Sonrotoclax Plus Azacitidine in Patients With MDS-IB2

• Sonrotoclax (Drug), also known as BGB-11417: Sonrotoclax is administered orally once daily. Phase Ib target doses are 40, 80, 160, and 320 mg; phase II uses the recommended phase II dose. In cycle 1, a four-day ramp-up administers one-eighth, one-quarter, one-half, and the full target dose on days 1, 2, 3, and 4, respectively. Treatment at the target dose is then continued for 14 days. From cycle 2 onward, sonrotoclax is generally administered on days 1-14 of each 28-day cycle. Dose interruptions, reductions, and adjustments to treatment duration or concomitant medications follow the protocol.
• Azacitidine (AZA) (Drug): Azacitidine is administered at 75 mg/m² once daily by subcutaneous injection or intravenous infusion for seven consecutive days per 28-day cycle. In cycle 1, azacitidine is administered on days 4-10, beginning when sonrotoclax reaches its target dose. From cycle 2 onward, azacitidine is administered on days 1-7. Treatment delays and dose modifications are permitted according to protocol-defined toxicity and recovery criteria.

Primary outcomes

• Dose-Limiting Toxicities (DLTs) [Cycle 1 Day 1 through Cycle 1 Day 28; up to Day 42 if required for assessment of unresolved hematologic toxicity.]: Incidence of protocol-defined DLTs during the first treatment cycle.
• Maximum Tolerated Dose / Recommended Phase 2 Dose [Through completion of the Phase Ib dose-escalation stage, approximately 12 months]: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Sonrotoclax
• Composite Response Rate (CRR) [From the first dose through completion of up to 4 treatment cycles, approximately 4 months]: Proportion of participants achieving complete remission (CR), complete remission with limited count recovery (CRL), or complete remission with partial hematologic recovery (CRh).

Secondary outcomes

• Duration of Response (DoR) [Up to 36 months]: Time from the first documented response to disease progression, relapse, or death from any cause, whichever occurs first.
• Measurable Residual Disease (MRD) Negativity Rate [From baseline through the end of study treatment, up to approximately 12 months]: Proportion of evaluable participants who achieve MRD-negative status during study treatment.
• Progression-Free Survival (PFS) [From the date of the first dose of study treatment to the date of the first documented disease progression, transformation to acute myeloid leukemia, or death from any cause, whichever occurs first, assessed up to 36 months.]: Time from the first dose of study treatment to the first documented disease progression, transformation to acute myeloid leukemia, or death from any cause, whichever occurs first.
• Overall Survival (OS) [Up to 36 months]: Time from the first dose of study treatment to death from any cause.
• Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) Rate [Up to 36 months]: Proportion of participants who undergo allogeneic hematopoietic stem cell transplantation after treatment with sonrotoclax plus azacitidine.
• Incidence of Treatment-Emergent Adverse Events [From the first dose of study treatment through 30 days after the last dose, assessed up to 12 months.]: Incidence and severity of treatment-emergent adverse events, serious adverse events, Grade 3 or higher adverse events, infections, and tumor lysis syndrome.

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

1. Age 18 to 70 years, male or female.
2. Voluntarily willing to participate in the study, able to understand and sign written informed consent, and willing to comply with study treatment, assessments, and follow-up.
3. Newly diagnosed with myelodysplastic syndromes with increased blasts-2 (MDS-IB2) according to the current World Health Organization (WHO) diagnostic criteria.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
5. Estimated life expectancy of at least 12 weeks.
6. Adequate organ function to tolerate study treatment, including:

   1. Total bilirubin ≤1.5 × upper limit of normal (ULN);
   2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN;
   3. Creatinine clearance ≥40 mL/min;
   4. Left ventricular ejection fraction (LVEF) ≥50%;
   5. Baseline oxygen saturation >92%.
7. Able to take oral medication and without gastrointestinal disorders that would significantly affect drug absorption.
8. Considered by the investigator to be able to safely receive sonrotoclax initiation and dose ramp-up.
9. Participants of childbearing potential must have a negative pregnancy test and agree to use effective contraception during the study and for the protocol-specified period after the last dose of study treatment.

Exclusion Criteria:

1. Disease already transformed to acute myeloid leukemia (AML).
2. Prior treatment with chemotherapy, sonrotoclax, or other BCL-2 inhibitors.
3. Uncontrolled active infection, including severe bacterial, fungal, or viral infection.
4. Active hepatitis B, hepatitis C, human immunodeficiency virus (HIV) infection, or active tuberculosis that is not adequately controlled.
5. Significant uncontrolled cardiac, hepatic, renal, or other major organ dysfunction that, in the investigator's judgment, would preclude safe study treatment.
6. Active graft-versus-host disease (GVHD) after prior allogeneic hematopoietic stem cell transplantation or ongoing requirement for systemic immunosuppressive therapy.
7. Anticipated need for continuous use of a strong CYP3A inhibitor during sonrotoclax initiation and dose ramp-up that cannot be discontinued or replaced.
8. Uncontrolled high risk of tumor lysis syndrome (TLS) that, in the investigator's judgment, makes the participant unsuitable for sonrotoclax treatment.
9. Pregnant or breastfeeding women.
10. Known severe hypersensitivity to sonrotoclax, azacitidine, or any of their excipients.
11. Concurrent participation in another interventional clinical study without meeting applicable discontinuation requirements.
12. Any other condition that, in the investigator's judgment, makes the participant unsuitable for participation in the study.