Overview

This is a phase II, open-label, multi-center study evaluating the efficacy and safety of sonrotoclax (SA) in combination with azacitidine (AZA) plus individualized targeted or chemotherapeutic agents in adult participants with newly diagnosed acute myeloid leukemia (AML). Eligible participants will be stratified into different treatment arms based on genetic background (FLT3/IDH1 mutation status) and fitness for intensive chemotherapy. All participants will receive sonrotoclax with dose escalation from 20 mg/day to 320 mg/day, followed by maintenance dosing, which may be temporarily held by the investigator from Day 14 to Day 28 of each 28-day cycle based on the participant's condition, combined with azacitidine 75 mg/m²/day intravenously on Days 1-7. For participants fit for intensive chemotherapy, additional anthracycline (daunorubicin 60 mg/m²/day or idarubicin 10 mg/m²/day on Days 1-3) will be administered. For participants with FLT3 mutations, gilteritinib 80 mg once daily on Days 1-14 will be added; for those with IDH1 mutations, ivosidenib 500 mg once daily on Days 1-28 will be added.

Eligibility

Inclusion Criteria:

• Newly diagnosed AML confirmed by bone marrow morphology and immunophenotyping (5th edition WHO diagnostic criteria)
• Subjects with APL excluded according to fusion gene and chromosome results
• ECOG performance status 0-3
• Age ≥ 18 years
• White blood cell count must be \< 25 × 10⁹/L at the start of study treatment (can be reduced by leukapheresis and/or hydroxyurea)
• Subjects must have adequate organ function, defined as follows: Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN), unless elevated due to leukemic organ involvement; serum total bilirubin \< 3 × ULN; higher levels are acceptable if attributable to ineffective erythropoiesis, leukemic organ involvement, or Gilbert syndrome; serum creatinine \< 3 × ULN, or estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula
• Written informed consent obtained from the subject or legal representative

Exclusion Criteria:

• FAB classification as M3, or molecularly confirmed APL
• Refractory / relapsed subjects
• Subjects with a history of myeloproliferative neoplasms (MPN);
• Subjects with a history of myelodysplastic syndromes (MDS);
• Subjects with a history of chronic myeloid leukemia (CML);
• Subjects with mixed phenotype acute leukemia (MPAL);
• Documented central nervous system leukemia; or documented extramedullary leukemia (e.g., myeloid sarcoma, skin infiltration), excluding liver, spleen, and lymph node involvement;
• Hypersensitivity or allergy to any of the study drugs;
• Physical conditions or organ system dysfunction that impairs the ability to swallow capsules or tablets, or significantly affects gastrointestinal function and/or absorption (including malabsorption syndrome, small bowel resection, or uncontrolled inflammatory bowel disease);
• Cardiac conditions meeting any of the following:a) Long QT syndrome or QTc interval \> 480 ms;b) Second- or third-degree atrioventricular block; severe, uncontrolled arrhythmia requiring medical treatment;c) History of myocardial infarction, unstable angina, severe unstable ventricular arrhythmia, or any other treatable arrhythmia, clinically significant pericardial disease within 6 months prior to enrollment; or electrocardiographic evidence of acute ischemia or active conduction system abnormalities;
• Previous or current concurrent malignancy other than adequately controlled non-melanoma skin basal cell carcinoma, in situ breast/cervical carcinoma, or other malignancies adequately controlled without treatment for more than 6 months;
• Significantly abnormal liver or renal function (serum bilirubin, AST, ALT, or serum creatinine \> 3 × upper limit of normal; excluding those deemed by the investigator to be related to AML);
• Subjects who have received previous anti-AML therapies other than hydroxyurea for cytoreduction, including but not limited to BCL-2, FLT3, IDH1 inhibitors, or other investigational agents;
• Coagulopathy unrelated to AML;
• HIV infection, syphilis infection, HCV infection, or active HBV infection (HBsAg positive; or HBsAg negative / HBcAb positive with HBV DNA \> 1.0 × ULN);
• Other uncontrolled active infection (as judged by the investigator);
• Pregnant or breastfeeding women;
• Unable to understand or comply with the study protocol;
• Participation in other relevant clinical studies within 30 days (excluding diagnostic studies);
• Subjects deemed inappropriate for study participation by the investigator.