A Worldwide Study Testing the New Drug Olverembatinib for Patients with Chronic Phase Chronic Myeloid Leukemia (POLARIS-2)

Prior treatment

• For Part A only: T315I or V299L mutation at any time prior to starting study treatment.
• Plan to undergo allogeneic hematopoietic stem cell transplantation
• Another malignancy within 1 year prior to study entry. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection and are considered disease-free at the time of study entry
• Treatment with medications that meet one of the following criteria and cannot be discontinued at least 7 days prior to the first dose of olverembatinib or bosutinib. • Moderate or strong inhibitors of CYP3A4 • Moderate or strong inducers of CYP3A4
• Previous treatment with or known / suspected hypersensitivity to olverembatinib or any of its excipients
• For Part A only: Previous treatment with or known / suspected hypersensitivity to bosutinib or any of its excipients
• Participation in an investigational study within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is shorter
• Prior diagnosis of CML AP or BP
• Previous treatment with hematopoietic stem-cell transplantation.

Other illness

• Presence of significant congenital or acquired bleeding disorder unrelated to CML
• Active infection that requires systemic drug therapy, including active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery).
• (EU only) For Part A only: patient with impairment of hepatic function, which is contraindicated in the bosutinib Summary of Product Characteristics.

Lab values

• Clinically significant, uncontrolled, or active cardiovascular disease, specifically including any of the following prior to starting study treatment: • Any history of myocardial infarction (MI) within 6 months. • Unstable angina within 3 months. • Any history of cerebrovascular accident within 1 year. • Transient ischemic attacks (TIA) within 3 months. • Any history of peripheral vascular or visceral infarction within 6 months. • Congestive heart failure (CHF) (New York Heart Association [NYHA] class III or IV) within 6 months. • Left ventricular ejection fraction (LVEF) less than lower limit of normal, per local institutional standards, within 6 months History of clinically significant atrial arrhythmia (such as atrial fibrillation with increased risk of thrombosis) or any history of ventricular arrhythmia (determined by the treating physician). • Venous thromboembolism, including deep venous thrombosis or pulmonary embolism, within 3 months prior to enrollment. Patients who have experienced a venous thromboembolic event should only be eligible if the condition is well controlled with optimal intervention (as determined by the treating physician). Continued prophylactic anticoagulation is acceptable. • Patients with revascularization procedures, including cardiac bypass within the 6 months and stenting within the past 3 months. • QTcF at screening ≥450 msec (male patients), ≥470 msec (female patients).

Other

• Pregnant or nursing (lactating) women
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using adequate methods of contraception during dosing and for 4 months after last dose of olverembatinib and certain period according to the locally approved prescribing information for bosutinib. (Refer to protocol section 9.2.12.1 subsection pregnancy protection)

• Age ≥ 18 years old.
• Adequate organ functions as defined below: • Creatinine clearance ≥30 mL/min as calculated using Cockcroft-Gault formula. • Total bilirubin < 1.5 × ULN except for patients with Gilbert’s syndrome who may only be included if total bilirubin ≤ 3.0 × ULN or direct bilirubin ≤ 1.5× ULN. • AST < 3 × ULN • ALT < 3 × ULN • Serum amylase ≤ 1.5 × ULN. For serum lipase ≤ 1.0 × ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis • Alkaline phosphatase ≤ 2.5 × ULN
• Must have the following electrolyte values within normal limits or corrected to be within normal limits with supplements prior to first dose of study medication: • Potassium (potassium increase of up to 6.0 mmol/L is acceptable at study entry if associated with creatinine clearance within normal limits) • Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable at study entry if associated with creatinine clearance within normal limits)Magnesium, except for magnesium increase > ULN – 3.0 mg/dL; > ULN – 1.23 mmol/L associated with creatinine clearance (calculated using Cockcroft-Gault formula) within normal limits
• Diagnosis of CML-CP according to CML NCCN Guidelines version 1.2024
• Evidence of typical BCR::ABL1 transcript at the timing of screening which are amenable to standardized RQ-PCR quantification.
• Must meet all the following laboratory values at the screening visit: • Peripheral blood myeloblasts < 15% • Peripheral blood myeloblasts and promyelocytes combined < 30% • Peripheral blood basophils < 20% • ≥ 50 × 109/L (≥ 50,000/mm3) platelets • Transient prior therapy related thrombocytopenia (<50,000/mm3 for ≤ 30 days prior to screening) is acceptable. • No evidence of extramedullary infiltrates of leukemia cells, except for hepatomegaly or splenomegaly
• Part A: Prior treated with at least two approved TKIs, such as imatinib, nilotinib, dasatinib, radotinib, flumatinib, ponatinib, or asciminib
• Part B: Patients must meet all three of the following criteria at screening. • Previously treated with at least one approved TKIs, such as imatinib, nilotinib, dasatinib, bosutinib, radotinib, flumatinib, ponatinib, or asciminib. • Have T315I mutation at screening. • There are no other effective and/or tolerable therapies available
• Failure (adapted from the 2025 ELN Guidelines; Apperley et al, 2025) or intolerance to the most recent TKI therapy at the time of screening. • Failure is defined for CML-CP patients (CP at the time of initiation of last therapy) as follows. Patients must meet at least one of the following criteria. Three months after the initiation of therapy: BCR::ABL1 (IS) >10% and confirmed within 1-3 months. Six months after the initiation of therapy: BCR::ABL1 (IS) >10%. Twelve months after initiation of therapy: BCR::ABL1 (IS) >1% • At any time after the initiation of therapy, if new BCR::ABL1 mutations that cause resistance to current treatment are developed (refer to the latest version of the NCCN or ELN guidelines), and BCR::ABL1 (IS) > 0.1%. • At any time after the initiation of therapy, loss of response • At any time after the initiation of therapy, new clonal chromosome abnormalities in Ph+ cells: high risk ACA in Ph+ cells, and BCR>>ABL1 (IS) >0.1% • Intolerance is defined as below. Patients intolerant to the most recent TKI therapy must have BCR::ABL1 (IS) ratio more than 0.1% at screening.  Non-hematological intolerance: patients with grade 3 or 4 toxicity while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the patient if response is already suboptimal)  Hematological intolerance: patients with grade 3 or 4 toxicity (ANC or platelets) while on therapy that is recurrent after dose reduction to the lowest doses recommended in label.
• ECOG performance status (PS) ≤ 2.
• Written informed consent obtained prior to any screening procedures.