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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ascentage Pharma Group Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15], Diseases [C] - Neoplasms [C04]

Trial duration

16 Apr 2025 → ongoing

Decision date (initial)

2025-01-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Ascentage Pharma Group Inc.

External identifiers

EU CT number

2024-511495-32-00

ClinicalTrials.gov

NCT06423911

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic, Pharmacogenetic

Part A: To compare the major molecular response (MMR) rate at 24 weeks of olverembatinib versus bosutinib
Part B: To evaluate the MMR rate by 24 weeks of olverembatinib in CML-CP patients with T315I mutation

Secondary objectives 14

1. Part A: To compare the MMR rate at 96 weeks of olverembatinib versus bosutinib
2. Part A: To compare additional efficacy parameters of olverembatinib versus bosutinib
3. Part A:To compare the safety profile of olverembatinib versus bosutinib
4. Part A:To characterize the population pharmacokinetics (Pop PK) of olverembatinib in the CML-CP population
5. Part A:To evaluate health utility measures of olverembatinib vs. bosutinib based on EuroQol 5 Dimension (EQ-5D).
6. Part A:To evaluate patient-reported outcome (PRO) quality of life (QoL) measures of olverembatinib vs. bosutinib based on EORTC QLQ-C30.
7. Part B:To evaluate the MMR rate by 96 weeks of olverembatinib in CML-CP patients with T315I mutation
8. Part B:To evaluate additional efficacy parameters of olverembatinib in CML-CP patients with T315I mutation
9. Part B:To evaluate the safety profile of olverembatinib in CML-CP patients with T315I mutation
10. Part B:To characterize the population PK of olverembatinib in the CML-CP population with T315I mutation
11. Part B:To evaluate health utility measures of olverembatinib based on EuroQol 5 Dimension (EQ-5D)
12. Part B:To evaluate PRO QoL measures of olverembatinib based on EORTC QLQ-C30
13. Part A: To compare the impact of treatment on patients on work productivity and activity impairment from baseline to end of treatment (EOT) between treatment arms in all patients based on the Work Productivity and Activity Impairment General Health (WPAI-GH) questionnaire.
14. Part B: To evaluate the impact of treatment on patients on work productivity and activity impairment from baseline to EOT in all patients based on the WPAI-GH.

Conditions and MedDRA coding

Chronic Phase Chronic Myeloid Leukemia

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Age ≥ 18 years old.
2. Diagnosis of CML-CP according to CML NCCN Guidelines version 1.2024
3. Evidence of typical BCR::ABL1 transcript at the timing of screening which are amenable to standardized RQ-PCR quantification.
4. 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
5. Part A: Prior treated with at least two approved TKIs, such as imatinib, nilotinib, dasatinib, radotinib, flumatinib, ponatinib, or asciminib
6. 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
7. 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.
8. ECOG performance status (PS) ≤ 2.
9. Written informed consent obtained prior to any screening procedures.
10. 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
11. 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

Exclusion criteria 16

1. For Part A only: T315I or V299L mutation at any time prior to starting study treatment.
2. 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
3. Previous treatment with or known / suspected hypersensitivity to olverembatinib or any of its excipients
4. For Part A only: Previous treatment with or known / suspected hypersensitivity to bosutinib or any of its excipients
5. Participation in an investigational study within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is shorter
6. Pregnant or nursing (lactating) women
7. 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)
8. Prior diagnosis of CML AP or BP
9. Previous treatment with hematopoietic stem-cell transplantation.
10. Plan to undergo allogeneic hematopoietic stem cell transplantation
11. 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).
12. Presence of significant congenital or acquired bleeding disorder unrelated to CML
13. 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
14. Active infection that requires systemic drug therapy, including active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection.
15. 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).
16. (EU only) For Part A only: patient with impairment of hepatic function, which is contraindicated in the bosutinib Summary of Product Characteristics.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part A: MMR rate at 24 weeks
2. Part B: MMR rate by 24 weeks

Secondary endpoints 33

1. Part A: MMR rate at 96 weeks
2. Part A: Cytogenetic response rate (complete, partial, major, minor, minimal, no response) at and by all scheduled data collection time points, including 24, 48 and 96 weeks
3. Part A: MMR, MR4, MR4.5 rate at all scheduled data collection time points (except 24 and 96 weeks which are already covered by primary and key secondary endpoints)
4. Part A: MMR, MR4, MR4.5 rate by all scheduled data collection time points including 24, 48 and 96 weeks
5. Part A: Time to MMR, MR4, MR4.5
6. Part A: Duration of MMR, MR4, MR4.5
7. Part A: Time to complete cytogenetic response (CCyR)
8. Part A: Duration of CCyR
9. Part A: Time to treatment failure
10. Part A: Progression free survival
11. Part A: OS
12. Part A: Type, frequency, and severity of adverse events
13. Part A:Changes in laboratory values that fall outside the normal ranges and clinically notable ECG and other safety data (vital signs, physical examination)
14. Part A:Trough plasma concentration; key PK parameters including apparent clearance, apparent volume of distribution and other appropriate parameters
15. Part A: Change in health utility from baseline over time according to EQ-5D-5L
16. Part A: Change in work productivity and activity impairment over time according to WPAI- GH
17. Part B: MMR rate by 96 weeks
18. Part B:Cytogenetic response rate (complete, partial, major, minor, minimal, no response) by all scheduled data collection time points, including 24, 48 and 96 weeks
19. Part B:MMR, MR4, MR4.5 rate by all scheduled data collection time points (except 24 and 96 weeks, which are already covered by primary and key secondary endpoints)
20. Part B:Time to MMR, MR4, MR4.5
21. Part B:Duration of MMR, MR4, MR4.5
22. Part B:Time to CCyR
23. Part B:Duration of CCyR
24. Part B: Time to treatment failure
25. Part B:Progression free survival
26. Part B:OS
27. Part B:Type, frequency, and severity of adverse events.
28. Part B:Changes in laboratory values that fall outside the normal ranges and clinically notable ECG and other safety data (vital signs, physical examination)
29. Part B:Trough plasma concentration; key PK parameters including apparent clearance, apparent volume of distribution and other appropriate parameters
30. Part B:Change in QoL from baseline over time according to EORTC QLQ-C30
31. Part B:Change in work productivity and activity impairment over time according to WPAI- GH
32. Part A: Change in Quality of Life (QoL) over time according to EORTC QLQ-C30
33. Part B: Change in health utility from baseline over time according to EQ-5D-5L

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ascentage Pharma Group Inc.

Sponsor organisation

Ascentage Pharma Group Inc.

Address

700 King Farm Boulevard

City

Rockville

Postcode

20850-5736

Country

United States

Scientific contact point

Organisation

Ascentage Pharma Group Inc.

Contact name

Yifan Zhai, M.D., Ph.D.

Public contact point

Organisation

Ascentage Pharma Group Inc.

Contact name

Yifan Zhai, M.D., Ph.D.

Third parties 10

Locations

6 EU/EEA countries · 56 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 86 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

13 submissions — initial application plus substantial / non-substantial modifications