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Study to Evaluate 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 Adults With TP53 Mutant Acute Myeloid Leukemia (ENHANCE-2)

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ClinicalTrials.gov Identifier: NCT04778397
Recruitment Status : Recruiting
First Posted : March 3, 2021
Last Update Posted : May 13, 2022
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Brief Summary:
The primary objective of this study is to compare the efficacy of magrolimab + azacitidine versus venetoclax + azacitidine in adults with previously untreated TP53 mutant acute myeloid leukemia (AML) who are appropriate for non-intensive therapy as measured by overall survival (OS).

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Biological: Magrolimab Drug: Venetoclax Drug: Azacitidine Drug: Cytarabine Drug: Daunorubicin Drug: Idarubicin Drug: Steroidal Eye Drops Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 346 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : July 1, 2021
Estimated Primary Completion Date : August 2024
Estimated Study Completion Date : July 2025


Arm Intervention/treatment
Experimental: Magrolimab + Azacitidine
Participants will receive an escalating dose of magrolimab and a fixed dose of azacitidine.
Biological: Magrolimab
Administered intravenously (IV).
Other Name: GS-4721

Drug: Azacitidine
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).

Active Comparator: Control Arm: Venetoclax + Azacitidine
Participants who are appropriate for non-intensive therapy will receive an escalating dose of venetoclax and a fixed dose of azacitidine.
Drug: Venetoclax
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).

Drug: Azacitidine
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).

Active Comparator: Control Arm: 7+3 Chemotherapy
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

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, 3000 mg/m^2 on Days 1, 3, and 5 once every 12 hours for up to 4 cycles.


Drug: Daunorubicin
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).

Drug: Idarubicin
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).

Drug: Steroidal Eye Drops
Administered per institutional standard during consolidation.




Primary Outcome Measures :
  1. Overall Survival (OS) in Participants Appropriate for Non-intensive Therapy [ Time Frame: Randomization up to death or end of study (up to 27 months) whichever occurs first ]
    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.


Secondary Outcome Measures :
  1. Overall Survival in All Participants [ Time Frame: Randomization up to death or end of study (up to 27 months) whichever occurs first ]
    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.

  2. Event-Free Survival (EFS) in All Participants [ Time Frame: Randomization up to end of study (up to 27 months) ]
    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.

  3. Transfusion Independence Conversion Rate in All Participants [ Time Frame: First dose date up to last dose date (Maximum: 24 months) ]
    The transfusion independence conversion rate is the percentage of participants who have a 56-day or longer period with no RBC or whole blood or platelet 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 transfusion dependence at baseline is defined as having received a transfusion within the 28 days prior to the first dose of study treatment.

  4. Rate of Complete Remission (CR) in All Participants [ Time Frame: 6 months for the Magrolimab + Azacitidine; Control Arm: Venetoclax + Azacitidine arm, and 2 months for Control Arm: 7+3 Chemotherapy ]
    The rate of CR is the percentage of participants who achieve a CR, including complete remission without minimal residual disease (CR MRD-) and complete remission with positive or unknown minimal residual disease (CR MRD+/unk) as defined by investigators based on European Leukemia Net 2017 recommendations for AML (ELN 2017 AML) with modifications, while on study prior to initiation of any new anti-AML therapy or stem cell transplant (SCT).

  5. Rate of CR Without Minimal Residual Disease (CR MRD-) in All Participants [ Time Frame: 6 months for the Magrolimab + Azacitidine; Control Arm: Venetoclax + Azacitidine arm, and 2 months for Control Arm: 7+3 Chemotherapy ]
    The rate of CR MRD- is the percentage of participants who achieve a CR MRD- 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. Time Until Meaningful Definitive Deterioration (TUDD) on the EORTC QLQ-C30 GHS/QoL Scale in All Participants [ Time Frame: Day 1 of each cycle (up to 24 months); Cycle=28 days ]
    TUDD on European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) scale is defined as time from randomization date to earlier date that score is consistently at least 1 threshold value worse than baseline score/death. 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. Those whose score does not reach meaningful definitive deterioration and whose deaths are not observed during study will be censored at their last GHS/QoL scale assessment.

  7. TUDD on the EORTC QLQ-C30 Physical Functioning Scale in All Participants [ Time Frame: Day 1 of each cycle (up to 24 months); Cycle=28 days ]
    TUDD on the EORTC QLQ C30 physical functioning scale is defined as time from the date of randomization to the earlier date that the score is consistently at least 10 points worse than the baseline score or death. 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. Those whose score does not reach meaningful definitive deterioration and whose deaths are not observed during the study will be censored at their last physical functioning scale assessment date.

  8. Rate of CR and Complete Remission with Partial Hematologic Recovery (CR+CRh) in All Participants [ Time Frame: 6 months for the Magrolimab + Azacitidine; Control Arm: Venetoclax + Azacitidine arm, and 2 months for Control Arm: 7+3 Chemotherapy ]
    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.

  9. Duration of Complete Remission (DCR) [ Time Frame: 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) ]
    The DCR is measured from the time the assessment criteria are first met for CR (including CR MRD- and CR MRD+/unk) 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.

  10. Duration of CR+CRh [ Time Frame: 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) ]
    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 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.

  11. 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 [ Time Frame: First dose date up to last dose date (Maximum: 24 months) plus 70 days ]
  12. Percentage of Participants Experiencing Grade ≥ 3 Treatment-Emergent Laboratory Abnormalities According to the NCI CTCAE Version 5.0 [ Time Frame: First dose date up to last dose date (Maximum: 24 months) plus 70 days ]
  13. Serum Concentration of Magrolimab [ Time Frame: 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) ]
  14. Rate of Anti-Magrolimab Antibody Incidence [ Time Frame: 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) ]
    Rate of anti-magrolimab antibody incidence is defined as the percentage of participants with anti-magrolimab antibodies.



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:

  • Individuals with confirmation of 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
  • 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 ontreatment 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.


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): NCT04778397


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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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: NCT04778397    
Other Study ID Numbers: GS-US-546-5857
2020-003949-11 ( EudraCT Number )
First Posted: March 3, 2021    Key Record Dates
Last Update Posted: May 13, 2022
Last Verified: May 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
Cytarabine
Azacitidine
Daunorubicin
Venetoclax
Idarubicin
Ophthalmic Solutions
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors
Pharmaceutical Solutions
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Antineoplastic Agents, Immunological