A Biomarker-Directed Phase 2 Trial of SY-1425, a Selective Retinoic Acid Receptor Alpha Agonist, in Adult Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 155
- 试验地点
- 12
- 主要终点
- Overall Response Rate (ORR) in Biomarker Positive AML or HR-MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine
研究概览
简要总结
The purpose of this study is to determine the activity of tamibarotene in participants with relapsed/refractory (R/R) AML (administered as a monotherapy or in combination with azacitidine), R/R higher-risk MDS (HR-MDS) (administered as a monotherapy or in combination with daratumumab), newly diagnosed treatment naïve AML participants who are unlikely to tolerate standard intensive chemotherapy (administered as a monotherapy or in combination with azacitidine), or lower-risk MDS (LR-MDS) (administered as a monotherapy).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Relapsed and/or refractory non-APL AML that has failed to achieve a complete remission (CR) or partial remission (PR) following standard induction therapy, or has relapsed after any duration of CR or PR i. Must have measurable disease with bone marrow blasts ≥5%at screening
- •Relapsed and/or refractory HR-MDS (High / Very High Risk, as defined by the Revised International Prognostic Scoring System (IPSS-R)) that has failed to achieve a CR or PR, or any hematologic improvement (HI, per IWG 2006 criteria) after standard therapy with hypomethylating agents (e.g., azacitidine, decitabine), or has relapsed after any duration of CR or PR or HI i. Must have measurable disease with bone marrow blasts >5% at screening
- •Newly diagnosed, treatment-naïve non-APL AML in participants who, at the time of study entry are unlikely to tolerate standard intensive chemotherapy due to age, performance status, or comorbidities based on at least one of the following criteria:
- •i. Age ≥ 75 years old
- •ii. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 3
- •iii. Cardiac history of congestive heart failure (CHF) or documented ejection fraction (EF) ≤ 50%
- •iv. Pulmonary disease with diffusing capacity of lung for carbon monoxide ≤ 65% or Forced Expiratory Volume in 1 Second ≤ 65%
- •v. Creatinine clearance ≥ 30 milliliter (mL)/minute (min) to < 45 mL/min
- •vi. Hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 x upper limit of normal (ULN)
- •vii. Any other comorbidity that the Investigator judges to be incompatible with intensive chemotherapy, and reviewed and approved by the Sponsor prior to enrollment
- •Transfusion-dependent LR-MDS without the del 5q abnormality, in participants refractory to erythropoietin treatment or unlikely to respond to erythropoietin treatment (EPO >500).
- •i. LR-MDS: Very Low /Low / Intermediate Risk, as defined by IPSS-R.
- •ii.Red blood cell (RBC) transfusion-dependent anemia defined as no eight consecutive weeks without RBC transfusions within the 16 weeks prior to study entry, or ≥4 RBC transfusions within the 8 weeks prior to study entry.
- •iii.Refractory to or ineligible for erythropoiesis-stimulating agents (ESAs) is defined as RBC-Transfusion Dependence despite ESA treatment of ≥40,000 units/week recombinant human erythropoietin for 8 weeks or an equivalent dose of darbepoetin (150 µg/week) or serum EPO level >500 milliunits (mU)/mL in participants not previously treated with ESAs.
- •Participants must be evaluated for the RARA super-enhancer associated biomarker or RARA pathway associated biomarker at the time of study screening.
- •a. Participants treated with tamibarotene monotherapy and in combination with daratumumab, and R/R AML participants treated with tamibarotene in combination with azacitidine must be positive as defined by a pre-determined cut-off
- •Must be amenable to serial bone marrow aspirates and peripheral blood sampling during the study.
- •ECOG Performance Status (PS) of 0, 1 or
- •For newly diagnosed AML participants < 75 years of age, ECOG 0-3; for ≥ 75 years of age, ECOG 0-
- •Adequate organ function as defined by:
- •Total bilirubin ≤ 1.5 x the upper limit of normal (ULN), unless suspected to have Gilbert's disease. For newly diagnosed AML participants < 75 years of age, total bilirubin ≤ 3 x ULN; for ≥ 75 years of age, total bilirubin ≤ 1.5 x ULN.
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN or ≤ 5 x ULN if documented liver infiltration with leukemia cells
- •Serum creatinine ≤ 2.0 x ULN or calculated creatinine clearance ≥ 45 mL/min based on the Cockroft-Gault glomerular filtration rate estimation. For newly diagnosed AML participants < 75 years of age, creatinine clearance ≥ 30 mL/min; for ≥ 75 years of age, creatinine clearance ≥ 45 mL/min.
- •Discontinued use of chemotherapy, radiation therapy, or growth factors for at least 2 weeks prior to first study treatment, with the exception of hydroxyurea.
- •No investigational agents within 2 weeks prior to first study treatment.
- •No strong inducers of CYP3A4 within 2 weeks prior to first study treatment.
- •Resolved acute effects of any prior AML/MDS therapy to baseline or ≤ Grade 1 CTCAE severity.
排除标准
- •Acute promyelocytic leukemia (APL, M3 subtype of AML) or participants with a t(9:22) cytogenetic translocation.
- •Hyperleukocytosis (leukocytes ≥25 x 109/L) at study entry. The participants may be treated with hydroxyurea according to routine practice, and enroll in the study when the leukocyte count falls below 25 x 109/L.
- •Participants known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a participant who refuses blood product support.
- •Prior treatment with all-trans retinoic acid (ATRA) or systemic retinoid for the treatment of hematologic malignancy.
- •Tamibarotene and daratumumab combination only - Prior or concurrent exposure to daratumumab or other CD38 therapies.
- •Tamibarotene and daratumumab combination only - Participant has either of the following:
- •Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is <50% of predicted normal.
- •Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.
- •Participants with active malignancy (not including basal cell carcinoma, non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer treated with hormone therapy). Participants with history of other cancers should be free of disease for at least 2 years.
- •Participants with hypertriglyceridemia defined as >1000 mg/dL (CTCAE Grade 4).
- •Participants with clinically significant cardiac disease including one of the following currently or in the previous 6 months: myocardial infarction, unstable cardiac function due to unstable angina or congestive heart failure, congenital long QT syndrome, torsades de pointes or significant ventricular arrhythmias.
- •Participants with known active uncontrolled central nervous system (CNS) leukemia.
- •Participants taking Vitamin A supplements (>10,000 IU/d) unless discontinued prior to first dose of study drug, or having hypervitaminosis.
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
R/R Non-APL AML or R/R HR-MDS: Tamibarotene Monotherapy
Participants with R/R non-APL AML or R/R HR-MDS will receive tamibarotene at 6 mg/m^2/day in 2 divided doses on Days 1-28 of a 28-day cycle.
干预措施: Tamibarotene (Drug)
Newly Diagnosed Non-APL AML: Tamibarotene Monotherapy
Newly diagnosed, treatment-naive participants with non-APL AML who were unlikely to tolerate standard intensive chemotherapy will receive tamibarotene at 6 mg/m^2/day in 2 divided doses on Days 1-28 of a 28-day cycle.
干预措施: Tamibarotene (Drug)
Newly Diagnosed Non-APL AML: Tamibarotene and Azacitidine
Newly diagnosed, treatment-naive participants with non-APL AML who are unlikely to tolerate standard intensive chemotherapy will receive tamibarotene at 6 mg/m^2/day in 2 divided doses on Days 8-28 of a 28-day cycle, and azacitidine at 75 mg/m^2 once daily on Days 1-7 of a 28-day cycle.
干预措施: Tamibarotene (Drug)
Newly Diagnosed Non-APL AML: Tamibarotene and Azacitidine
Newly diagnosed, treatment-naive participants with non-APL AML who are unlikely to tolerate standard intensive chemotherapy will receive tamibarotene at 6 mg/m^2/day in 2 divided doses on Days 8-28 of a 28-day cycle, and azacitidine at 75 mg/m^2 once daily on Days 1-7 of a 28-day cycle.
干预措施: Azacitidine (Drug)
LR-MDS: Tamibarotene Monotherapy
Participants with transfusion-dependent LR-MDS without the del 5q abnormality who are refractory to erythropoietin (EPO) treatment or unlikely to respond to EPO treatment will receive tamibarotene at 6 mg/m^2/day in 2 divided doses on Days 1-28 of a 28-day cycle.
干预措施: Tamibarotene (Drug)
R/R non-APL AML or R/R HR-MDS: Tamibarotene and Daratumumab
Participants with R/R non-APL AML or R/R HR-MDS will receive tamibarotene at 6 mg/m^2/day in 2 divided doses during a 7-day lead-in and on Days 1-28 of a 28-day cycle. Participants will also receive daratumumab at 16 mg/kg starting on Cycle 1 Day 1 once weekly for 8 weeks, followed by dosing every 2 weeks for 16 weeks, followed by dosing every 4 weeks.
干预措施: Tamibarotene (Drug)
R/R non-APL AML or R/R HR-MDS: Tamibarotene and Daratumumab
Participants with R/R non-APL AML or R/R HR-MDS will receive tamibarotene at 6 mg/m^2/day in 2 divided doses during a 7-day lead-in and on Days 1-28 of a 28-day cycle. Participants will also receive daratumumab at 16 mg/kg starting on Cycle 1 Day 1 once weekly for 8 weeks, followed by dosing every 2 weeks for 16 weeks, followed by dosing every 4 weeks.
干预措施: Daratumumab (Drug)
R/R non-APL AML: Tamibarotene and Azacitidine
Participants with R/R non-APL AML will receive tamibarotene at 6 mg/m^2/day in 2 divided doses on Days 8-28 of a 28-day cycle, and azacitidine at 75 mg/m^2 once daily on Days 1-7 of a 28-day cycle.
干预措施: Tamibarotene (Drug)
R/R non-APL AML: Tamibarotene and Azacitidine
Participants with R/R non-APL AML will receive tamibarotene at 6 mg/m^2/day in 2 divided doses on Days 8-28 of a 28-day cycle, and azacitidine at 75 mg/m^2 once daily on Days 1-7 of a 28-day cycle.
干预措施: Azacitidine (Drug)
结局指标
主要结局
Overall Response Rate (ORR) in Biomarker Positive AML or HR-MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine
时间窗: Up to 48 months
ORR was defined as: AML: number of participants with complete remission (CR), CR with incomplete blood count recovery (CRi), CR with partial hematologic recovery (CRh), partial remission(PR), or morphologic leukemia-free state (MLFS) determined by the investigator per revised International Working Group (IWG) AML criteria. HR-MDS: the number of participants with CR, PR, marrow CR (mCR), or HI determined by the investigator per revised IWG MDS criteria.
Transfusion Independence Rate (TIR) for LR-MDS Participants Treated With Tamibarotene Monotherapy
时间窗: Up to 48 months
TIR was defined as the number of participants who achieved transfusion independence defined as 8 consecutive weeks of red blood cell (RBC) transfusion independence.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Treated With Tamibarotene in Combination With Daratumumab
时间窗: Up to 48 months
A TEAE was any untoward medical occurrence associated with use of a study drug/study participation, whether or not considered related to study drug after first dose. A TEAE was any unfavorable/unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with the study drug. A serious TEAE resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect in the offspring of a participant who received study drug or other important medical events. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
次要结局
- ORR in AML Participants Positive for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine(Up to 48 months)
- ORR in AML Participants Positive for the Interferon Regulatory Factor 8 (IRF8) Biomarker and Negative for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine(Up to 48 months)
- ORR in AML Participants Negative for the RARA Super-enhancer Associated Biomarker Treated With Tamibarotene in Combination With Azacitidine(Up to 48 months)
- ORR for AML or HR-MDS Participants Treated With Tamibarotene in Combination With Daratumumab(Up to 48 months)
- Event-Free Survival (EFS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab(Up to 48 months)
- Duration of Response (DOR) in AML Participants Treated With Tamibarotene in Combination With Azacitidine(Up to 48 months)
- Overall Survival (OS) in AML and HR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab(Up to 48 months)
- Hematologic Improvement (HI) in AML, HR-MDS and LR-MDS Participants Treated With Tamibarotene Monotherapy, or in Combination With Azacitidine or Daratumumab(Up to 48 months)
- Number of Participants With TEAEs in AML and MDS Participants Treated With Tamibarotene Monotherapy or in Combination With Azacitidine(Up to 48 months)