A Single-arm, Open-label Study of Olverembatinib, CD3/CD19 Bispecific T-cell Engager, and Chidamide in Patients With Newly Diagnosed Ph+ALL

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Prednisone, Olverembatinib, Blinatumomab, Chidamide
  Phase One. Induction Consolidation, for 1 year. 1.1 Pretreatment ×1 cycle. Prednisone，1mg/kg/d, from day 1 to 14; 1.2 Induction Therapy × 1 cycle. A: OlverembAtinib (at a dose of 40 mg Qod), from day 8 to 42. B: Blinatumomab (at a dose of 28 μg per day), from day 15 to 28. C: Chidamide (at a dose of 10 mg Qod), from day 9 to 41. 1.3 Consolidation Block × 5 cycles. A: Olverembatinib (at a dose of 40 mg Qod) was administered from day 1 to 42. B: Blinatumomab (at a dose of 28 μg perday) was admin

Первичные конечные точки

• Complete Molecular Response (CMR) [Срок оценки: at 3 months]

Вторичные конечные точки (9)

• Overall survival (OS) [Срок оценки: at 3 and 5 years]
• Event-free survival (EFS) [Срок оценки: at 3 and 5 years]
• Adverse Events [Срок оценки: at 1, 3 and 5 years]
• Event-free survival (EFS) of IKZF1del subgroup [Срок оценки: at 3 and 5 years]
• Overall survival (OS) of IKZF1del subgroup [Срок оценки: at 3 and 5 years]
• Event-free survival (EFS) of IKZF1plus subgroup [Срок оценки: at 3 and 5 years]
• Overall survival (OS) of IKZF1plus subgroup [Срок оценки: at 3 and 5 years]
• Event-free survival (EFS) of IKZF1plus/CD20 subgroup [Срок оценки: at 3 and 5 years]
• Overall survival (OS) of IKZF1plus/CD20 subgroup [Срок оценки: at 3 and 5 years]

Критерии участия

Критерии включения

• 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.

Критерии исключения

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Dept of Hematology, Nanfang Hospital, Southern Medical University — Гуанчжоу

Публикации

• Foa R, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo MC, Canichella M, Viero P, Ferrara F, Lunghi M, Fabbiano F, Bonifacio M, Fracchiolla N, Di Bartolomeo P, Mancino A, De Propris MS, Vignetti M, Guarini A, Rambaldi A, Chiaretti S; GIMEMA Investigators. Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. N Engl J Med. 2020 Oct 22;383(17):1613-1623. doi: 10.1056/NEJMoa PMID 33085860
• Jabbour E, Short NJ, Jain N, Huang X, Montalban-Bravo G, Banerjee P, Rezvani K, Jiang X, Kim KH, Kanagal-Shamanna R, Khoury JD, Patel K, Kadia TM, Daver N, Chien K, Alvarado Y, Garcia-Manero G, Issa GC, Haddad FG, Kwari M, Thankachan J, Delumpa R, Macaron W, Garris R, Konopleva M, Ravandi F, Kantarjian H. Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia PMID 36402146

Идентификаторы

NCT: NCT06220487 · NFEC-2023-441

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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