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

• ClinicalTrials.gov Identifier: NCT04313881
• Recruitment Status: Terminated
• First Posted: March 18, 2020
• Results First Posted: March 21, 2024
• Last Update Posted: March 21, 2024
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Tracking Information

• First Submitted Date: March 11, 2020
• First Posted Date: March 18, 2020
• Results First Submitted Date: February 15, 2024
• Results First Posted Date: March 21, 2024
• Last Update Posted Date: March 21, 2024
• Actual Study Start Date: September 9, 2020
• Actual Primary Completion Date: September 13, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 15, 2024)

• 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.

Original Primary Outcome Measures (submitted: March 17, 2020)

CR rate and duration of CR [ Time Frame: 6 months after last patient randomized ]

To evaluate the efficacy of magrolimab + azacitidine, compared to that of azacitidine + placebo, in previously untreated patients with intermediate/high/very high risk MDS by IPSS-R as measured by CR and duration of CR

Current Secondary Outcome Measures (submitted: February 15, 2024)

• 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.

Original Secondary Outcome Measures (submitted: March 17, 2020)

• Overall Survival [ Time Frame: Through Study Completion, up to 4 years after the last patient is randomized. ]
  To evaluate the survival benefit of magrolimab + azacitidine compared to azacitidine + placebo
• ORR [ Time Frame: From Start of treatment until disease progression/recurrence, up to 4 years after the last patient is randomized. ]
  To evaluate the objective response rate (ORR) of magrolimab + azacitidine compared to that of azacitidine + placebo
• DOR [ Time Frame: From Start of treatment until disease progression/recurrence, up to 4 years after the last patient is randomized. ]
  To evaluate the duration of response (DOR) of magrolimab + azacitidine compared to that of azacitidine + placebo
• Red Blood Cell (RBC) transfusion independence rate [ Time Frame: Any time between randomization and initiation of any new MDS therapy among all patients who are RBC transfusion-dependent at Baseline, assessed up to 4 years after the last patient is randomized. ]
  Proportion of patients who have a 56-day or longer period with no RBC transfusions
• Duration of RBC transfusion independence [ Time Frame: The date on which measurement criteria are first met for RBC transfusion independence to the first date of RBC transfusion prior to initiation of any new MDS therapy, assessed up to 4 years after the last patient is randomized. ]
  To evaluate duration of RBC transfusion independence of magrolimab + azacitidine compared to that of azacitidine + placebo
• Progression Free Survival (PFS) [ Time Frame: From Randomization to the date of documented disease progression, relapse, or death from any cause. This can be assessed up to 4 years after the last patient is randomized. ]
  To evaluate the efficacy of magrolimab + azacitidine, compared to that of azacitidine + placebo, as measured by PFS
• Event Free Survival (EFS) [ Time Frame: From Randomization tot he date of documented treatment failure, disease progression, relapse, or death from any cause. This can be assessed up to 4 years after the last patient is randomized. ]
  To evaluate the efficacy of magrolimab + azacitidine compared to that of azacitidine + placebo as measured by EFS
• Relapse-free Survival (RFS) [ Time Frame: From the date on which measurement criteria are first met for CR to date of documented relapse or death for patients who achieve CR. This can be assessed up to 4 years after the last patient is randomized. ]
  To evaluate RFS of magrolimab + azacitidine compared to that of azacitidine + placebo
• Minimal residual disease (MRD)-negative response rate [ Time Frame: Prior to initiation of any new MDS therapy ]
  the proportion of patients who achieve a morphologic CR or marrow CR based on Investigator-assessed International Working Group (IWG) criteria and reach MRD-negative disease status
• Time to transformation to acute myeloid leukemia (AML) [ Time Frame: From Randomization to date of documented AML diagnosis. This can be measured up to 4 years after the last patient is randomized ]
  To assess time to transformation to AML of magrolimab + azacitidine compared to that of azacitidine + placebo
• Measurement of AEs [ Time Frame: Adverse events will be collected beginning at screening and then at all subsequent time points. This can be assessed up to 4 years after the last patient is randomized. ]
  This will be measured in accordance to National Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.00

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Magrolimab + Azacitidine Versus Azacitidine + Placebo in Untreated Participants With Myelodysplastic Syndrome (MDS)
• 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Myelodysplastic Syndromes

Intervention

• Drug: Magrolimab
  Administered intravenously
  Other Names:

  • Hu5F9-G4
  • GS-4721
• Drug: Azacitidine
  Administered either subcutaneously (SC) or intravenously (IV) according to region-specific drug labeling
• Drug: Placebo
  Placebo to match magrolimab administered intravenously

Study Arms

• Experimental: Magrolimab + 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.

  Interventions:

  • Drug: Magrolimab
  • Drug: Azacitidine
• 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.

  Interventions:

  • Drug: Azacitidine
  • Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: August 17, 2023): 539
• Original Estimated Enrollment (submitted: March 17, 2020): 180
• Actual Study Completion Date: September 13, 2023
• Actual Primary Completion Date: September 13, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Canada, Czechia, Finland, France, Germany, Hong Kong, Hungary, Italy, Netherlands, New Zealand, Norway, Poland, Portugal, Spain, Switzerland, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT04313881
• Other Study ID Numbers: 5F9009; 2020-004287-26 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Gilead Sciences
• Original Responsible Party: Same as current
• Current Study Sponsor: Gilead Sciences
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

• PRS Account: Gilead Sciences
• Verification Date: March 2024