Clinical trial NCT06220487: A Single-arm, Open-label Study of Olverembatinib, CD3/CD19 Bispecific T-cell Engager, and Chidamide in Patients With Newly Diagnosed Ph+ALL
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia
Philadelphia Chromosome
Philadelphia-Positive ALL
Adult ALL
IKZF1 Gene Mutation
Keywords: Olverembatinib
CD3/CD19 Bispecific T-cell Engager
Histone Deacetylase Inhibitor
Chidamide
Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia
Acute Lymphoblastic Leukemia
Ph-positive
Lead sponsor: Nanfang Hospital, Southern Medical University
Sponsor class: OTHER
First posted: 2024-01-24
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Signed written informed consent;
2. Newly diagnosed adult B-precursor Ph+ ALL;
3. Age greater or equal to 18 years;
4. ECOG Performance Status 0-1;
5. Ineligible for allo-HSCT.
6. 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.
7. Pancreatic function as defined below:

   Serum amylase less or equal to 1.5 x ULN Serum lipase less or equal to1.5 x ULN
8. Normal cardiac function;
9. Negative HIV test, negative HBV DNA and HCV RNA;
10. Negative pregnancy test in women of childbearing potential.

Exclusion Criteria:

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

Primary outcomes:
measure: Complete Molecular Response (CMR)
timeFrame: at 3 months
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: at 3 and 5 years
measure: Event-free survival (EFS)
timeFrame: at 3 and 5 years
measure: Adverse Events
timeFrame: at 1, 3 and 5 years
measure: Event-free survival (EFS) of IKZF1del subgroup
timeFrame: at 3 and 5 years
measure: Overall survival (OS) of IKZF1del subgroup
timeFrame: at 3 and 5 years
measure: Event-free survival (EFS) of IKZF1plus subgroup
timeFrame: at 3 and 5 years
measure: Overall survival (OS) of IKZF1plus subgroup
timeFrame: at 3 and 5 years
measure: Event-free survival (EFS) of IKZF1plus/CD20 subgroup
timeFrame: at 3 and 5 years
measure: Overall survival (OS) of IKZF1plus/CD20 subgroup
timeFrame: at 3 and 5 years
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Dept of Hematology, Nanfang Hospital, Southern Medical University
state: Guangdong
Study officials:
affiliation: Department of Hematology Nanfang Hospital
name: Hongsheng Zhou, M.D., Ph.D
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Hematology Nanfang Hospital
name: Zhixiang Wang, M.D., Ph.D
role: STUDY_DIRECTOR
affiliation: Department of Hematology Nanfang Hospital
name: Ting Zhang, M.D., Ph.D
role: STUDY_DIRECTOR
affiliation: Department of Hematology Nanfang Hospital
name: Ren Lin, M.D., Ph.D
role: STUDY_DIRECTOR
affiliation: Department of Hematology Nanfang Hospital
name: Congcong Wang
role: STUDY_DIRECTOR
affiliation: Department of Hematology Nanfang Hospital
name: Jiali Yao
role: STUDY_DIRECTOR
affiliation: Department of Hematology Nanfang Hospital
name: Qianwei Liu, Ph.D
role: STUDY_DIRECTOR
References:
citation: 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/NEJMoa2016272.
citation: 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: a US, single-centre, single-arm, phase 2 trial. Lancet Haematol. 2023 Jan;10(1):e24-e34. doi: 10.1016/S2352-3026(22)00319-2. Epub 2022 Nov 16.