Study of Magrolimab Versus Placebo in Combination With Venetoclax and Azacitidine in Participants With Acute Myeloid Leukemia (ENHANCE-3)

• ClinicalTrials.gov Identifier: NCT05079230
• Recruitment Status: Terminated
• First Posted: October 15, 2021
• Last Update Posted: April 16, 2024
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Tracking Information

• First Submitted Date: October 4, 2021
• First Posted Date: October 15, 2021
• Last Update Posted Date: April 16, 2024
• Actual Study Start Date: July 7, 2022
• Actual Primary Completion Date: April 11, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 1, 2023)

Overall Survival (OS) [ Time Frame: Randomization up to death or end of study (up to 5 years) whichever occurs first ]

OS is measured from the date of randomization to the date of death from any cause.

Original Primary Outcome Measures (submitted: October 4, 2021)

• Complete Remission (CR) [ Time Frame: Up to 7 months ]
  CR is defined as the proportion of 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).
• Overall Survival (OS) [ Time Frame: Randomization up to death or end of study (up to 5 years) whichever occurs first ]
  OS is measured from the date of randomization to the date of death from any cause.

Current Secondary Outcome Measures (submitted: December 1, 2023)

• Rate of Complete Remission (CR) + Complete Remission With Partial Hematologic Recovery (CRh) [ Time Frame: Up to 7 months ]
  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).
• Rate of Complete Remission (CR) [ Time Frame: Up to 7 months ]
  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)
• Event-Free Survival (EFS) [ Time Frame: Randomization up to end of study (up to 5 years) ]
  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.
• Duration of CR + CRh in Participants who achieved Complete Remission (CR) or Complete Remission With Partial Hematologic Recovery (CRh) [ Time Frame: Up to 5 years ]
  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).
• Duration of Complete Remission (DCR) in Participants who achieved Complete Remission (CR) [ Time Frame: Up to 5 years ]
  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).
• Rate of CR/Complete Remission With Partial Hematologic Recovery Without Minimal Residual Disease (CRhMRD-) [ Time Frame: Up to 5 years ]
  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.
• Rate of Complete Remission Without Minimal Residual Disease (CRMRD-) [ Time Frame: Up to 5 years ]
  The CRMRD- rate is the proportion of participants who achieve a CRMRD- within 6 cycles of treatment.
• Transfusion Independence Conversion Rate [ Time Frame: First dose date up to End of Treatment (EOT) (up to 5 years) ]
  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.
• 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 [ Time Frame: Randomization up to end of study (up to 5 years) ]
  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.
• TTD on the EORTC QLQ-C30 Physical Functioning Scale [ Time Frame: Randomization up to end of study (up to 5 years) ]
  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.
• Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: First dose date up to last dose date (up to 5 years) plus 70 days ]
• Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities [ Time Frame: First dose date up to last dose date (up to 5 years) plus 70 days ]
• Serum Concentration of Magrolimab over time [ Time Frame: First dose date up to EOT (up to 5 years) ]
• Rate of Anti-Magrolimab Antibody Incidence [ Time Frame: First dose date up to EOT (up to 5 years) ]
  Rate of anti-magrolimab antibody incidence is defined as the percentage of participants with anti-magrolimab antibodies.
• Magnitude of Anti-Magrolimab Antibody Incidence [ Time Frame: First dose date up to EOT (up to 5 years) ]

Original Secondary Outcome Measures (submitted: October 4, 2021)

• Rate of Complete Remission Without Minimal Residual Disease (CRMRD-) [ Time Frame: Up to 7 months ]
  The CRMRD- rate is the proportion of participants who achieve a complete remission without minimal residual disease within 6 cycles of treatment as determined by investigators.
• Rate of Complete Remission (CR) + Complete Remission With Partial Hematologic Recovery (CRh) [ Time Frame: Up to 7 months ]
  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).
• Duration of Complete Remission (DCR) in Participants who achieved Complete Remission (CR) [ Time Frame: Up to 5 years ]
  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).
• Duration of CR + CRh in Participants who achieved Complete Remission (CR) or Complete Remission With Partial Hematologic Recovery (CRh) [ Time Frame: Up to 5 years ]
  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).
• Transfusion Independence Conversion Rate [ Time Frame: First dose date up to End of Treatment (EOT) (up to 5 years) ]
  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.
• Event-Free Survival (EFS) [ Time Frame: Randomization up to end of study (up to 5 years) ]
  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.
• Time Until Meaningful Definitive Deterioration (TUDD) 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 [ Time Frame: Randomization up to end of study (up to 5 years) ]
  The TUDD on the EORTC QLQ-C30 GHS/QoL scale is defined as time from randomization date to earlier date that score is consistently at least one threshold value worse than the baseline score 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.
• TUDD on the EORTC QLQ-C30 Physical Functioning Scale [ Time Frame: Randomization up to end of study (up to 5 years) ]
  TUDD on the EORTC QLQ C30 physical functioning scale is defined as time from the date of randomization to the date of death or the first date of the consistent deteriorations of at least one threshold value as compared with the baseline score, 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.
• Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: First dose date up to last dose date (up to 5 years) plus 70 days ]
• Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities [ Time Frame: First dose date up to last dose date (up to 5 years) plus 70 days ]
• Serum Concentration of Magrolimab [ Time Frame: First dose date up to EOT (up to 5 years) ]
• Rate of Anti-Magrolimab Antibody Incidence [ Time Frame: First dose date up to EOT (up to 5 years) ]
  Rate of anti-magrolimab antibody incidence is defined as the percentage of participants with anti-magrolimab antibodies.
• Magnitude of Anti-Magrolimab Antibody Incidence [ Time Frame: First dose date up to EOT (up to 5 years) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Magrolimab Versus Placebo in Combination With Venetoclax and Azacitidine in Participants With Acute Myeloid Leukemia
• Official Title: 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Acute Myeloid Leukemia

Intervention

• Drug: Magrolimab
  Administered intravenously (IV)
  Other Name: GS-4721
• Drug: Venetoclax
  Tablets administered orally
  Other Name: VENCLEXTA®
• Drug: Azacitidine
  Administered according to region-specific drug labeling, either subcutaneously (SC) or intravenously (IV)
• Drug: Magrolimab Placebo
  Administered intravenously (IV)

Study Arms

• Experimental: Magrolimab + Venetoclax + Azacitidine

  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.

  Interventions:

  • Drug: Magrolimab
  • Drug: Venetoclax
  • Drug: Azacitidine
• Placebo Comparator: Magrolimab Placebo + Venetoclax + Azacitidine

  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.

  Interventions:

  • Drug: Venetoclax
  • Drug: Azacitidine
  • Drug: Magrolimab Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: April 12, 2024): 378
• Original Estimated Enrollment (submitted: October 4, 2021): 432
• Actual Study Completion Date: April 11, 2024
• Actual Primary Completion Date: April 11, 2024 (Final data collection date for primary outcome measure)

Eligibility 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/Exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Canada, Czechia, France, Germany, Hong Kong, Hungary, Israel, Italy, Korea, Republic of, Netherlands, Norway, Poland, Spain, Switzerland, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT05079230
• Other Study ID Numbers: GS-US-590-6154; 2021-003434-36 ( EudraCT Number ); MOH_2022-08-15_011983 ( Registry Identifier: Israel Clinical Research Site )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Gilead Sciences
• Original Responsible Party: Same as current
• Current Study Sponsor: Gilead Sciences
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

• PRS Account: Gilead Sciences
• Verification Date: April 2024