Study of Magrolimab in Combination With Azacitidine Versus Physician's Choice of Venetoclax in Combination With Azacitidine or Intensive Chemotherapy in Patients With TP53 Mutant Acute Myeloid Leukemia That Have Not Been Treated

Study Overview
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Brief Summary
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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).

Official Title
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A Phase 3, Randomized, Open-Label Study Evaluating the Safety and Efficacy of Magrolimab in Combination With Azacitidine Versus Physician's Choice of Venetoclax in Combination With Azacitidine or Intensive Chemotherapy in Previously Untreated Patients With TP53 Mutant Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Magrolimab
* Drug: Venetoclax
* Drug: Azacitidine
* Drug: Cytarabine
* Drug: Daunorubicin
* Drug: Idarubicin
* Drug: Steroidal Eye Drops


Participation Criteria
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Eligibility Criteria
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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 RBC-direct therapies, are 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/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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Magrolimab + Azacitidine<br>Participants will receive an escalating dose of magrolimab and a fixed dose of azacitidine. | Drug: Magrolimab<br>* Administered intravenously (IV).<br>* Other names: GS-4721;Drug: Azacitidine<br>* 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).<br>|
| Active Comparator: Control Arm: Venetoclax + Azacitidine<br>Participants who are appropriate for non-intensive therapy will receive an escalating dose of venetoclax and a fixed dose of azacitidine. | Drug: Venetoclax<br>* 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).<br>Drug: Azacitidine<br>* 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).<br>|
| Active Comparator: Control Arm: 7+3 Chemotherapy<br>Participants who are appropriate for intensive therapy will receive 7+3 chemotherapy: 7 day treatment with cytarabine and 3 day treatment with daunorubicin or idarubicin during induction and high-dose cytarabine and steroidal eye drops during consolidation. | Drug: Cytarabine<br>* 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.<br>Drug: Daunorubicin<br>* 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).<br>Drug: Idarubicin<br>* 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).<br>Drug: Steroidal Eye Drops<br>* Administered per institutional standard during consolidation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in Participants Appropriate for Non-intensive Therapy | The OS is measured from the date of randomization to the date of death from any cause. Those whose deaths are not observed during the study will be censored at their last known alive date. | Randomization up to death or end of study (up to 27 months) whichever occurs first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival in All Participants | The OS is measured from the date of randomization to the date of death from any cause. Those whose deaths are not observed during the study will be censored at their last known alive date. | Randomization up to death or end of study (up to 27 months) whichever occurs first | 
| Event-Free Survival (EFS) in All Participants | The EFS is defined as time from the date of randomization to the earliest date of documented relapse from complete remission (CR), treatment failure (defined as failure to achieve CR within 6 months of treatment with magrolimab + azacitidine or venetoclax + azacitidine, or up to 2 months of treatment with 7 + 3 chemotherapy), or death from any cause. Response assessments or death post SCT or new anti-AML therapies will be included. Those who are not observed to have one of these events during the study will be censored at the date of their last response assessment with clear documentation of no relapse during the study. The date of randomization will be assigned as the event date for participants with treatment failure. | Randomization up to end of study (up to 27 months) | 
| Rate of Complete Remission (CR) in All Participants | The rate of CR is the percentage of participants who achieve 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). | 6 months for the Magrolimab + Azacitidine; Control Arm: Venetoclax + Azacitidine arm, and 2 months for Control Arm: 7+3 Chemotherapy | 
| Rate of CR Without Minimal Residual Disease (CR MRD-) in All Participants | The rate of CR MRD- is 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. | 6 months for the Magrolimab + Azacitidine; Control Arm: Venetoclax + Azacitidine arm, and 2 months for Control Arm: 7+3 Chemotherapy | 
| Rate of CR and Complete Remission with Partial Hematologic Recovery (CR+CRh) in All Participants | The CR+CRh rate is the percentage of participants who achieve a CR (including CR MRD- and CR MRD+/unk) or CRh as defined by CR with partial platelet and absolute neutrophil count (ANC) recovery while on study prior to initiation of any new anti-AML therapy or SCT. | 6 months for the Magrolimab + Azacitidine; Control Arm: Venetoclax + Azacitidine arm, and 2 months for Control Arm: 7+3 Chemotherapy | 
| Duration of Complete Remission (DCR) | The DCR is measured from the time the assessment criteria are 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). Those who are not observed to have relapsed disease or death while on study will be censored at the date of their last response assessment with no evidence of relapse. If participants start taking new anti-AML therapies (excluding maintenance therapy) before relapse, the DCR will be censored at the last response assessment before the initiation of the new anti-AML therapies. | First CR achieved within 6 months for the Magrolimab + Azacitidine; Control Arm: Venetoclax + Azacitidine arm, and 2 months for Control Arm: 7+3 Chemotherapy up to the end of study (up to 27 months) | 
| Duration of CR+CRh | The duration of CR+CRh is measured from the time the assessment criteria are 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). Those who are not observed to have relapsed disease or death while on study will be censored at the date of their last response assessment with no evidence of relapse. If patients start taking new anti-AML therapies (excluding maintenance therapy) before relapse, the duration of CR + CRh will be censored at the last response assessment before the initiation of the new anti-AML therapies. | First CR or CRh achieved within 6 months for the Magrolimab + Azacitidine; Control Arm: Venetoclax + Azacitidine arm, and 2 months for Control Arm: 7+3 Chemotherapy up to the end of study (up to 27 months) | 
| Percentage of Participants Experiencing Grade ≥ 3 Treatment-Emergent Adverse Events (TEAEs) According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 |  | First dose date up to last dose date (Maximum: 24 months) plus 70 days | 
| Percentage of Participants Experiencing Grade ≥ 3 Treatment-Emergent Laboratory Abnormalities According to the NCI CTCAE Version 5.0 |  | First dose date up to last dose date (Maximum: 24 months) plus 70 days | 
| Serum Concentration of Magrolimab |  | Within 72 hours predose on Day 1 of Cycle 1, within 12 hours predose on Day 8 of Cycle 1 and Day 1 of Cycles 2, 3, 5, 7, 10, 13, and end of treatment (EOT) EOT=Maximum: 24 months (Cycle=28 days) | 
| Rate of Anti-Magrolimab Antibody Incidence | Rate of anti-magrolimab antibody incidence is defined as the percentage of participants with anti-magrolimab antibodies. | Within 72 hours predose on Day 1 of Cycle 1, within 12 hours predose on Day 1 of Cycles 2, 3, 5, 7, 10, 13 and end of treatment (EOT) EOT=Maximum: 24 months (Cycle=28 days) |