Magrolimab + Azacitidine Versus Azacitidine + Placebo in Untreated Participants With Myelodysplastic Syndrome (MDS) (ENHANCE)
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| ClinicalTrials.gov Identifier: NCT04313881 |
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Recruitment Status :
Terminated
(Study discontinued due to futility based on a planned analysis)
First Posted : March 18, 2020
Results First Posted : March 21, 2024
Last Update Posted : March 21, 2024
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Myelodysplastic Syndromes | Drug: Magrolimab Drug: Azacitidine Drug: Placebo | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 539 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | 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 |
| Actual Study Start Date : | September 9, 2020 |
| Actual Primary Completion Date : | September 13, 2023 |
| Actual Study Completion Date : | September 13, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Magrolimab + Azacitidine
Participants will receive the following magrolimab and azacitidine dosing regimens: Magrolimab: Magrolimab Priming Dose:
Magrolimab Maintenance Dose:
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
Administered intravenously
Other Names:
Drug: Azacitidine Administered either subcutaneously (SC) or intravenously (IV) according to region-specific drug labeling |
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Placebo Comparator: Control Arm (Placebo + 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. |
Drug: Azacitidine
Administered either subcutaneously (SC) or intravenously (IV) according to region-specific drug labeling Drug: Placebo Placebo to match magrolimab administered intravenously |
- Percentage of Participants With Complete Remission (CR) [ Time Frame: 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) [ Time Frame: 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.
- Duration of CR (DOCR) [ Time Frame: From randomization up to 31.01 months ]DOCR=Time from first CR date to the first date of relapse, disease progression (PD) or death, 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.
- Objective Response Rate (ORR) [ Time Frame: 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.
- Duration of Response (DOR) [ Time Frame: 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, whichever occurs earlier.
Disease progression and relapse have been defined in outcome measure number 3. KM estimates were used for analysis.
- Red Blood Cell (RBC) Transfusion Independence Rate [ Time Frame: 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) [ Time Frame: 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
- Percentage of Participants With CR Rate in Participants With TP53 Mutation [ Time Frame: 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 [ Time Frame: 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. Transformation assessments post SCT were to be included in the analysis.
Morphologic CR and marrow CR are defined in outcome measures 1 and 4, respectively.
Percentages were rounded off.
- Time to Transformation to AML [ Time Frame: 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. KM estimates were used for analysis.
- Progression Free Survival (PFS) [ Time Frame: 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.
CR, PR and PD are defined in outcome measures 1, 4 and 5 respectively. KM estimates were used for analysis.
- Functional Assessment of Cancer Therapy-Anemia (FACT-Anemia) Response Rate [ Time Frame: 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.
- Percentage of Participants Experiencing Treatment-Emergent Adverse Events [ Time Frame: First dose date up to 135.9 weeks plus 70 days (Up to 2.8 years) ]
Treatment-emergent adverse events (TEAEs) are defined as any AEs with an onset date on or after the study drug start date and no later than 70 days after the study drug last dose date or the day before initiation of new anticancer therapy including SCT (whichever is earlier). If the AE onset date is on or before the last dose date, the AE is considered as TEAE regardless of the start of new anticancer therapy.
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol imposed intervention, regardless of attribution.
An event is considered "serious", if it results in any of the following outcomes: death, life-threatening, inpatient or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, and important medical events.
- Serum Concentration of Magrolimab [ Time Frame: 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 [ Time Frame: 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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04313881
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| Study Director: | Gilead Study Director | Gilead Sciences |
Documents provided by Gilead Sciences:
| Responsible Party: | Gilead Sciences |
| ClinicalTrials.gov Identifier: | NCT04313881 |
| Other Study ID Numbers: |
5F9009 2020-004287-26 ( EudraCT Number ) |
| First Posted: | March 18, 2020 Key Record Dates |
| Results First Posted: | March 21, 2024 |
| Last Update Posted: | March 21, 2024 |
| Last Verified: | March 2024 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Preleukemia Myelodysplastic Syndromes Syndrome Disease Pathologic Processes Bone Marrow Diseases Hematologic Diseases Precancerous Conditions Neoplasms |
Azacitidine Magrolimab Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Enzyme Inhibitors Antineoplastic Agents, Immunological |