Study of Magrolimab Versus Placebo in Combination With Venetoclax and Azacitidine in Participants With Acute Myeloid Leukemia

Phase 3TerminatedNCT05079230

Gilead Sciences378 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

378

Conditions

Acute Myeloid Leukemia

Interventions

MagrolimabDRUG

Administered intravenously (IV)

VenetoclaxDRUG

Tablets administered orally

AzacitidineDRUG

Administered according to region-specific drug labeling, either subcutaneously (SC) or intravenously (IV)

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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/Exclusion criteria may apply.

Locations (164)

Outcomes

Primary Outcomes

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

Secondary Outcomes

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

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

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.

Data from ClinicalTrials.gov

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Administered intravenously (IV)

University of Arkansas for Medical Sciences

Little Rock, Arkansas, United States

City of Hope (City of Hope National Medical Center, City of Hope Medical Center)

Duarte, California, United States

Community Cancer Institute

Fresno, California, United States

UC Irvine Health- Chao Family Comprehensive Cancer Center

Orange, California, United States

Baptist MD Anderson Cancer Center

Jacksonville, Florida, United States

Moffitt Cancer Center

Tampa, Florida, United States

Loyola University Medical Center

Maywood, Illinois, United States

Parkview Research Center

Fort Wayne, Indiana, United States

Indiana Blood and Marrow Transplantation - Clinic

Indianapolis, Indiana, United States

The University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States

...and 154 more locations

Time frame: Up to 1.6 years

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

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

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

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

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

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

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

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

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

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

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.

Percentage of Participants With Anti-Magrolimab Antibodies

Percentages were rounded off.

Time frame: Up to 1.6 years

Maximum Levels of Serum Anti-Magrolimab Antibodies

Time frame: Up to 1.6 years