10 / 25 |
| other Total, other adverse events | 92 / 96 | 94 / 98 | 27 / 27 | 23 / 23 |
| serious Total, serious adverse events | 84 / 96 | 76 / 98 | 20 / 27 | 14 / 23 |
Outcome results
Primary
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
Population: Participants from the Intent-to-Treat Analysis (ITT) Set who were appropriate for non-intensive therapy were analyzed. As per the pre-specified analysis, the data in this outcome measure was reported only for the non-intensive therapy groups.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Overall Survival (OS) in Participants Appropriate for Non-intensive Therapy | 4.4 months |
| Control Arm: Venetoclax + Azacitidine (Non-Intensive Therapy) | Overall Survival (OS) in Participants Appropriate for Non-intensive Therapy | 6.6 months |
p-value: 0.50795% CI: [0.783, 1.637]Stratified log-rank test
Secondary
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
Population: Participants from the Intent-To-Treat Analysis Set with who achieved CR+CRh within 6 months in all participants (2 months for participants receiving 7 + 3 chemotherapy) were analyzed. As per the pre-specified analysis, the data for this outcome measure were analyzed together for all participants who received magrolimab + azacitidine and participants who received venetoclax + azacitidine or 7+3 chemotherapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Duration of CR+CRh | 9.5 months |
| Control Arm: Venetoclax + Azacitidine (Non-Intensive Therapy) | Duration of CR+CRh | 4.9 months |
Secondary
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
Population: Participants from the Intent-To-Treat Analysis Set who achieved CR within 6 months in all participants (2 months for participants receiving 7 + 3 chemotherapy) were analyzed. As per the pre-specified analysis, the data for this outcome measure were analyzed together for all participants who received magrolimab + azacitidine and participants who received venetoclax + azacitidine or 7+3 chemotherapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Duration of CR (DCR) | 9.5 months |
| Control Arm: Venetoclax + Azacitidine (Non-Intensive Therapy) | Duration of CR (DCR) | 4.9 months |
Secondary
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
Population: Participants from the Intend-To-Treat Analysis Set were analyzed. As per the pre-specified analysis, the data for this outcome measure were analyzed together for all participants who received magrolimab + azacitidine and participants who received venetoclax + azacitidine or 7+3 chemotherapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Event-Free Survival (EFS) in All Participants | 0.0 months |
| Control Arm: Venetoclax + Azacitidine (Non-Intensive Therapy) | Event-Free Survival (EFS) in All Participants | 0.0 months |
p-value: 0.066195% CI: [1.043, 1.848]Stratified Log-rank test
Secondary
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
Population: Participants from the Intend-To-Treat Analysis Set were analyzed. As per the pre-specified analysis, the data for this outcome measure were analyzed together for all participants who received magrolimab + azacitidine and participants who received venetoclax + azacitidine or 7+3 chemotherapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Overall Survival in All Participants | 4.4 months |
| Control Arm: Venetoclax + Azacitidine (Non-Intensive Therapy) | Overall Survival in All Participants | 6.6 months |
p-value: 0.323795% CI: [0.845, 1.654]Stratified Log-rank test
Secondary
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
Population: Participants from Safety Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Percentage of Participants Experiencing Grade 3 or 4 Treatment-Emergent Laboratory Abnormalities | 96.9 percentage of participants |
| Control Arm: Venetoclax + Azacitidine (Non-Intensive Therapy) | Percentage of Participants Experiencing Grade 3 or 4 Treatment-Emergent Laboratory Abnormalities | 99.0 percentage of participants |
| Magrolimab + Azacitidine (Intensive Therapy) | Percentage of Participants Experiencing Grade 3 or 4 Treatment-Emergent Laboratory Abnormalities | 100 percentage of participants |
| Control Arm: 7+3 Chemotherapy (Intensive Therapy) | Percentage of Participants Experiencing Grade 3 or 4 Treatment-Emergent Laboratory Abnormalities | 95.7 percentage of participants |
Secondary
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
Population: The Safety Analysis Set included all participants who took at least 1 dose of any study treatment, with treatment assignment designated according to the actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Percentage of Participants Experiencing Grade ≥ 3 Treatment-Emergent Adverse Events (TEAEs) | 96.9 percentage of participants |
| Control Arm: Venetoclax + Azacitidine (Non-Intensive Therapy) | Percentage of Participants Experiencing Grade ≥ 3 Treatment-Emergent Adverse Events (TEAEs) | 95.9 percentage of participants |
| Magrolimab + Azacitidine (Intensive Therapy) | Percentage of Participants Experiencing Grade ≥ 3 Treatment-Emergent Adverse Events (TEAEs) | 92.6 percentage of participants |
| Control Arm: 7+3 Chemotherapy (Intensive Therapy) | Percentage of Participants Experiencing Grade ≥ 3 Treatment-Emergent Adverse Events (TEAEs) | 95.7 percentage of participants |
Secondary
Percentage of Participants With Anti-Magrolimab Antibodies
Percentages were rounded-off.
Time frame: Up to 2 years
Population: 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 + Azacitidine (Non-Intensive Therapy) | Percentage of Participants With Anti-Magrolimab Antibodies | 10.4 percentage of participants |
| Control Arm: Venetoclax + Azacitidine (Non-Intensive Therapy) | Percentage of Participants With Anti-Magrolimab Antibodies | 11.1 percentage of participants |
Secondary
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.
Time frame: Up to 2.1 years
Population: Participants from the Intent-To-Treat Analysis Set were analyzed. As per the pre-specified analysis, the data for this outcome measure were analyzed together for all participants who received magrolimab + azacitidine and participants who received venetoclax + azacitidine or 7+3 chemotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Rate of Complete Remission (CR) in All Participants | 9.4 percentage of participants |
| Control Arm: Venetoclax + Azacitidine (Non-Intensive Therapy) | Rate of Complete Remission (CR) in All Participants | 29.5 percentage of participants |
95% CI: [0.123, 0.506]
Secondary
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
Population: Participants from the Intent-To-Treat Analysis Set were analyzed. As per the pre-specified analysis, the data for this outcome measure were analyzed together for all participants who received magrolimab + azacitidine and participants who received venetoclax + azacitidine or 7+3 chemotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Rate of CR and CR With Partial Hematologic Recovery (CR+CRh) in All Participants | 10.2 percentage of participants |
| Control Arm: Venetoclax + Azacitidine (Non-Intensive Therapy) | Rate of CR and CR With Partial Hematologic Recovery (CR+CRh) in All Participants | 34.1 percentage of participants |
95% CI: [0.108, 0.428]
Secondary
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
Population: Participants from the Intent-To-Treat Analysis Set were analyzed. As per the pre-specified analysis, the data for this outcome measure were analyzed together for all participants who received magrolimab + azacitidine and participants who received venetoclax + azacitidine or 7+3 chemotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Rate of CR Without Minimal Residual Disease (CR MRD-) in All Participants | 0.8 percentage of participants |
| Control Arm: Venetoclax + Azacitidine (Non-Intensive Therapy) | Rate of CR Without Minimal Residual Disease (CR MRD-) in All Participants | 10.1 percentage of participants |
95% CI: [0.009, 0.559]
Secondary
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
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) posttreatment serum concentration of magrolimab. Participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Serum Concentration of Magrolimab | Day 1 Predose | 0.0 μg/mL | Standard Deviation 0 |
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Serum Concentration of Magrolimab | Day 11 Predose | 111 μg/mL | — |
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Serum Concentration of Magrolimab | Day 29 Predose | 311 μg/mL | Standard Deviation 195 |
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Serum Concentration of Magrolimab | Day 4 Predose | 0.0 μg/mL | — |
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Serum Concentration of Magrolimab | Day 8 Predose | 0.0 μg/mL | Standard Deviation 0 |
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Serum Concentration of Magrolimab | Day 29 1 hour Postdose | 376 μg/mL | — |
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Serum Concentration of Magrolimab | Day 57 Predose | 402 μg/mL | Standard Deviation 262 |
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Serum Concentration of Magrolimab | Day 57 1 hour Postdose | 967 μg/mL | Standard Deviation 351 |
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Serum Concentration of Magrolimab | Day 113 Predose | 138 μg/mL | Standard Deviation 96 |
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Serum Concentration of Magrolimab | Day 169 Predose | 198 μg/mL | Standard Deviation 129 |
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Serum Concentration of Magrolimab | Day 253 Predose | 294 μg/mL | Standard Deviation 181 |
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Serum Concentration of Magrolimab | Day 281 Predose | 263 μg/mL | — |
| Magrolimab + Azacitidine (Non-Intensive Therapy) | Serum Concentration of Magrolimab | Day 337 Predose | 251 μg/mL | Standard Deviation 114 |