study of hs-10382 combination in patients with chronic myeloid leukemia (cml)

Conditions: Chronic Myelogenous Leukemia; CML Chronic Phase; CML Accelerated Phase

Summary: hs-10382 is a small molecular, oral potent, allosteric inhibitor. by binding a myristoyl site of the bcr-abl1 protein, hs-10382 locks bcr-abl1 into an inactive conformation. flumatinib is the first approved second generation tki in china and a derivative of imatinib. the primary objective of this study is to evaluation the safety and tolerability and of hs-10382 combination therapy in patients with chronic myeloid leukemia (cml). the secondary objectives is to evaluate the pk profile, major metabolites and efficacy of hs-10382 in cml-cp/ap subjects after combination therapy, and to explore the kinase domain mutations associated with tki resistance


Eligibility criteria:
inclusion criteria: * signed informed consent form. * men or women aged more than or equal to (≥) 18 years, and less than (\<) 75 years. * cml-cp/ap patients with the ph chromosome or bcr-abl1 fusion genes. * patient with cml-cp/ap who are resistant to or intolerant to previous tkis therapy. * ecog performance status of 0-1 and no worsening within 2 weeks before the first dose. * life expectancy ≥ 12 weeks. * 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: * cml-cp patients who have acquired ccyr and have not lost it. * patients with cml-cp who have progressed to ap or blast phase(bp.) * patients with cml-ap who have obtained chr or no evidence of cml in peripheral blood. * patients with cml-ap who have progressed to bp. * previous treatment with a bcr-abl1 tki allosteric inhibitor . * 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%. * myocardial infarction occurred within 6 months of the first scheduled dose of study drug.; * congestive heart failure occurred within 6 months of the first scheduled dose of study drug.; * uncontrollable angina. * history of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis * any severe or uncontrolled systemic diseases (i.e. uncontrolled hypertension or diabetes). * clinically severe gastrointestinal dysfunction that may affect drug intake, transport or absorption. * severe infection within 4 weeks prior to the first scheduled dose of study drug * inadequate other organ function. * history of other malignancies. * history of hypersensitivity to any active or inactive ingredient of hs-10382 and flumatinib. * history of neuropathy or mental disorders, including epilepsy and dementia. * 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

Keywords: cml-cp/ap hs-10382 flumatinib allosteric inhibitor