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Study Evaluating the Safety and Effectiveness Magrolimab Versus Placebo in Combination With Venetoclax and Azacitidine in Participants With Acute Myeloid Leukemia (AML) (ENHANCE-3)

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ClinicalTrials.gov Identifier: NCT05079230
Recruitment Status : Not yet recruiting
First Posted : October 15, 2021
Last Update Posted : February 7, 2022
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Brief Summary:
The primary objectives of this study are to compare the efficacy of magrolimab + venetoclax + azacitidine versus placebo + venetoclax + azacitidine in participants with previously untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Magrolimab Drug: Venetoclax Drug: Azacitidine Drug: Magrolimab Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 432 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Estimated Study Start Date : February 2022
Estimated Primary Completion Date : July 2025
Estimated Study Completion Date : July 2025


Arm Intervention/treatment
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.

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)

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.

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)




Primary Outcome Measures :
  1. 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).

  2. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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).

  3. 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).

  4. 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).

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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 ]
  10. 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 ]
  11. Serum Concentration of Magrolimab [ Time Frame: First dose date up to EOT (up to 5 years) ]
  12. 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.

  13. Magnitude of Anti-Magrolimab Antibody Incidence [ Time Frame: First dose date up to EOT (up to 5 years) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05079230


Contacts
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Contact: Gilead Clinical Study Information Center 1-833-445-3230 (GILEAD-0) GileadClinicalTrials@gilead.com

Locations
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United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences
Additional Information:
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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT05079230    
Other Study ID Numbers: GS-US-590-6154
2021-003434-36 ( EudraCT Number )
First Posted: October 15, 2021    Key Record Dates
Last Update Posted: February 7, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Magrolimab
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Azacitidine
Venetoclax
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Antineoplastic Agents, Immunological