Magrolimab + Azacitidine Versus Azacitidine + Placebo in Untreated Participants With Myelodysplastic Syndrome (MDS)

Phase 3

Terminated

Conditions: Myelodysplastic Syndromes

Interventions: Drug: Magrolimab
Drug: Placebo
Drug: Azacitidine

Registration Number: NCT04313881

Lead Sponsor: Gilead Sciences

Brief Summary: The primary objective of this study is to evaluate the efficacy of magrolimab in combination with azacitidine compared to that of azacitidine plus placebo in previously untreated participants with intermediate/high/very high risk myelodysplastic syndrome (MDS) by Revised International Prognostic Scoring System (IPSS-R) as measured by complete remission (CR) and overall survival (OS).

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 539

Inclusion Criteria

Participants with Myelodysplastic Syndrome (MDS) defined according to World Health Organization classification, with Revised International Prognostic Scoring System (IPSS-R) prognostic risk category of intermediate, high, or very high risk.
Adequate performance status and hematological, liver, and kidney function.

Key

Exclusion Criteria

Immediate eligibility for allogenic stem cell transplant (SCT), as determined by the investigator, with an available donor.
Prior treatment with Cluster of Differentiation (CD) 47 or Signal-regulatory protein alpha (SIRPα)-targeting agents.
Any prior antileukemic therapy for treatment of intermediate, high, very high risk MDS per IPSS-R.
Second malignancy, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, or other malignancies for which participants are not on active anticancer therapies and have had no evidence of active malignancy for at least ≥ 1 year.
Contraindications to azacitidine.
Clinical suspicion of active central nervous system (CNS) involvement by MDS.
Known active or chronic hepatitis B or C infection or human immunodeficiency virus in medical history .
Active hepatitis B virus and/or active hepatitis C virus, and/or HIV following testing at screening.
Pregnancy or active breastfeeding.

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control Arm (Placebo + Azacitidine)	Placebo	Participants will receive the following placebo dosing regimens to mirror magrolimab dosing regimen in addition to azacitidine: Placebo: On Days 1 and 4; Day 8; Days 11, 15, followed by weekly administration for 5 doses (on Days 22, 29, 36, 43, and 50). Additionally, placebo was administered on Day 57 and every 2 weeks thereafter. Azacitidine: 75 mg/m\^2 on Days 1 to 7 (or Days 1 to 5 and 8 to 9) of each cycle.
Magrolimab + Azacitidine	Azacitidine	Participants will receive the following magrolimab and azacitidine dosing regimens: Magrolimab: Magrolimab Priming Dose: * 1 mg/kg on Days 1 and 4 * 15 mg/kg on Day 8 * 30 mg/kg on Days 11, 15, followed by weekly administration for 5 doses (on Days 22, 29, 36, 43, and 50) Magrolimab Maintenance Dose: * 30 mg/kg on Day 57 and 30 mg/kg every 2 weeks thereafter. Azacitidine: 75 mg/m\^2 on Days 1 to 7 (or Days 1 to 5 and 8 to 9) of each 28-day cycle.
Control Arm (Placebo + Azacitidine)	Azacitidine	Participants will receive the following placebo dosing regimens to mirror magrolimab dosing regimen in addition to azacitidine: Placebo: On Days 1 and 4; Day 8; Days 11, 15, followed by weekly administration for 5 doses (on Days 22, 29, 36, 43, and 50). Additionally, placebo was administered on Day 57 and every 2 weeks thereafter. Azacitidine: 75 mg/m\^2 on Days 1 to 7 (or Days 1 to 5 and 8 to 9) of each cycle.
Magrolimab + Azacitidine	Magrolimab	Participants will receive the following magrolimab and azacitidine dosing regimens: Magrolimab: Magrolimab Priming Dose: * 1 mg/kg on Days 1 and 4 * 15 mg/kg on Day 8 * 30 mg/kg on Days 11, 15, followed by weekly administration for 5 doses (on Days 22, 29, 36, 43, and 50) Magrolimab Maintenance Dose: * 30 mg/kg on Day 57 and 30 mg/kg every 2 weeks thereafter. Azacitidine: 75 mg/m\^2 on Days 1 to 7 (or Days 1 to 5 and 8 to 9) of each 28-day cycle.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Complete Remission (CR)	From randomization up to 31.01 months	The percentage of participants (CR rate) are participants who reach morphologic CR (morphological blast of ≤ 5% and recovery of absolute neutrophil count (ANC), platelets, and hemoglobin from complete blood counts as well as peripheral blast) based on Investigator-assessed International Working Group (IWG) myelodysplastic syndrome (MDS) criteria on or prior to initiation of any new anticancer therapy, including stem cell therapy (SCT). Percentages were rounded off.
Overall Survival (OS)	From randomization up to 32.62 months	OS is defined as the number of months measured from the date of randomization to the date of death from any cause. Kaplan Meier (KM) estimates were used for analysis.

Secondary Outcome Measures

Name	Time	Method
Duration of CR (DOCR)	From randomization up to 31.01 months	DOCR=Time from first CR date to the first date of relapse, disease progression (PD) or death, prior to initiation of any new anticancer therapy excluding SCT whichever occurs earlier. PD is defined as: \<5% blasts: ≥50 increase in blasts to \>5% blasts,5%-10% blasts: ≥50% increase in blasts to \>10% blasts, 10%-20% blasts: ≥50% increase in blasts to \>20% blasts,20%-30% blasts: ≥50% increase in blasts to \>30% blasts, any of the following: at least 50% decrement from maximum remission/response in granulocytes or platelets. Reduction in Hgb by ≥2 g/dL / Transfusion dependence. Relapse is defined as return to pretreatment bone marrow blast percentage / decrement of ≥ 50% from maximum remission/response levels in granulocytes or platelets/ reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence. CR is defined in outcome measure 1. KM estimates were used for analysis.
Duration of Response (DOR)	From randomization up to 31.01 months	DOR is measured from time measurement criteria are first met for objective response to first date of relapse, disease progression (PD) /death, prior to initiation of any new anticancer therapy excluding SCT whichever occurs earlier. Disease progression and relapse have been defined in outcome measure number 3. KM estimates were used for analysis.
Percentage of Participants With CR in Participants With TP53 Mutation	From randomization up to 31.01 months	CR in TP53 mutant population is defined as the percentage of participants who achieve a morphologic CR based on investigator assessments using IWG criteria on or prior to initiation of any new anticancer therapy, including SCT in TP53 mutant population. Percentages were rounded off.
Minimal Residual Disease (MRD)-Negative Response Rate	From randomization up to 31.01 months	The MRD-negative response rate is defined as the percentage of participants who achieved a morphologic CR or marrow CR based on Investigator-assessed IWG criteria and reached MRD-negative disease status prior to initiation of any new anticancer therapy, including SCT. MRD-negative disease status was assessed using a multiparameter flow cytometry-based assay performed by a central laboratory. Morphologic CR and marrow CR are defined in outcome measures 1 and 4, respectively. Percentages were rounded off.
Time to Transformation to AML	From randomization up to 31.01 months	Time to transformation to AML is defined as the time from randomization to the collection date of bone marrow sample leading to documented AML diagnosis. Transformation assessments post SCT were included in the analysis.KM estimates were used for analysis.
Functional Assessment of Cancer Therapy-Anemia (FACT-Anemia) Response Rate	Up to week 136	The FACT-Anemia response rate is defined as the percentage of participants who showed clinically meaningful improvement in health-related quality of life (HRQoL) based on the score from the FACT-Anemia instrument prior to initiation of any new anticancer therapy, including SCT. The minimal clinically meaningful difference of 7.0 was used as cutoff for clinically meaningful improvement. The FACT-Anemia instrument consists of 5 subscales, including physical well-being, emotional well-being, functional well-being, social well-being, and anemia symptoms. Each subscale measures items on a 5-point Likert scale from 0 to 4, where 0 = not at all and 4 = very much. The subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest quality of life (QOL) and 100 denotes the highest QOL. Percentages were rounded off.
Objective Response Rate (ORR)	From randomization up to 31.01 months	ORR is defined as the percentage of participants who reach objective response including CR, partial remission (PR), marrow CR or hematological improvement prior to initiation of any new anticancer therapy including SCT for MDS per IWG 2006 criteria per investigator's evaluation. CR is defined in outcome measure 1. PR is defined as all CR criteria if abnormal before treatment except, one marrow blasts decreased by ≥ 50% over pretreatment but still \> 5% cellularity and morphology not relevant. Marrow CR is defined as bone marrow ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment, stable disease with any hematological improvement, peripheral blood: if hematological improvement responses, they were noted in addition to marrow CR. Stable Disease: Failure to achieve at least PR, but no evidence of progression for \> 8 weeks. Percentages were rounded off.
Red Blood Cell (RBC) Transfusion Independence Rate	From randomization up to 31.01 months	RBC transfusion independence rate is defined as the percentage of participants who have a 56-day or longer period with no RBC transfusions at any time between randomization and initiation of any new anticancer therapy, including SCT, among all participants who were RBC transfusion-dependent at Baseline. Percentages were rounded off.
Event Free Survival (EFS)	From randomization up to 31.01 months	EFS is defined as the time from randomization to transformation to acute myeloid leukemia (AML) or death from any cause, whichever occurs first. Transformation assessments and deaths post SCT were included in the analysis. KM estimates were used for analysis
Progression Free Survival (PFS)	From randomization up to 31.01 months	PFS is defined as the time from randomization to the date of documented DP (including treatment failure by IWG criteria or relapse after PR/CR), or death from any cause, whichever occurs first. Response assessments and deaths post SCT were included in the analysis. Treatment failure is defined as, Death during treatment or disease progression characterized by worsening cytopenia, increase in percentage of bone marrow blasts, or progression to a more advanced MDS FAB subtype than pretreatment. Relapse after CR or PR = Return to pretreatment bone marrow blast percentage / Decrement of ≥ 50% from maximum remission/response levels in granulocytes or platelets / Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence. CR, PR and PD are defined in outcome measures 1, 4 and 5 respectively. KM estimates were used for analysis.
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAE)	First dose date up to 135.9 weeks plus 70 days (Up to 2.8 years)	TEAE's are defined as any AEs with an onset date on or after the study drug start date, no later than 70 days after study drug last dose date or day before initiation of new anticancer therapy including SCT. If AE onset date is on or before last dose date, it is considered as TEAE regardless of start of new anticancer therapy. An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with use of an investigational product or other protocol imposed intervention, regardless of attribution. An event is considered "serious", if it results death, life-threatening, inpatient or prolongation hospitalization, incapacity or substantial disruption of the ability to conduct normal functions, a congenital anomaly/birth defect, and important medical events.
Serum Concentration of Magrolimab	Preinfusion on Days 0, 7, 28, 56, 112, 168, 252 and 336	Pretreatment assessments for the initial dose may be collected up to 72 hours before administration of study treatment; thereafter, pretreatment assessments are to be collected within 24 hours prior to study treatment administration.
Percentage of Participants With Positive Anti-magrolimab Antibodies	Up to 72 hours before administration of any treatment at Day 1, Cycle 1; within 24 hours prior to any study drug administration at Day 1 of Cycles 2, 3, 5, 7, 10, and 13 and End of Treatment (± 7 Days after last study drug dose); Cycle length is 28 Days	Percentages were rounded off.

Trial Locations

Locations (169): University of Alabama Birmingham
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Birmingham, Alabama, United States
University of Arkansas for Medical Sciences IRB
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Little Rock, Arkansas, United States
City of Hope
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Duarte, California, United States
UC San Diego Moores Cancer Center
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La Jolla, California, United States
UCLA Ronald Reagan Medical Center
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Los Angeles, California, United States
UC Irvine Health
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Orange, California, United States
Stanford Cancer Institute
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Palo Alto, California, United States
University of California, Davis Comprehensive Cancer Center
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Sacramento, California, United States
University of Miami Hospital and Clinics / Sylvester Comprehensive Cancer Center
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Miami, Florida, United States
Moffitt Cancer Center
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Tampa, Florida, United States
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University of Alabama Birmingham
🇺🇸Birmingham, Alabama, United States