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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Magrolimab Versus Placebo in Combination With Venetoclax and Azacitidine in Newly Diagnosed, Previously Untreated Patients With Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Magrolimab
* Drug: Venetoclax
* Drug: Azacitidine
* Drug: Magrolimab Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Magrolimab + Venetoclax + Azacitidine<br>Participants will receive magrolimab: 1 mg/kg priming dose 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 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 on Days 1-7 or Days 1-5 and 8-9 of each cycle Each cycle is 28 days. | Drug: Magrolimab<br>* Administered intravenously (IV)<br>* Other names: GS-4721;Drug: Venetoclax<br>* Tablets administered orally<br>* Other names: VENCLEXTA®;Drug: Azacitidine<br>* Administered according to region-specific drug labeling, either subcutaneously (SC) or intravenously (IV)<br>|
| Placebo Comparator: Magrolimab Placebo + Venetoclax + Azacitidine<br>Participants will receive magrolimab placebo: Days 1, 4, 8, 11, and 15, then every week for 5 doses and every 2 weeks thereafter venetoclax: 100 mg 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 on Days 1-7 or Days 1-5 and 8-9 of each cycle Each cycle is 28 days. | Drug: Venetoclax<br>* Tablets administered orally<br>* Other names: VENCLEXTA®;Drug: Azacitidine<br>* Administered according to region-specific drug labeling, either subcutaneously (SC) or intravenously (IV)<br>Drug: Magrolimab Placebo<br>* Administered intravenously (IV)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is measured from the date of randomization to the date of death from any cause. | Randomization up to death or end of study (up to 5 years) whichever occurs first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Complete Remission (CR) + Complete Remission With Partial Hematologic Recovery (CRh) | The CR + CRh rate is the proportion of participants who achieve a CR (including CRMRD- and complete remission with positive or unknown minimal residual disease (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). | Up to 7 months | 
| Rate of Complete Remission (CR) | CR is defined as the proportion of the participants who achieve CR 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) | Up to 7 months | 
| Event-Free Survival (EFS) | EFS is 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. | Randomization up to end of study (up to 5 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 is measured from the time the assessment criteria are 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). | Up to 5 years | 
| Duration of Complete Remission (DCR) in Participants who achieved Complete Remission (CR) | The DCR is measured from the time the assessment criteria are 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). | Up to 5 years | 
| Rate of CR/Complete Remission With Partial Hematologic Recovery Without Minimal Residual Disease (CRhMRD-) | The CR/CRhMRD- rate is the proportion of participants who achieve a CRMRD- or CRhMRD- within 6 cycles of treatment while on study prior to initiation of any new anti-AML therapy or SCT. | Up to 5 years | 
| Rate of Complete Remission Without Minimal Residual Disease (CRMRD-) | The CRMRD- rate is the proportion of participants who achieve a CRMRD- within 6 cycles of treatment. | Up to 5 years | 
| Transfusion Independence Conversion Rate | The transfusion independence conversion rate includes both red blood cell (RBC) transfusion independence rate and platelet transfusion independence rate. The RBC transfusion independence conversion rate is the proportion of participants who have a 56-day or longer period with no RBC or whole blood transfusions at any time between the date of first dose of study treatment and discontinuation of study treatment among all participants who are RBC transfusion dependent at baseline. The platelet transfusion independence conversion rate is the proportion of participants who have a 56-day or longer period with no platelet transfusions at any time between the date of first dose of study treatment and discontinuation of study treatment among all participants who are platelet transfusion dependent at baseline. | First dose date up to End of Treatment (EOT) (up to 5 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 is defined as time from the date of randomization to the time a patient experienced at least 1 threshold value deterioration from baseline or death, whichever is 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 means better GHS/QoL. | Randomization up to end of study (up to 5 years) | 
| TTD on the EORTC QLQ-C30 Physical Functioning Scale | The TTD on the EORTC QLQ-C30 physical functioning scale is defined as time from the date of randomization to the time a patient 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. | Randomization up to end of study (up to 5 years) | 
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) |  | First dose date up to last dose date (up to 5 years) plus 70 days | 
| Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities |  | First dose date up to last dose date (up to 5 years) plus 70 days | 
| Serum Concentration of Magrolimab over time |  | First dose date up to EOT (up to 5 years) | 
| Rate of Anti-Magrolimab Antibody Incidence | Rate of anti-magrolimab antibody incidence is defined as the percentage of participants with anti-magrolimab antibodies. | First dose date up to EOT (up to 5 years) | 
| Magnitude of Anti-Magrolimab Antibody Incidence |  | First dose date up to EOT (up to 5 years) |