Flumatinib Versus Imatinib Combined With Chemotherapy for de Novo Ph+ ALL

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Acute Leukemia

Intervention / Treatment
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* Drug: Flumatinib
* Drug: Imatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 18 to 65 years, male or female; 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. Eastern Cooperative Oncology Group (ECOG) Performance status 0-2; 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; Cardiac color Doppler ultrasound ejection fraction ≥ 45%; Subject has provided written informed consent prior to any screening procedure; Exclusion Criteria: Lymphoid blast crisis of chronic myelocytic leukemia (CML); Previous or ongoing systemic anti-ALL therapy (including but not restricted to TKI and/or radiotherapy, except for appropriate pre-treatment); Patients with clinical manifestations of central or extramedullary invasion of leukemia at diagnosis; Identification of T315I mutation; Concurrent participation in another clinical study with an investigational medical product; Any concurrent severe and/or uncontrolled medical condition, which could, in the opinion of the investigator, compromise participation in the study; History of neurological or psychiatric disorders, including epilepsy or dementia; Major surgery within 4 weeks or failure to recover from previous surgery; Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention; 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; 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; Active known positive HIV serology; Active serious infection not controlled by oral or intravenous antibiotics; Patients with known allergies or contraindications to the study drug; Patients with bleeding disorders unrelated to ALL.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: flumatinib arm<br>600 mg QD oral administration, fasting (2 hours before administration and 1 hour after administration). | Drug: Flumatinib<br>* Flumatinib 600 mg qd will be given orally along with combination chemotherapy starting day 8 of induction chemotherapy. Flumatinib will be given continuously (if it's tolerable) for 2 years since achievement of complete remission (CR) as part of consolidation chemotherapy and maintenance therapy. Patients can receive allogeneic hematopoietic stem cell transplantation (HSCT),or patients in whom MCR was achieved within 3 months after treatment and continued until transplantation can receive autologous HSCT whenever possible during their first CR. Otherwise, they will finish the consolidation and maintenance chemotherapy.<br>|
| Active Comparator: imatinib arm<br>600 mg QD oral administration, with a meal | Drug: Imatinib<br>* Imatinib 600 mg qd will be given orally along with combination chemotherapy starting day 8 of induction chemotherapy. Imatinib will be given continuously (if it's tolerable) for 2 years since achievement of complete remission (CR) as part of consolidation chemotherapy and maintenance therapy. Patients can receive allogeneic hematopoietic stem cell transplantation (HSCT),or patients in whom MCR was achieved within 3 months after treatment and continued until transplantation can receive autologous HSCT whenever possible during their first CR. Otherwise, they will finish the consolidation and maintenance chemotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse free survival | From the date of complete remission(CR) until the date of documented relapse or death due to any cause or the last follow-up day | up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of adverse events | The incidence and severity of neutropenia, anemia, rash, hypophosphatemia, edema, limb pain, and other adverse events. | through study completion, up to 24 months | 
| The composite CR rate | Both CR and molecular CR are obtained at the end of induction | up to 2 month | 
| The complete remission (CR) rate，CRi rate and overall remission rate（ORR） |  | up to 2 month | 
| The minimal residual disease (MRD) negative rate by Flow Cytometry (FCM) |  | up to 24 months | 
| The molecular CR rate |  | up to 6 months | 
| The rate of primary induction failure(PIF) |  | up to 6 months | 
| The duration of molecular CR |  | up to 24 months | 
| The duration of CR |  | up to 24 months | 
| Time to treatment failure |  | up to 24 months | 
| The cumulative recurrence rate |  | up to 24 months | 
| The CNS recurrence rate |  | up to 24 months | 
| Event free survival(EFS) |  | up to 24 months | 
| Overall survival(OS) |  | up to 24 months | 
| The rate of interruption and discontinuation due to AE |  | up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute lymphoblastic leukemia, flumatinib