A Study of HS-10382 Versus Investigator-selected TKIs in Adult Patients With Newly Diagnosed Ph+ CML-CP

This study is a phase III, multi-center, open-label, randomized study of oral HS-10382 160 mg BID versus Investigator selected TKI (imatinib, nilotinib, dasatinib, or flumatinib) in adult patients with newly diagnosed Ph+ CML-CP.

Approximately 408 patients will be randomized in a 1:1 ratio to HS-10382 and Investigator selected TKI to join the treatment period.

Randomization will be stratified based on the following two stratification factors:

ELTS score (low versus intermediate versus high)

Pre-randomization selected TKI (imatinib versus 2G TKI (nilotinib or dasatinib or flumatinib)).

Prior to randomization, the Investigator, in consultation with the patient, considering the current treatment paradigm and patient characteristics and comorbidities, will make a selection of preference for imatinib or 2G TKI (nilotinib or dasatinib or flumatinib) if the patient is randomized to the comparator arm. The stratified randomization based on these two stratification factors will help to achieve a balance across the treatment arms for the possible comorbidities and baseline characteristics of patients enrolled in the study.

To further ensure that the distribution of patients, between imatinib and 2G TKIs (nilotinib or dasatinib or flumatinib), in the Investigator selected TKI arm is reflective of the use of these agents in clinical practice, the enrollment into the strata of imatinib versus 2G TKI (nilotinib or dasatinib or flumatinib) based on the pre-randomization selection of TKI will be managed by Interactive Response Technology to be approximately 50% versus 50%.

Duration of Study treatment: Patients on the study will continue to receive the assigned treatment until the End of Study, premature discontinuation due to treatment failure, disease progression or intolerance, due to Investigator or participant decision.

• HS-10382 (Drug): Comes in 40 mg tablets and taken orally
• Imatinib (Drug): Comes in 100 mg tablets and taken orally
• Dasatinib (Drug): Comes in 20 mg, 50 mg and 70 mg tablets and taken orally
• Nilotinib (Drug): Comes in 150 mg capsules and taken orally
• Flumatinib (Drug): Comes in 0.2 g tablets and taken orally

Primary outcomes

• Percentage of Participants With Major Molecular Response (MMR) at Week 48 [At Week 48]: Molecular response is assessed using BCR-ABL1 transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).

Secondary outcomes

• Major Molecular Response at Week 96 [At Week 96]: Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).
• Major Molecular Response at Scheduled Data Collection Time Points [Planned total follow-up duration of 5 years]: Molecular response is assessed using BCR-ABL transcript levels measured by realtime quantitative polymerase chain reaction. MMR is defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value).
• Time to Discontinuation of Study Treatment Due to Adverse Events (TTDAE) [Planned total follow-up duration of 5 years]: TTDAE is defined as the time from the date of first dose of study treatment to the date of discontinuation of study treatment due to Adverse Event (AE). For patients ongoing without study treatment discontinuation, on or prior to the analysis cut-off date, the time will be censored at the at the analysis cut-off date.
• Change From Baseline in EORTC QLQ-C30 Scales [Planned total follow-up duration of 5 years]: The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assesses the quality of life of cancer patients. It consists of functioning scales, symptom scales, and the global health status quality of life (QoL) scale. A high score for functional and QoL items/scales from the QLQ-30 represents better function and QOL. A high score in symptoms items from QLQ-30 represents worse symptoms.
• Change From Baseline in EORTC QLQ-CML24 Scales [Planned total follow-up duration of 5 years]: The QLQ-CML24 consists of multi-scale items: symptom burden, impact on worry/mood, impact on daily life, body image problems, satisfaction with care and information and satisfaction with social life. A higher score on most of the item scales in QLQ-CML24 reflects a larger impairment in the corresponding domain, with the exception of the satisfaction with care and information, and problems and satisfaction with social life, where a higher score reflects a higher level of satisfaction.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Men or women who are ≥ 18 years old at the time of signing the informed consent form
2. The physical condition score (PS) of the Eastern Cooperative Oncology Group (ECOG) in the United States ranges from 0 to 1
3. First diagnosis of Ph+CML-CP within the first 3 months of randomization: positive for Ph chromosome t (9; 22) in bone marrow cytogenetics and/or positive for BCR/ABL fusion gene in molecular biology testing
4. Organ function testing meets protocol requirements and is deemed eligible.
5. Female participants of childbearing age are willing to take appropriate contraceptive measures and should not breastfeed from the time of signing informed consent until 6 months after the last use of the study treatment; Male participants were willing to use barrier contraception (i.e. condoms) from the time of signing informed consent until 6 months after the last use of the study treatment. The TKI participants selected by the researchers can follow the contraceptive requirements in the TKI instructions.
6. Female participants who have a negative blood pregnancy test result or documented evidence of no pregnancy risk.
7. Voluntarily participate in this clinical trial, understand the research procedures, and be able to sign a written informed consent form

Exclusion Criteria:

1. It is known that there is an accelerated or rapidly changing phase of CML
2. It is known that atypical CML (non P210 protein) exists
3. Known presence of central nervous system leukemia or primary chronic myelofibrosis (excluding secondary myelofibrosis grade 1 caused by CML)
4. History of acute or chronic pancreatitis (within 1 year prior to first administration) or long-term alcohol abuse
5. Known to have major congenital or acquired hemorrhagic diseases unrelated to the disease under study
6. Previous participants with malignant tumors other than CML.
7. Impaired cardiac function or cardiac repolarization abnormality.
8. Severe, uncontrolled, or active cardiovascular or cerebrovascular disease.
9. Severe or uncontrolled diabetes mellitus.
10. Severe or uncontrolled hypertension.
11. Serious arteriovenous thrombosis events.
12. History of splenectomy, solid organ or bone marrow/hematopoietic stem cell transplantation, excluding corneal transplantation.
13. Serious infections occurred within 4 weeks prior to the first administration.
14. Clinically significant gastrointestinal dysfunction.
15. Presence of known active infectious disease.
16. Hepatic encephalopathy, hepatorenal syndrome, or ≥ Child Pugh B-grade cirrhosis.
17. History of severe neurological or mental disorders.
18. Have a history of severe allergies or allergic reactions to any components of HS-10382 and TKIs selected by the investigators.
19. Major surgery (craniotomy/thoracotomy/laparotomy) within 12 weeks prior to first dose.
20. Other toxicities from prior antineoplastic therapy with severity of Grade ≥2.
21. Pregnant or lactating female participants, or those planning pregnancy during the study.
22. Any other condition deemed by the investigator to interfere with the participant's ability to participate in the study, not covered above.