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

JRCT ID: jRCT2071220076

Registered date:29/11/2022

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Acute Myeloid Leukemia
• Date of first enrollment: 08/12/2022
• Target sample size: 346
• Countries of recruitment: Australia,Japan,Belgium,Japan,Canada,Japan,France,Japan,Germany,Japan,Hong Kong,Japan,Italy,Japan,Spain,Japan,Sweden,Japan,Switzerland,Japan,United Kingdom,Japan,United States,Japan,Austria,Japan,Denmark,Japan
• Study type: Interventional

Intervention(s)

Biological: Magrolimab
Administered intravenously (IV).
Other Name: GS-4721
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).
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, 1500 or 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.

Outcome(s)

Primary Outcome

1. 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.
[Time Frame: Randomization up to death or end of study (up to 27 months) whichever occurs first]

Secondary Outcome

2. 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.
[Time Frame: Randomization up to death or end of study (up to 27 months) whichever occurs first]

3. 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 + zacytidine or venetoclax + zacytidine, or up to 2 months of treatment with 7 + 3 chemotherapy), or death from any cause. 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.
[ Time Frame: Randomization up to end of study (up to 27 months) ]

4. Transfusion Independence Conversion Rate in All Participants
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.
[Time Frame: First dose date up to last dose date (Maximum: 24 months)]

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

6. 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- 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.
[ Time Frame: 6 months for the Magrolimab + Azacitidine; Control Arm: Venetoclax + Azacitidine arm, and 2 months for Control Arm: 7+3 Chemotherapy ]

7. Time Until Meaningful Definitive Deterioration (TUDD) on the EORTC QLQ-C30 GHS/QoL Scale in All Participants
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 10 points 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.
[ Time Frame: Day 1 of each cycle (up to 24 months); Cycle=28 days ]

8. 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.

9. 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.
[ Time Frame: 6 months for the Magrolimab + Azacitidine; Control Arm: Venetoclax + Azacitidine arm, and 2 months for Control Arm: 7+3 Chemotherapy ]

10. 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.

11. 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 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.
[ 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) ]

12. 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 ]

13. 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 ]

14. 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) ]

15. Rate of Anti-Magrolimab Antibody Incidence
Rate of anti-magrolimab antibody incidence is defined as the percentage of participants with anti-magrolimab antibodies.
[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)]

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include 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 <= 20x10^3/microliter prior to randomization. If the individual's WBC is > 20x10^3/microliter prior to randomization, the individual can be enrolled, assuming all other eligibility criteria are met. However, the WBC should be >= 20x10^3/ microliter 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 <= 20x10^3/ microliter 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 x upper limit of normal (ULN)
Alanine aminotransferase <= 3.0 x ULN
Total bilirubin <= 1.5 x ULN, or primary unconjugated bilirubin <= 3.0 x 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).

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Exclude 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 (SIRP-alpha)-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.

Related Information

• Primary Sponsor: Omote Masayuki
• Secondary ID(s): NCT04778397