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)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 2
- 试验地点
- 3
- 主要终点
- Number of Participants With Adverse Events (AEs) Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0
研究概览
简要总结
The primary purpose of the study is to evaluate the preliminary safety and efficacy of oral decitabine/cedazuridine in combination with magrolimab.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 ≤
- •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.
- •Hemoglobin ≥9 grams per deciliter (g/dL) on the first day of drug administration, transfusions allowed.
- •Willing to undergo blood transfusions as per parameters of protocol and clinically necessary.
- •White blood cell count ≤20×103/microliters (μL) prior to first dose and throughout study. Hydroxyurea could have been used to achieve this goal prior to and during the first 56 days of magrolimab administration.
排除标准
- •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.
研究组 & 干预措施
Oral Decitabine/Cedazuridine + Magrolimab
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).
干预措施: Decitabine/Cedazuridine (Drug)
Oral Decitabine/Cedazuridine + Magrolimab
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).
干预措施: Magrolimab (Drug)
结局指标
主要结局
Number of Participants With Adverse Events (AEs) Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0
时间窗: From signing of informed consent to 30 days after last dose of study drug (Up to 8 weeks)
An AE is any untoward medical occurrence in a subject or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention.
Number of Participants With Dose-Limiting Toxicities (DLTs)
时间窗: From signing of informed consent to 30 days after last dose of study drug (Up to 8 weeks)
DLTs are defined as any of the following toxicities at least possibly 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 drug-related toxicity that result in treatment delay of \>2 weeks after Cycle 1 (28 days) is complete.
Complete Response (CR) Rate
时间窗: Up to 44 months
CR defined as per International Working Group (IWG) criteria 2006: Bone marrow (BM) ≤5% myeloblasts with normal maturation of all cell lines; Persistent dysplasia; Peripheral blood; Hemoglobin (Hgb) ≥11 g/dL; Platelets ≥100×109/L; Neutrophils ≥1.0×109/Lb; Blasts 0%. Per the response criteria the response must last ≥4 weeks.
次要结局
- 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 (up to 44 months))
- Overall Response Rate (ORR)(Up to 44 months)
- Rate of Hematologic Improvement (HI)(Up to 44 months)
- Duration of Progression Free Survival (PFS)(Up to 44 months)
- Leukemia-free Survival (LFS)(Up to 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 (up to 44 months))
- Duration of Response (DOR)(Up to 44 months)
- Overall Survival (OS)(Up to 44 months)
- Number of Participants With International Prognostic Scoring System for Myelodysplastic Syndromes (IPSS-M) Score(Up to Day 42)
- Number of Participants With p53 Mutation(Up to Day 42)