Clinical trial NCT05071482: Flumatinib Versus Imatinib Combined With Chemotherapy for de Novo Ph+ ALL
Official title: Flumatinib Versus Imatinib Combined With Multiagent Chemotherapy for Newly Diagnosed Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia: A Prospective, Open-label，Randomized，Multi-center Clinical Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Acute Leukemia
Keywords: acute lymphoblastic leukemia
flumatinib
Lead sponsor: Institute of Hematology & Blood Diseases Hospital, China
Sponsor class: OTHER
First posted: 2021-10-08
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Compared with patients with philadelphia chromosome-negative Acute Lymphoblastic Leukemia (Ph- ALL), patients with Ph-positive (Ph+) ALL exhibit a comparatively poor prognosis. Fortunately, significant improvements have been found in response rates, disease-free survival (DFS), and overall survival (OS) for patients with Ph+ ALL with the introduction of tyrosine kinase inhibitor (TKI) therapy to treatment regimens. Based on improvements in efficacy and tolerability, next-generation TKIs have been widely used in first-line treatment for chronic myeloid leukemia (CML). Flumatinib, a TKI with more potent binding affinity for BCR-ABL1 tyrosine kinase than imatinib, demonstrated higher rates of responses, faster and deeper responses in FESTnd trial, which suggested that flumatinib might show improved clinical efficacy for treating Ph+ ALL compared with imatinib. The investigators therefore hypothesized that the addition of flumatinib to combinatorial chemotherapy regimen would demonstrate greater efficacy compared with the prior use of imatinib in treating Ph+ ALL. This study explored the safety and efficacy of flumatinib versus imatinib when combined with multi-agent chemotherapy in patients with newly diagnosed Ph+ ALL.


Eligibility criteria: Inclusion Criteria:

1. Patients aged 18 to 65 years, male or female;
2. Newly diagnosed Philadelphia chromosome positive(either t(9;22) and/or BCR-ABL positive and/ or FISH positive) acute lymphoblastic leukemia; Patients will be diagnosed according to morphologic,immunologic, cytogenetic and molecular(MICM) criteria, including bone marrow morphology, immunophenotype, cytogenetic and molecular genetic (BCR/ABL gene, qualitative and quantitative analysis) examination.
3. Eastern Cooperative Oncology Group (ECOG) Performance status 0-2;
4. Adequate end organ function as defined by: Total bilirubin ≤ 1.5 x upper limit of normal（ULN）; serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) ≤ 2.5 x ULN or ≤5 x ULN if leukemic involvement of the liver is present; Creatinine ≤ 1.5 x ULN; Serum amylase and lipase ≤ 1.5 x ULN; Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related; normal electrolytes: Potassium ≥ LLN; Magnesium ≥ LLN; Phosphorus ≥ LLN;
5. Cardiac color Doppler ultrasound ejection fraction ≥ 45%;
6. Subject has provided written informed consent prior to any screening procedure;

Exclusion Criteria:

1. Lymphoid blast crisis of chronic myelocytic leukemia (CML);
2. Previous or ongoing systemic anti-ALL therapy (including but not restricted to TKI and/or radiotherapy, except for appropriate pre-treatment);
3. Patients with clinical manifestations of central or extramedullary invasion of leukemia at diagnosis;
4. Identification of T315I mutation;
5. Concurrent participation in another clinical study with an investigational medical product;
6. Any concurrent severe and/or uncontrolled medical condition, which could, in the opinion of the investigator, compromise participation in the study;
7. History of neurological or psychiatric disorders, including epilepsy or dementia;
8. Major surgery within 4 weeks or failure to recover from previous surgery;
9. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention;
10. Female patients who are pregnant or breast feeding or patients of childbearing potential and male patients whose sexual partner(s) are women of childbearing potential not willing to use a highly effective method of contraception;
11. Clinically significant, uncontrolled or active cardiovascular disease, specifically including, but not restricted to: any history of myocardial infarction, stroke, or revascularization; unstable angina or transient ischemic attack within 6 months prior to enrolment; congestive heart failure within 6 months prior to enrolment or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards; history of clinically significant (as determined by the treating physician) atrial arrhythmia; any history of ventricular arrhythmia; any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism;Uncontrolled hypertension;
12. Active known positive HIV serology;
13. Active serious infection not controlled by oral or intravenous antibiotics;
14. Patients with known allergies or contraindications to the study drug;
15. Patients with bleeding disorders unrelated to ALL.

Primary outcomes:
measure: Relapse free survival
timeFrame: up to 24 months
Secondary outcomes:
measure: The rate of adverse events
timeFrame: through study completion, up to 24 months
measure: The composite CR rate
timeFrame: up to 2 month
measure: The complete remission (CR) rate，CRi rate and overall remission rate（ORR）
timeFrame: up to 2 month
measure: The minimal residual disease (MRD) negative rate by Flow Cytometry (FCM)
timeFrame: up to 24 months
measure: The molecular CR rate
timeFrame: up to 6 months
measure: The rate of primary induction failure(PIF)
timeFrame: up to 6 months
measure: The duration of molecular CR
timeFrame: up to 24 months
measure: The duration of CR
timeFrame: up to 24 months
measure: Time to treatment failure
timeFrame: up to 24 months
measure: The cumulative recurrence rate
timeFrame: up to 24 months
measure: The CNS recurrence rate
timeFrame: up to 24 months
measure: Event free survival(EFS)
timeFrame: up to 24 months
measure: Overall survival(OS)
timeFrame: up to 24 months
measure: The rate of interruption and discontinuation due to AE
timeFrame: up to 24 months
Other outcomes:
measure: ABL kinase region mutation status at molecular relapse (MREL) and hematologic relapse (HREL)
timeFrame: up to 24 months
measure: The plasma and cerebrospinal fluid (CSF) level of flumatinib
timeFrame: up to 3 months
Locations:
city: Tianjin
country: China
facility: Institute of Hematology & Blood Diseases Hospital
Study officials:
References: