A Study of the Efficacy and Safety of Flumatinib in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase.

Study Overview
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Brief Summary
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It's a double-blind , randomized ,multi-center study. The purpose of this study is to explore the efficacy and safety of flumatinib 400mg once daily (QD) versus 600mg QD as the first line therapy in patients with chronic myleiod leukemia(CML) in chronic phase(CP).

Detailed Description
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This is a dose-optimization study of flumatinib in adult patient with newly diagnosed CML-CP. The objective of this study is to compare the efficacy and safety of flumatinib 400mg QD with that of 600mg QD. Eligible patients are randomized in a 1:1 ratio to receive either fluamtinib 400mg QD or flumatinib 600mg QD. Randomization is stratified based on Sokal risk score (<0.8,0.8 1.2,>1.2). Patients will discontinue study therapy due to treatment failure, disease progression or intolerance to study medication or due to investigator's or participant's decision. The primary efficacy endpoint is the rate of early molecular response , as measured by RQ-PCR at 3 months. Hematologic response, molecular response and cytogenetic response will be assessed at baseline and a certain frequency after treatment, until study completion.

Official Title
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A Double-blind , Randomized, Multicenter, Phase 4 Study to Evaluate Efficacy and Safety of Oral Flumatinib 400mg Versus 600mg in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase.

Conditions
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CML, Chronic Phase

Intervention / Treatment
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* Drug: Flumatinib mesylate tablets (400mg)
* Drug: Flumatinib mesylate tablets (600mg)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form. Men or women aged more than or equal to (≥) 18 years, and less than (<) 75 years. ECOG performance status of 0-2. Patients with philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) within 6 months of diagnosis. Adequate organ function. Men or women should be using adequate contraceptive measures throughout the study; Females should not be breastfeeding at the time of screening, during the study and until 6 months after completion of the study. Females must have evidence of non-childbearing potential. Exclusion Criteria: Known atypical CML or presence of additional chromosomal abnormalities. Known presence of the T315I mutation. Treatment with tyrosine kinase inhibitor(s) prior to randomization. Any treatment with anti-CML activity for longer than 2 weeks(exception of hydroxyurea or anagrelide) or hematopoietic stem cell transplantation prior to randomization . Prior treatment with splenectomy. Impaired cardiac function including any one of the following: Resting corrected QT interval (QTc) > 470 ms obtained from electrocardiogram (ECG), using the screening clinic's ECG machine and Fridericia's formula for QT interval correction (QTcF). Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, Left ventricular ejection fraction (LVEF) ≤ 50%. During screening period, ECG examination showed average heart rate <50 beats per minute. Myocardial infarction occurred within 12 months of randomization; Congestive heart failure occurred within 6 months of randomization; Uncontrollable angina. Stroke or transient ischemic attack within 6 months of randomization. Any severe or uncontrolled systemic diseases (i.e. uncontrolled hypertension or diabetes). Clinically severe gastrointestinal dysfunction that may affect drug intake, transport or absorption. The presence of active infectious diseases has been known prior to randomization History of significant congenital or acquired bleeding disorders unrelated to CML Inadequate other organ function. History of other malignancies. History of hypersensitivity to any active or inactive ingredient of flumatinib. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued. Major surgery within 4 weeks of randomization. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 within 4 weeks of randomization. Any disease or condition that, in the opinion of the investigator, would compromise the safety of the patient or interfere with study assessments. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Flumatinib (400mg)<br>Flumatinib 400mg QD | Drug: Flumatinib mesylate tablets (400mg)<br>* Flumatinib 400mg +Placebo for flumatinib are administered orally daily. Patients are randomized to flumatinib 400mg QD.<br>|
| Experimental: Flumatinib (600mg)<br>Flumatinib 600mg QD | Drug: Flumatinib mesylate tablets (600mg)<br>* Flumatinib 600mg is administered orally daily. Patients are randomized to flumatinib 600mg QD.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early molecular response(EMR) rate at 3 months | Molecular response is assessed using BCR-ABL transcript levels and measured by realtime quantitative polymerase chain reaction(RQ-PCR). Early molecular response is defined as a ratio BCR-ABL/ABL ≤10% on the international scale (IS). | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major molecular response(MMR) rate at month 3,6,9 and 12 | Major molecular response is defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale as measured by RQ-PCR. | 3, 6, 9 and 12 months | 
| MR4.0 rate at month 3,6,9 and 12 | MR4.0 is defined as BCR-ABL/ABL ≤0.01% on the international scale. | 3, 6, 9 and 12 months | 
| MR4.5 rate at month 3,6,9 and 12 | MR4.5 is defined as BCR-ABL/ABL ≤0.0032% on the international scale. | 3, 6, 9 and 12 months | 
| Complete cytogenetic response（CCyR）rate at month 3,6,9 and 12 | Cytogenetic response (CyR) is based on the prevalence of Ph+ cells in metaphase from bone marrow (BM) sample . CCyR is defined as 0% Ph+ metaphases in the bone marrow. | 3, 6, 9 and 12 months | 
| Complete hematologic response(CHR) rate at month 1,2,3,4,5,6,9 and 12 | Hematologic response will be assessed by complete blood count (CBC) and physical examination at each visit. CHR is defined as all of the following present: white blood cell(WBC) count <10×109/L Platelet count <450 ×109/L Peripheral blood basophils <5% No blasts and no promyelocytes in peripheral blood < 5% myelocytes plus metamyelocytes in peripheral blood No evidence of extramedullary disease, including no splenomegaly or hepatomegaly | 1,2,3,4,5,6,9 and 12 months | 
| Time to first MMR | Evaluate the time from the date of randomization to the date of first documented MMR during treatment. | up to 36 months | 
| Time to first CCyR | Evaluate the time from the date of randomization to the date of first documented CCyR during treatment. | up to 36 months | 
| Duration of MMR | Duration of MMR is defined as the time from the date of first documented MMR to the earliest date of loss of MMR. | up to 36 months | 
| Duration of CCyR | Duration of CCyR is defined as the time from the date of first documented CCyR to the earliest date of loss of CCyR. | up to 36 months | 
| Event-free survival (EFS) | EFS is defined as the time from the date of randomization to the earliest occurrence of the following events: death due to any cause ; loss of CHR ,loss of PCyR ;loss of CCyR ; discontinuation of study treatment due to AE or treatment failure ; progression to AP/BC | up to 36 months | 
| Progression-free survival (PFS) | PFS is defined as the time from the date of randomization to the earliest occurrence of progression to AP/BC or death from any cause. | up to 36 months | 
| Overall survival (OS) | OS is defined as the time from the date of randomization to the date of death from any cause. | Frame:12 and 36 months | 
| The incidence and severity of adverse events ((AE) | Assessed by number and severity of adverse events as recorded on the case report form NCI CTCAE v5.0. | up to 36 months | 
| Pharmacokinetics (PK) of HS-10096：Tmax | Serum concentrations of HS-10096 will be collected and analyzed to evaluate the PK of HS-10096.Tmax is the time to reach maximum (peak) plasma drug concentration after dose administration (hr). | Up to approximately 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CML, Chronic Phase, Flumatinib, BCR-ABL TKI, Dose-optimization, Double-blind, Phase 4