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

Sponsor

Gilead Sciences (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05079230

Collaborator

(none)

432

Enrollment

Locations

Arms

35.8

Anticipated Duration (Months)

30.9

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

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

Study Design

Study Type:

Interventional

Anticipated 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

Actual Study Start Date :

Jul 7, 2022

Anticipated Primary Completion Date :

Jul 1, 2025

Anticipated Study Completion Date :

Jul 1, 2025

Arms and Interventions

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

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 Names:

GS-4721

Drug: Venetoclax

Tablets administered orally

Other Names:

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 Names:

VENCLEXTA®

Drug: Azacitidine

Administered according to region-specific drug labeling, either subcutaneously (SC) or intravenously (IV)

Drug: Magrolimab Placebo

Administered intravenously (IV)

Outcome Measures

Primary Outcome Measures

Complete Remission (CR) [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) [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

Rate of Complete Remission Without Minimal Residual Disease (CRMRD-) [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) [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) [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) [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 [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) [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 [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 [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) [First dose date up to last dose date (up to 5 years) plus 70 days]
Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities [First dose date up to last dose date (up to 5 years) plus 70 days]
Serum Concentration of Magrolimab [First dose date up to EOT (up to 5 years)]
Rate of Anti-Magrolimab Antibody Incidence [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 [First dose date up to EOT (up to 5 years)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	MidAmerica Division, Inc., c/o Research Medical Center	Kansas City	Missouri	United States	64132
2	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08901
3	Brooke Army Medical Center	Fort Sam Houston	Texas	United States	78234
4	MD Anderson Cancer Center	Houston	Texas	United States	77030
5	Tuen Mun Hospital	Hong Kong		Hong Kong
6	Samsung Medical Center	Seoul		Korea, Republic of	06351
7	Severance Hospital	Seoul		Korea, Republic of	120-752
8	Centrum Onkologii Ziemi Lubelskiej im. Sw. Jana z Dukli, Oddzial Hematologiczny	Lublin		Poland	20090
9	Szpital Wojewodozki w Opolu Sp. z 0.0. Oddzial Klinixzny Hematologii, Onkologii Hematologicznej i Chorob Wemnetrznych	Opole		Poland	45-372
10	Hospital Universitario Araba	Alava		Spain
11	Hospital Universitario Reina Sofia	Cordoba		Spain	14004
12	Hospital Universitario Quironsalud Madrid	Madrid		Spain
13	Hospital Universitario Ramon y Cajal	Madrid		Spain
14	Complejo Hospitalario Universitario de Santiago de Compostela	Santiago de Compostela		Spain	15706