ENHANCE-2: 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

Sponsor

Gilead Sciences (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04778397

Collaborator

(none)

346

Enrollment

Locations

Arms

Anticipated Duration (Months)

7.5

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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

Study Design

Study Type:

Interventional

Anticipated 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 :

Jul 1, 2021

Anticipated Primary Completion Date :

Aug 1, 2024

Anticipated Study Completion Date :

Jul 1, 2025

Arms and Interventions

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 Names: 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, 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.

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 Names:

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, 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 Measures

Primary Outcome Measures

Overall Survival (OS) in Participants Appropriate for Non-intensive Therapy [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

Overall Survival in All Participants [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.
Event-Free Survival (EFS) in All Participants [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.
Transfusion Independence Conversion Rate in All Participants [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.
Rate of Complete Remission (CR) in All Participants [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).
Rate of CR Without Minimal Residual Disease (CR MRD-) in All Participants [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.
Time Until Meaningful Definitive Deterioration (TUDD) on the EORTC QLQ-C30 GHS/QoL Scale in All Participants [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.
TUDD on the EORTC QLQ-C30 Physical Functioning Scale in All Participants [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.
Rate of CR and Complete Remission with Partial Hematologic Recovery (CR+CRh) in All Participants [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.
Duration of Complete Remission (DCR) [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.
Duration of CR+CRh [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.
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 [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope (City of Hope National Medical Center, City of Hope Medical Center)	Duarte	California	United States	91010
2	USC/ Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
3	UC Irvine Health	Orange	California	United States	92868
4	Colorado Blood Cancer Institute	Denver	Colorado	United States	80218
5	Miami Cancer Institute	Miami	Florida	United States	33176
6	Memorial Cancer Institute	Pembroke Pines	Florida	United States	33028
7	Winship Cancer Institute	Atlanta	Georgia	United States	30322
8	The University of Chicago Medical Centre	Chicago	Illinois	United States	60637
9	Tulane Medical center	New Orleans	Louisiana	United States	70112
10	MidAmerica Division, Inc., c/o Research Medical Center	Kansas City	Missouri	United States	64132
11	Washington University School of Medicine - Siteman Cancer Center	Saint Louis	Missouri	United States	63110
12	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
13	UNC Hospitals, The University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
14	The Ohio State University Wexner Medical Center/ James Cancer Hospital	Columbus	Ohio	United States	43210
15	University of Oklahoma Health Sciences Center - OU Health Stephenson Cancer Center	Oklahoma City	Oklahoma	United States	73104
16	Thomas Jefferson University, Sidney Kimmel Cancer Center, Clinical Research Organization	Philadelphia	Pennsylvania	United States	19107
17	St. Francis Cancer Center	Greenville	South Carolina	United States	29607
18	Prisma Health Cancer Institute	Greenville	South Carolina	United States	29615
19	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
20	Canberra Hospital	Garran	Australian Capital Territory	Australia	2605
21	Westmead Hospital / Department of Haematology and Bone Marrow Transplantation	Westmead	New South Wales	Australia	2145
22	Princess Alexandra Hospital	Woolloongabba	Queensland	Australia	4102
23	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
24	Andrew Love Cancer Centre, University Hospital Geelong	Geelong	Victoria	Australia	3220
25	The Alfred	Melbourne	Victoria	Australia	3004
26	Fiona Stanley Hospital	Murdoch	Western Australia	Australia	6150
27	Royal Perth Hospital	Perth	Western Australia	Australia	6000
28	Queen Elizabeth II Health Sciences Centre	Halifax		Canada	B3H 1V7
29	CHU d'Angers	Angers cedex		France	49933
30	CHU de Caen	Caen cedex		France	14033
31	CHU de Nantes, Hotel Dieu	Nantes		France	44093
32	CHU Nice - Hopital Archet 1	Nice		France	6200
33	IUCT Oncopole	Toulouse		France	31059
34	Department of Hematology and Oncology, Braunschweig Community Hospital	Braunschweig		Germany	38114
35	Universitatsklinikum Heidelberg, Innere Medizin V, Hamatologie, Onkologie und Rheumatologie	Heidelberg		Germany	69120
36	Prince of Wales Hospital, The Chinese University of Hong Kong	Hong Kong		Hong Kong
37	Queen Mary Hospital	Hong Kong		Hong Kong
38	SCDU Ematologia e Terrapie cellulari AO O Ordine Mauriziano Torino	Torino		Italy	10122
39	Hospital Clinic de Barcelona	Barcelona		Spain	08036
40	Hospital Universitari I Politècnic La Fe	Valencia		Spain	46026
41	Universitatsspital Basel - Klinik fur Hamatrologie, Bereich Innere Medizin	Basel		Switzerland	4031
42	Inselspital, Universitatsspital Bern - Universitatsklinik fur Medizinisch Onkologie	Berne		Switzerland	CH 3010
43	Cambridge University Hospital NHS Foundation Trust	Cambridge		United Kingdom	CB2 0QQ
44	NHS Tayside	Dundee		United Kingdom	DD1 9SY
45	University College London Hospitals NHS Foundation Trust	London		United Kingdom	NW1 2PG
46	Oxford University Hospital NHS Foundation Trust	Oxford		United Kingdom	OX3 7LE