A Global Study Testing the New Drug Olverembatinib combined with chemotherapy for Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (POLARIS-1)

Prior treatment

• Prior history of chronic myelocytic leukemia and diagnosis of chronic myelocytic leukemia in lymphoid blast phase (BP)
• Active fungal/bacterial/viral infection that requires systemic treatment, including but not limited to human immunodeficiency virus (HIV), active viral hepatitis B and hepatitis C, known active COVID-19 (those who have received COVID-19 vaccine or other attenuated live vaccine more than 28 days before enrollment are acceptable).
• A major surgery within 14 days prior to the first dose of the study drug (except for minor surgeries such as bone marrow biopsy and deep vein catheterization) or those who haven’t fully recovered from previous surgeries, at the discretion of the investigator.
• Other malignancies within 2 years prior to enrollment, with the exception of: adequately treated cervical carcinoma in situ or breast carcinoma in situ; completely excised skin basal cell carcinoma or localized squamous cell carcinoma of the skin. It is necessary to discuss with the Sponsor for patients with a history of localized malignancy that has been cured by excision (or other methods) which will not affect safety and efficacy evaluation of the study, at the discretion of the investigator.
• Previous or current clinical CNS diseases, e.g., epilepsy, epileptic seizure of children or adults, paresis, alogia, apoplexy, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or mental aberration
• Use of anticoagulants and/or antiplatelet drugs at therapeutic doses, but those using low-dose anticoagulants for keeping the central line patent are acceptable.
• Use of a drug for other concomitant diseases which interacts with the study drug (e.g., strong CYP2C9 inducers or inhibitors and moderate to strong CYP3A4 inducers or inhibitors) within 7 days or 5 half-lives prior to the first dose (whichever is shorter).
• Any venous thromboembolism within 6 months before randomization, including but not limited to deep vein thrombosis (DVT) or lung embolism
• Use of prohibited drugs within 7 days or 5 half-lives prior to the first dose (whichever is shorter);

Other illness

• Any disease or medical condition that is unstable or might affect the patient’s safety or study compliance, such as uncontrolled hypertension, uncontrolled diabetes mellitus, active hemorrhage (within 3 months), severe respiratory system disorder (e.g., chronic obstructive pulmonary disease, severe asthma, etc.), significant renal, nervous, endocrine, metabolic, immune, hepatic, digestive diseases, and mental diseases, etc.
• Diseases seriously affect oral administration and absorption of drugs or those who have active peptic ulcer
• Hemorrhagic disorder unrelated to the tumor: such as congenital hemorrhagic disorder (e.g., angiohaemophilia von Willebrand disease), acquired hemorrhagic disorder diagnosed within 1 year (e.g., acquired factor VIII inhibitor), etc.
• Hypersensitivity to ingredients, excipients or analogues of drugs used in the study
• Any symptom or disease that may compromise patients' safety or interfere with the efficacy and safety assessment of the study drug, or any other situation or condition unsuitable for participating in the study. In special circumstances, a decision will be made after the investigator discusses with the Sponsor
• Autoimmune disorders that may involve CNS.

Lab values

• Use of drugs that are known to possibly cause prolonged ECG QT
• Presence of any of the following heart injuries at screening: a. New York Heart Association (NYHA) Class III to IV; b. Uncontrolled angina, congestive cardiac failure or myocardial infarction within 6 months prior to the first dose; c. Second-degree type II, third-degree atrioventricular (AV) block or PR interval > 250 ms, etc.; d. Various factors that have a potential to increase the risk of prolonged QTcF or arrhythmia, such as cardiac failure, hypopotassaemia, congenital long QT syndrome, and a family history of sudden death of unknown cause before the age of 40 years in a first-degree relative;

Other

• Contraindications to glucocorticoids and unsuitable for participating in the study, at the discretion of the investigator
• Females who are pregnant, breastfeeding, or planning to become pregnant during the study or within 4 months of Olverembatinib after the last dose
• Clinical manifestations of central nervous system (CNS) leukemia or ALL extramedullary infiltration, except lymphadenopathy or hepatosplenomegaly

• ≥ 18 years old.
• Meet 2016 WHO classification and diagnostic criteria for Philadelphia chromosome- or BCR/ABL1-positive Ph+ ALL. Patients must be newly diagnosed with Ph+ ALL and haven't received systemic anti-leukaemia therapy previously, except for hydroxycarbamide treatment, vincristine treatment no more than once, and steroids therapy for no more than 28 days.
• Life expectancy of ≥ 3 months.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
• Adequate organ function as indicated below: • Hepatic function: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × Upper Limit of Normal (ULN), serum total bilirubin ≤ 1.5 × ULN (and for patients with Gilbert’s syndrome serum total bilirubin ≤ 3.0 x ULN); • Renal function: Serum creatinine ≤ 1.5 × ULN; or 24 h creatinine clearance (CrCL) must be ≥ 50 mL/min (Cockcroft-Gault formula) when serum creatinine is > 1.5 × ULN; • Coagulation: International normalized ratio (INR), activated partial thromboplastin time (APTT), and prothrombin time (PT) all ≤ 1.5 × ULN; • Cardiac function index: Left ventricular ejection fraction (LVEF) > 50%; • Troponin I or T ≤ ULN; • QT interval corrected using the Fridericia's formula (QTcF) on electrocardiogram (ECG): QTcF ≤ 450 ms in males or ≤ 470 ms in females.
• Males and females of childbearing potential (only postmenopausal women who have not menstruated for at least 12 months or are surgically sterilized can be considered infertile) and their partners voluntarily take effective contraceptive measures throughout the treatment and until at least 4 months after the last dose of the study drug. Male patients are not allowed to donate sperm.
• Female patients of childbearing potential have negative serum pregnancy test results within 7 days prior to the first dose
• Patients must be able to understand and voluntarily sign a written informed consent form that has been approved by the Ethics Committee (EC) and voluntarily complete study procedures and follow-up examinations