A Single-arm, Open-label Study of Olverembatinib, CD3/CD19 Bispecific T-cell Engager, and Chidamide in Patients With Newly Diagnosed Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 67
- 试验地点
- 1
- 主要终点
- Complete Molecular Response (CMR)
研究概览
简要总结
ABC study is a phase 2, single-arm, open-label study of Olverembatinib, CD3/CD19 Bispecific T-cell Engager, and Chidamide in patients with newly diagnosed Philadelphia Chromosome-positive acute lymphoblastic leukemia (Ph+ALL). This study combined third generation TKI (Olverembatinib), histone deacetylase inhibitors (Chidamide) and CD3/CD19 bispecific T-cell engager (Blinatumomab) as first line regimen (ABC regimen) for Ph+ ALL. Investigatorsaim to explore the efficacy and safety of ABC regimen. The primary endpoint is the complete molecular remission （CMR） at 3 months, secondary endpoints are overall survival (OS), event-free survival (EFS), adverse event (AE), IKZF1del, IKZF1plus, IKZF1lpus/CD20 subgroup EFS/OS.
详细描述
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is now a relatively favorable-risk leukemia with the development of potent BCR::ABL1 tyrosine kinase inhibitors (TKIs). Achievement of an early and deep complete molecular remission (CMR) is an important end point in Ph+ ALL and identifies patients who may not need allogeneic hematopoietic stem cell transplantation (allo-HSCT). The chemotherapy-free D-ALBA trial of dasatinib and blinatumomab was safe and effective in patients with newly diagnosed Ph-positive ALL and resulted in an estimated 3-year OS rate of 80% (NEJM 2020, 2022). To further improve the outcomes, the potent third-generation TKIs, ponatinib and olverembatinib (ASH 2023, abs 1504), were added to chemotherapy or immunotherapy, resulted in an overall CMR rate of 84%-90%, a 5-year survival rate of 73%, most patients did not undergo allo-HSCT.
Of note, IKZF1plus subgroup still stands for high-risk for Ph+ALL and exhibit poor outcome even in TKI plus blinatumomab, which indicate IKZF1del confers resistance to immunotherapy. our previous study found that HDACi tucidinostat/chidamide could restore the expression and functionality of IKZF1 in IKZF1del samples, including increased expression of CD19 and reduced focal adhesion (Blood (2021) 138 (Supplement 1): 514.).
ABC study is a phase 2, single-arm, open-label study of Olverembatinib, CD3/CD19 Bispecific T-cell Engager, and Chidamide in patients with newly diagnosed Philadelphia Chromosome-positive acute lymphoblastic leukemia (Ph+ALL). This study combined third generation TKI (Olverembatinib), histone deacetylase inhibitors (Chidamide) and CD3/CD19 bispecific T-cell engager (Blinatumomab) as first line regimen (ABC regimen) for Ph+ ALL. Investigators aim to explore the efficacy and safety of ABC regimen. The primary endpoint is the complete molecular remission （CMR） at 3 months, secondary endpoints are overall survival (OS), event-free survival (EFS), adverse event (AE), IKZF1del, IKZF1plus, IKZF1lpus/CD20 subgroup EFS/OS.
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
- •Signed written informed consent;
- •Newly diagnosed adult B-precursor Ph+ ALL;
- •Age greater or equal to 18 years;
- •ECOG Performance Status 0-1;
- •Ineligible for allo-HSCT.
- •Renal and hepatic function as defined below:
- •AST (GOT), ALT (GPT), and AP <2 x upper limit of normal (ULN). Creatinine clearance equal or greater than 50 mL/min.
- •Pancreatic function as defined below:
- •Serum amylase less or equal to 1.5 x ULN Serum lipase less or equal to1.5 x ULN
- •Normal cardiac function;
- •Negative HIV test, negative HBV DNA and HCV RNA;
- •Negative pregnancy test in women of childbearing potential.
排除标准
- •History of receiving systemic chemotherapy or CAR-T therapy for ALL.
- •Impaired cardiac function, including any one of the following:
- •.LVEF <45% as determined by MUGA scan or echocardiogram. .Complete left bundle branch block. .Use of a cardiac pacemaker.
- •ST depression of >1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads. .Congenital long QT syndrome. .History of or presence of significant ventricular or atrial arrhythmia. .Clinically significant resting bradycardia (<50 beats per minute). .QTc >450 msec on screening ECG (using the QTcF formula). .Right bundle branch block plus left anterior hemiblock, bifascicular block. .Myocardial infarction within 3 months prior to starting olverembatinib . .Angina pectoris.
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of olverembatinib or chidamide (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). .History of or current autoimmune disease. .History of or current relevant CNS pathology. .Presence of CNS leukemia. .History of or current autoimmune disease. .History of other malignancies. .Presence active infection.
- •Nursing women or women of childbearing potential not willing to use an effective form of contraception during participation in the study and at least 3 months thereafter or male patients not willing to ensure effective contraception during participation in the study and at least three months thereafter.
- •Not eigiable for this study, decided by PI
研究组 & 干预措施
ABC protocol
Adult patients with Ph-positive ALL eligble for this study will begin treatment with ABC protocol, as (A) olverembAtinib, (B) Blinatumomab and (C) Chidamide after pre-treatment with glucocorticoid, including induction and consolidation therapy for one year, and subsequent maintenance therapy for three years.
干预措施: Prednisone, Olverembatinib, Blinatumomab, Chidamide (Drug)
结局指标
主要结局
Complete Molecular Response (CMR)
时间窗: at 3 months
CMR was defined as the absence of a detectable BCR::ABL1 transcript with a sensitivity of 0.01%.
次要结局
- Overall survival (OS) of IKZF1plus subgroup(at 3 and 5 years)
- Overall survival (OS)(at 3 and 5 years)
- Adverse Events(at 1, 3 and 5 years)
- Overall survival (OS) of IKZF1del subgroup(at 3 and 5 years)
- Event-free survival (EFS) of IKZF1plus subgroup(at 3 and 5 years)
- Event-free survival (EFS) of IKZF1plus/CD20 subgroup(at 3 and 5 years)
- Event-free survival (EFS)(at 3 and 5 years)
- Event-free survival (EFS) of IKZF1del subgroup(at 3 and 5 years)
- Overall survival (OS) of IKZF1plus/CD20 subgroup(at 3 and 5 years)