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

Study Overview
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Brief Summary
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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).

Official Title
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ENHANCE: A Randomized, Double-blind, Multicenter Study Comparing Magrolimab in Combination With Azacitidine Versus Azacitidine Plus Placebo in Treatment-naïve Patients With Higher Risk Myelodysplastic Syndrome

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Magrolimab
* Drug: Azacitidine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Magrolimab + Azacitidine<br>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 | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: GS-4721;Drug: Azacitidine<br>* Administered either subcutaneously (SC) or intravenously (IV) according to region-specific drug labeling<br>|
| Placebo Comparator: Control Arm (Placebo + Azacitidine)<br>Participants will receive the following placebo dosing regimens to mirror magrolimab dosing regimen in addition to azacitadine: Placebo 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) Placebo 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 cycle | Drug: Azacitidine<br>* Administered either subcutaneously (SC) or intravenously (IV) according to region-specific drug labeling<br>Drug: Placebo<br>* Placebo to match magrolimab administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants with Complete Remission (CR) | The CR rate is the proportion of participants who reach morphologic CR based on Investigator-assessed International Working Group (IWG) 2006 Myelodysplastic Syndrome (MDS) criteria prior to initiation of any new MDS therapy including stem cell therapy (SCT). | Up to 24 months | 
| Overall Survival (OS) | OS is defined as the length measured from randomization to the date of death from any cause. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of CR | The duration of CR is measured from the time measurement criteria are first met for CR to the first date of relapse or death, whichever occurs earlier. Those who are not observed to relapse or die will be censored at their last response assessment date with evidence of no relapse. Participants who achieve a CR and then proceed to an allogeneic SCT will continue to be followed for the response assessment post transplant, will be included in the analysis of duration of CR, and will not be censored at the time of transplant. | Up to 5 years | 
| Objective Response Rate (ORR) | ORR is the proportion of participants who reach objective response including CR, partial response (PR), marrow CR, or hematologic improvement per IWG 2006 MDS criteria prior to initiation of any new anticancer therapy for MDS, including SCT. | Up to 5 years | 
| Duration of Response (DOR) | DOR is measured from the time measurement criteria are first met for objective response to the first date of relapse, disease progression or death, whichever occurs earlier. Those who are not observed to relapse, disease progress or die will be censored at their last response assessment date with evidence of no relapse/no disease progression. Participants who achieve a response and then proceed to an allogeneic SCT will continue to be followed for the DOR post transplant, will be included in the analysis of DOR, and will not be censored at the time of transplant. | Up to 5 years | 
| Red Blood Cell (RBC) Transfusion Independence Rate | The RBC transfusion independence rate is the proportion 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 are RBC transfusion-dependent at baseline. | Up to 5 years | 
| Progression Free Survival (PFS) | The length of PFS is defined as the time from randomization to the date of documented disease progression (including treatment failure by IWG criteria or relapse after PR/CR), or death from any cause, whichever occurs first. Those who are not observed to have one of these events will be censored at their last response assessment date with evidence of no disease progression/relapse. | Up to 5 years | 
| Event Free Survival (EFS) | The length of EFS is defined as the time from randomization to transformation to acute myeloid leukemia (AML) or death from any cause, whichever occurs first. Participants who are not observed to have one of these events during the study will be censored at their last response assessment date with evidence of no transformation to AML. | Up to 5 years | 
| Minimal Residual Disease (MRD)-negative Response Rate | The MRD-negative response rate is defined as the proportion of participants who achieve a morphologic CR or marrow CR based on Investigator-assessed IWG criteria and reach MRD-negative disease status prior to initiation of any new anticancer therapy, including SCT. MRD-negative disease status will be assessed using a multiparameter flow cytometry-based assay performed by a central laboratory. | Up to 5 years | 
| Time to Transformation to AML | 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. Participants who are not observed to have transformation to AML will be censored at their last response assessment date with evidence of no AML diagnosis. | Up to 5 years | 
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events |  | Up to 5 years | 
| Serum Concentration of Magrolimab | 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. | Up to 12 hours before administration of any treatment at Days 1, 8, 15, 22 of Cycle1; at Day 1 of Cycles 2, 3, 5, 7, 9, and 13, and End of Treatment (± 7 Days after last study drug dose); Cycle length is 28 Days | 
| Anti-magrolimab Antibody Positivity Occurrence Rate |  | 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 | 
| Functional Assessment of Cancer Therapy-Anemia (FACT-Anemia) Response Rate | The FACT-Anemia response rate is defined as the proportion 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 for MDS, including SCT. 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. | Up to 5 years |