A Study of Oral Decitabine/Cedazuridine in Combination With Magrolimab in Participants With Intermediate- to Very High-Risk Myelodysplastic Syndromes (MDS)

Study Overview
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Brief Summary
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The primary purpose of the study is to evaluate the preliminary safety and efficacy of oral decitabine/cedazuridine in combination with magrolimab.

Official Title
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A Phase 2 Study of Oral Decitabine/Cedazuridine in Combination With Magrolimab for Previously Untreated Subjects With Intermediate- to Very High-Risk Myelodysplastic Syndromes (MDS)

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Decitabine/Cedazuridine
* Drug: Magrolimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological confirmation of previously untreated MDS (i.e., no hypomethylating agent [HMA], chemotherapy, or allogenic stem cell transplant [SCT] per World Health Organization 2016 classification with <20% bone marrow (BM) blasts per marrow biopsy/aspirate at screening. Projected life expectancy of at least 3 months. Overall Revised International Prognostic Scoring System for myelodysplastic syndromes (IPSS-R) score ≥3.5 MDS (immediate risk or higher). Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2. Hematopoietic stem cell transplant (HSCT) eligible without any pre-arranged HSCT on Cycle 1 Day 1, or HSCT ineligible. Blood type and screen (any of the 4 blood groups A, B, AB, and O [ABO]/rhesus factor [Rh]) along with extended red blood cell phenotyping or genotyping completed prior to study drug treatment. Exclusion Criteria: - Medical Conditions: Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive), or hepatitis C (e.g., hepatitis C virus ribonucleic acid [HCV RNA] is detected), or chronic hepatitis B or C infection or human immunodeficiency virus (HIV) infection in medical history, with the following exceptions: Those with a history of hepatitis with a negative polymerase chain reaction (either qualitative or quantitative) OR have documentation of stable disease with aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase <2.0×upper limit of normal (ULN) may be eligible for this study. Participants with history of HIV who have an undetectable viral load for the prior 3 months, and who agree to maintain antiviral therapy, may be eligible for the study. 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. Known inherited or acquired bleeding disorders that require medication or medical intervention. 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. -Prior/Concomitant Therapy: Immediate eligibility for an allogeneic SCT, as determined by the investigator, with an available donor. Prior therapy for MDS with chemotherapy, allogenic SCT, or ≥1 full cycle of treatment with any HMA. History of therapy-related MDS, MDS evolving from a pre-existing myeloproliferative neoplasm (MPN), MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia, and unclassifiable MDS/MPN. Prior anti-cluster of differentiation 47 (CD47) treatment. Previous SCT within 6 months before first dose administration, active graft-versus-host disease, or requiring transplant-related immunosuppression. -Other Exclusions: Known or suspected hypersensitivity to decitabine, cedazuridine, magrolimab, or any of their excipients. Known significant mental illness or other condition such as active alcohol or other substance abuse or addiction that, in the opinion of the investigator, predisposes the participant to high-risk of noncompliance with the protocol. Clinical suspicion of active central nervous system (CNS) involvement by MDS. History of psychiatric illness or substance abuse likely to interfere with the ability to comply with protocol requirements or give informed consent. Pregnant or actively breastfeeding.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral Decitabine/Cedazuridine + Magrolimab<br>Participants will receive 35 milligrams (mg) decitabine/100 mg cedazuridine as a fixed dose combination (FDC) tablet, orally, once daily (QD) on Days 1-5 of each 28-day cycle in combination with magrolimab, intravenous (IV) infusion of 1 milligrams per kilogram (mg/kg) on Days 1 and 4, 15 mg/kg on Day 8, 30 mg/kg on Days 11, 15, 22, 29, 36, 43, and 50, followed by a maintenance dose of 30 mg/kg on Day 57 and every 14 days thereafter until toxicity, progressive disease, withdrawal, death or end of study (approximately 44 months). | Drug: Decitabine/Cedazuridine<br>* Oral FDC tablets administration<br>* Other names: INQOVI;Drug: Magrolimab<br>* IV administration<br>* Other names: Hu5F9-G4;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 |  | Up to approximately 44 months | 
| Number of Participants With Dose-Limiting Toxicities (DLTs) | DLTs are defined as any of the following toxicities at least possible related to the treatment regimen: drug-related Grade ≥3 non-hematologic event; grade 4 neutropenia and thrombocytopenia that was not present prior to dosing, that last 28 days or longer and is not related to underlying disease; or any toxicity that result in treatment delay of >2 weeks after Cycle 1 (28 days) is complete due to drug-related toxicity. | Cycles 1 and 2 (Cycle=28 days) | 
| Complete Response (CR) Rate |  | Up to approximately 44 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve (AUC) of Oral Decitabine/Cedazuridine and Magrolimab |  | Decitabine/Cedazuridine: Multiple timepoints pre-dose and post dose up to Day 5 of Cycle 1 and Day 4 of Cycle 2 (Cycle=28 days); Magrolimab: Multiple timepoints pre-dose and post dose up to end of treatment (approximately 44 months) | 
| Overall Response Rate (ORR) | ORR is defined as percentage of participants with CR, partial response (PR), marrow complete response (mCR), and hematologic improvement (HI). | Up to approximately 44 months | 
| Rate of Hematologic Improvement (HI) | HI will include HI with Erythroid (HI-E), HI with Neutrophil (HI-N), or HI with Platelet (HI-P) based on the 2006 International Working Group Criteria (IWG 2006). HI-E: Hemoglobin (Hgb) increase ≥1.5g/dL, Relevant reduction of red blood cell (RBC) units transfusions by absolute ≥4 RBC transfusions/8 week compared with pretreatment transfusion number previous 8 week. Only RBC transfusions given for Hgb ≤9.0 g/dL. HI-P: Absolute increase ≥30x10^9/L starting >20x10^9/L platelets (PLTs); Increase from <20x10^9/L to >20x10^9/L and by≥100%. HI-N: ≥100% increase, absolute increase>0.5x10^9/L. | Up to approximately 44 months | 
| Duration of Progression Free Survival (PFS) |  | Up to approximately 44 months | 
| Leukemia-free Survival (LFS) | LFS is defined as the number of days from date of randomization to date when bone marrow or peripheral blood blasts reach ≥20%, or death. | Up to approximately 44 months | 
| Percentage of Participants With Minimal Residual Disease (MRD)-Negative Status |  | Day 1 of each 28-day Cycle starting from Cycle 3 up to end of study (approximately 44 months) | 
| Duration of Response (DOR) |  | Up to approximately 44 months | 
| Overall Survival (OS) |  | Up to approximately 44 months | 
| Number of Participants With International Prognostic Scoring System for Myelodysplastic Syndromes (IPSS-M) Score | The IPSS-M is an algorithm that uses clinical features of participants with MDS and assigns a prognostic score (0=good and increasing in risk by half-grades with the top score outlined below) for three prognostic variables: Marrow blasts (score 0-2.0); Karyotype (score 0-1.0); Cytopenias: neutrophil, platelets, and Hg counts (score 0-0.5). The three individual scores are summed resulting in a full range of 0- 3.5 and placed into risk categories: 0 = low risk; 0.5-1.0 = intermediate-1 risk; 1.5-2.0 = intermediate-2 risk; and >=2.5 = high risk. Higher scores indicate worst outcome. | At screening | 
| Number of Participants With p53 Mutation |  | At screening |