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

• ClinicalTrials.gov Identifier: NCT04313881
• Recruitment Status: Active, not recruiting
• First Posted: March 18, 2020
• Last Update Posted: December 9, 2022
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Tracking Information

• First Submitted Date: March 11, 2020
• First Posted Date: March 18, 2020
• Last Update Posted Date: December 9, 2022
• Actual Study Start Date: September 9, 2020
• Estimated Primary Completion Date: December 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 28, 2022)

• Proportion of Participants with Complete Remission (CR) [ Time Frame: Up to 24 months ]
  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).
• Overall Survival (OS) [ Time Frame: Up to 5 years ]
  OS is defined as the length measured from randomization to the date of death from any cause.

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: September 28, 2022)

• Duration of CR [ Time Frame: Up to 5 years ]
  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.
• Objective Response Rate (ORR) [ Time Frame: Up to 5 years ]
  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.
• Duration of Response (DOR) [ Time Frame: Up to 5 years ]
  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.
• Red Blood Cell (RBC) Transfusion Independence Rate [ Time Frame: Up to 5 years ]
  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.
• Progression Free Survival (PFS) [ Time Frame: Up to 5 years ]
  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.
• Event Free Survival (EFS) [ Time Frame: Up to 5 years ]
  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.
• Minimal Residual Disease (MRD)-negative Response Rate [ Time Frame: Up to 5 years ]
  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.
• Time to Transformation to AML [ Time Frame: Up to 5 years ]
  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.
• Percentage of Participants Experiencing Treatment-Emergent Adverse Events [ Time Frame: Up to 5 years ]
• Serum Concentration of Magrolimab [ Time Frame: 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 ]
  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.
• Anti-magrolimab Antibody Positivity Occurrence Rate [ 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 ]
• Functional Assessment of Cancer Therapy-Anemia (FACT-Anemia) Response Rate [ Time Frame: Up to 5 years ]
  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.

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

• Biological: Magrolimab
  Administered intravenously
  Other Names:

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

  • Biological: 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 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

  Interventions:

  • Drug: Azacitidine
  • Biological: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: February 8, 2021): 520
• Original Estimated Enrollment (submitted: March 17, 2020): 180
• Estimated Study Completion Date: December 2026
• Estimated Primary Completion Date: December 2026 (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: November 2022