Intermediate/high/very high risk myelodysplastic syndrome (MDS) MedDRA version: 21.1 Level: PT Classification code 10028533 Term: Myelodysplastic syndrome System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Gilead Sciences, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Participants with MDS defined according to WHO classification, with an IPSS-R prognostic risk category of intermediate, high, or very high risk. Note: participants who require AML-like therapy are not eligible. 2. White blood cell (WBC) count = 20 × 10^3/µL prior to randomization. If the participant's WBC is > 20 × 10^3/µL prior to randomization, the participant can be randomized, assuming all other eligibility criteria are met. Of note, while this does not impact eligibility, please ensure that the WBC is = 20 × 103/µL prior to the first dose of study treatment and prior to each magrolimab/placebo dose for priming doses of magrolimab. Patients can be treated with hydroxyurea (up to 4 g/day) throughout the study or prior to randomization to reduce the WBC to = 20 × 10^3/µL to enable eligibility and magrolimab dosing. Oral etoposide (up to 200 mg orally per day) may be given as an alternative to hydroxyurea for patients who are intolerant to hydroxyurea or cannot achieve sufficient WBC lowering on hydroxyurea. 3. Participant has provided informed consent. 4. Participant is willing and able to comply with clinic visits and procedures outlined in the study protocol. 5. Male or female, age = 18 years. 6. Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2. 7. Willing to undergo blood transfusions as deemed clinically necessary. 8. Pretreatment blood cross-match including ABO (any of the 4 blood groups A, B, AB, and O comprising the ABO system)/Rh (Rhesus factor), DAT (direct antiglobulin test), and phenotyping or genotyping completed. 9. Biochemical indices within the ranges shown below: a. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase = 3× upper limit of normal (ULN) b. Total bilirubin = 1.5 × ULN or 3.0 × ULN and primarily unconjugated if participant has a documented history of Gilbert's syndrome or genetic equivalent c. Serum creatinine = 1.5 × ULN or calculated glomerular filtration rate (GFR) = 40 mL/min/1.73 m2 10. All participants must have a documented hemoglobin =9.0 g/dL within 24 hours prior to the first two doses of magrolimab/placebo infusion. Participants who do not meet these criteria must be transfused and have their hemoglobin rechecked to meet the minimum hemoglobin threshold prior to administering each of the first 2 doses of magrolimab/placebo. Transfusions are allowed in order to meet hemoglobin eligibility 11. Female participants of childbearing potential must not be nursing or planning to be pregnant and must have a negative urine or serum pregnancy test within 30 days before randomization and within 72 hours before the first administration of study treatment. 12. Male participants and female participants of childbearing potential who engage in heterosexual intercourse must agree to use protocolspecified method(s) of contraception as described in Appendix H of protocol. 13. Willing to consent to mandatory pretreatment and on-treatment bone marrow biopsies (trephines), unless not feasible as determined by the Investigator and discussed with the Sponsor. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 180 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 340
Exclusion criteria
Exclusion criteria: 1. Prior treatment with CD47 or SIRPa-targeting agents. 2. Prior therapy for the treatment of MDS with an IPSS-R prognostic risk category of intermediate, high or very high risk (excluding hydroxyurea or oral etoposide), prior treatment with hypomethylating agents and/or low dose cytarabine. NOTE: Localized noncentral nervous system (CNS) radiotherapy, erythroid and/or myeloid growth factors, previous hormonal therapy with luteinizing hormone-releasing hormone (LHRH) agonists for prostate cancer, and treatment with bisphosphonates and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors are not criteria for exclusion. Prior lenalidomide is also not exclusionary. 3. Immediately eligible for an allogeneic SCT, as determined by the investigator, with an available donor. 4. Contraindications to azacitidine, including advanced malignant hepatic tumors or known hypersensitivity to azacitidine or mannitol. 5. Known inherited or acquired bleeding disorders. 6. Previous SCT within 6 months prior to randomization, active graftversus- host disease, or requiring transplant-related immunosuppression. 7. Clinical suspicion of active CNS involvement by MDS. 8. Significant medical diseases or conditions, as assessed by the Investigators and Sponsor, that would substantially increase the risk benefit ratio of participating in the study. This includes, but is not limited to, acute myocardial infarction within the last 6 months, unstable angina, uncontrolled diabetes mellitus, significant active infections, and congestive heart failure New York Heart Association Class III-IV. 9. 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. 10. History of psychiatric illness or substance abuse likely to interfere with the ability to comply with protocol requirements or give informed consent. 11. Pregnancy or active breastfeeding. 12. Known active or chronic hepatitis B or C infection or HIV infection in medical history. 13) Active hepatitis B virus (HBV) and/or active hepatitis C virus (HCV), and/or HIV following testing at screening: a) Participants who test positive for hepatitis B surface antigen (HBsAg). Participants who test positive for hepatitis B core antibody (anti-HBc) will require HBV DNA by quantitative polymerase chain reaction (PCR) for confirmation of active disease. b) Participants who test positive for HCV antibody. These participants will require HCV RNA by quantitative PCR for confirmation of active disease. c) Participants who test positive for HIV antibody. d) Participants not currently on antiviral therapy and who have an undetectable viral load in the prior 3 months may be eligible for the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy and survival benefit of magrolimab + azacitidine compared to azacitidine + placebo in previously untreated patients with intermediate/high/very high risk MDS by IPSS-R prognostic risk categories.;Secondary Objective: To evaluate the efficacy, safety, PK, immunogenicity and health-related quality of life, of magrolimab + azacitidine compared to azacitidine + placebo in previously untreated patients with intermediate/high/very high risk MDS by IPSS-R prognostic risk categories.;Primary end point(s): - Complete Remission (CR) rate as assessed by investigators - Overall Survival (OS);Timepoint(s) of evaluation of this end point: Response assessments will be done in conjunction with bone marrow assessments, according to the Schedule of Assessments (refer to protocol). Accompanying laboratory results ± 2 weeks from the protocol-specified bone marrow efficacy assessment can be used to support an efficacy assessment of CR. Response assessments are scheduled on Day 1 of Cycles 3, 5, and 7 and then every 3 cycles thereafter during study treatment. The length of OS is measured from randomization to the date of death from any cause. Those who are not observed to die during the study will be censored at their last known alive date. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Duration of complete remission (CR) - Objective Response rate (ORR) and Duration of Response (DOR) - Red Blood Cell (RBC) transfusion independence rate - Progression-free survival (PFS) - Event-free survival (EFS) - Minimum Residual Disease (MRD) - negative response rate - Time to transformation to Acute Myeloid Leukaemia (AML) - Measurement of Adverse Events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 - Magrolimab concentration versus time - Antidrug antibody (ADA) to magrolimab - Functional Assessment of Cancer Therapy (FACT) -Anemia response rate - CR rate in TP-53 mutant population -Transplantation Rate -Time to first transplant -RBC transfusion independence irrespective of RBC transfusiondependence at baseline;Timepoint(s) of evaluation of this end point: Response assessments of efficacy endpoints are scheduled on Day 1 of Cycles 3, 5, and 7 and then every 3 cycles thereafter during study treatment. All AEs that occur after the first dose of study treatment through 30 days after the last dose of study treatment are assessed. Pharmacokinetic measurements are collected at Day 1 and 8 of Cycle 1 and Day 1 of Cycles 2, 3, 5, 7, 10, and 13 and EOT. Measurements of Antidrug antibody (ADA) to magrolimab, are collected on Day 1 of Cycles 1, 2, 3, 5, 7, 10, and 13 and EOT. Patients-reported outcome assessments are scheduled for Day 1 of Cycles 1-3. | — |
Countries
Australia, Austria, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Hong Kong, Hungary, Ireland, Italy, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Spain, Switzerland, Turkey, United Kingdom, United States
Contacts
Public ContactClinical Trials Mailbox
Gilead Sciences International Ltd.
Outcome results
None listed