Venetoclax Combined With Olverembatinib and Predinisone in Treating Ph+ B-ALL

Official title

Venetoclax Combined With Olverembatinib and Predinisone in Treating Ph-positive Precursor B Cell Acute Lymphoblastic Leukemia: a Phase II, Single Arm and Multicenter Study

Overview

Precursor B cell acute lymphoblastic leukemia (B-ALL) is an aggressive type of leukemia, with high relapse rate and poor long term survival in adults. Philadelphia chromosome positive (Ph+) ALL is defined as ALL with translocation between chromosomes 9 and 22. And t(9;22)(q34;q11) is the most common chromosomal abnormality in ALL. Before the emergence of TKI, the prognosis of Ph+ ALL was extremely poor, and the long-term survival rate was only 10%-35%. Ph+ ALL accounts for about 30% of adult ALL. In this study, the investigators propose a treatment approach that combines Venetoclax with Olverembatinib and Predinisone in Ph+ B-ALL adults. The study aims to answer the safety and efficacy of this treatment regimen, and further improve the survival for those participants.

Detailed description

This is a prospective, single-arm, phase II and open-label study. A total of 36 Ph-positive B-ALL participants will be enrolled. The primary endpoint is complete molecular response (CMR) after three cycles of venetoclax combined with olverembatinib and prednisone regimen (VOP) in the treatment of de novo acute Philadelphia chromosome-positive (Ph+) B-lymphoblastic leukemia. The purpose of this study is to explore the safety and efficacy of the multi-drug combination regimen in the treatment of newly diagnosed Ph-positive B-ALL patients.

Interventions

• Drug Venetoclax
  BCL-2 inhibotor
• Drug Olverembatinib
  Tyrosine kinase inhibitor
• Drug Predinisone
  Glucocorticoids

Primary outcome measures

• complete molecular response (CMR) after three cycles [Time frame: At the end of Cycle 3（each cycle is 28 days）]

Secondary outcome measures (6)

• Complete remission with or without incomplete PB cell recovery(CR/CRi) rate [Time frame: after Cycle 1(each cycle is 28 days)]
• Event free survival (EFS) [Time frame: up to 2 years]
• Overall survival (OS) [Time frame: up to 2 years]
• Minimal residual disease (MRD) [Time frame: At the end of each cycle（each cycle is 28 days）, up to 2 years]
• Relapse free survival(RFS) [Time frame: up to 2 years]
• Incidence of Adverse Events [Time frame: From day 1 of treatment to 28 days after the last dose]

Eligibility criteria

Inclusion criteria

• Before enrollment, the patient must be diagnosed with de novo precursor B-cell acute lymphoblastic leukemia and positive for Philadelphia chromosome (presence of t(9;22) and/or BCR::ABL1 positive and/or FISH positive). The diagnostic criteria refer to the 2022 WHO classification;
• Age ≥ 18 years;
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2;
• Expected survival time ≥ 3 months;
• No organ dysfunction that would restrict the use of this protocol during the screening period;
• Understand the study and sign the informed consent form.
• Men, women of childbearing age (only postmenopausal women who have been menopausal for at least 12 months can be considered infertile), and their partners voluntarily take effective contraceptive measures deemed effective by the investigator during the treatment period and for at least 12 months after the last dose of the study drug.

Exclusion criteria

• Accelerated phase or blast crisis of chronic myeloid leukemia;
• Subjects with involvement of the central nervous system (CNS) or accompanied by extramedullary lesions;
• Subjects who have received systemic anti-leukemia treatment (including but not limited to TKI, radiotherapy or chemotherapy, except for the allowed pretreatment);
• Subjects with a history of myocardial infarction within 12 months, or have clinical manifestations of heart disease (including but not limited to unstable angina pectoris, congestive heart failure, uncontrolled hypertension and uncontrolled arrhythmia, etc.); left ventricular ejection fraction (LVEF) on echocardiography <50%;
• Diseases with abnormal functions of organs such as lung, liver, and kidney that may limit the patient's participation in this trial (including but not limited to severe infection, uncontrolled diabetes, active tuberculosis, asthma, COPD, bronchiectasis, etc.);
• History of other malignancies within the past 5 years, excluding localized thyroid cancer and in situ skin cancer;
• Serum total bilirubin > 1.5 ULN (upper limit of normal); ALT or AST > 2.5 ULN; serum creatinine > 1.5 ULN;
• Known HIV infection;
• Conditions affecting the use of the study drug as assessed by the investigator;
• Unable to understand or comply with the study protocol.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• The First Affiliated Hospital, Zhejiang University School of Medicine — Hangzhou

Publications

• Ravandi F, Jorgensen JL, Thomas DA, O'Brien S, Garris R, Faderl S, Huang X, Wen S, Burger JA, Ferrajoli A, Kebriaei P, Champlin RE, Estrov Z, Challagundla P, Wang SA, Luthra R, Cortes JE, Kantarjian HM. Detection of MRD may predict the outcome of patients with Philadelphia chromosome-positive ALL treated with tyrosine kinase inhibitors plus chemotherapy. Blood. 2013 Aug 15;122(7):1214-21. doi: 10. PMID 23836561
• Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematol PMID 26065651
• Sasaki K, Kantarjian HM, Short NJ, Samra B, Khoury JD, Kanagal Shamanna R, Konopleva M, Jain N, DiNardo CD, Khouri R, Garcia-Manero G, Kadia TM, Wierda WG, Khouri IF, Kebriaei P, Mehta RS, Champlin RE, Garris R, Cheung CM, Daver N, Thompson PA, Yilmaz M, Ravandi F, Jabbour E. Prognostic factors for progression in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in comple PMID 33793964
• Tang H, Jia W, Jia S, Dong R, Gao S, Feng J, Dong H, Gu H, Zhang T, Yuan R, Liu X, Cheng L, Zhou S, Gao G. A new chemotherapy-free regimen of olverembatinib in combination with venetoclax and dexamethasone for newly diagnosed Ph+ acute lymphoblastic leukemia: Preliminary outcomes of a prospective study. Am J Hematol. 2024 Jun;99(6):1177-1179. doi: 10.1002/ajh.27289. Epub 2024 Mar 14. No abstract a PMID 38482543
• Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Ca PMID 26308885
• Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O'Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. doi: 10.3324/haematol.2014. PMID 25682595
• Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. doi: 10.1182/blood-2013-09-529008. Epub 2013 Nov PMID 24277073
• Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell. 1984 Jan;36(1):93-9. doi: 10.1016/0092-8674(84)90077-1. PMID 6319012

Identifiers

NCT: NCT06754267 · IIT20240094C

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗