Phase II Study of Sonrotoclax Combined With Chemotherapy in the Treatment of Newly Diagnosed Acute Myeloid Leukemia

Risk-stratified Treatment of Sonrotoclax Combined With Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia: a Multicenter, Phase II Study

This single-armed study aims to investigate the safety and efficacy of sonrotoclax in combination with intensive chemotherapy in subjects with newly diagnosed AML. Subjects will be stratified based on the genetic risk classification of 2022 European LeukemiaNet (ELN) recommendations and MRD status to receive specific consolidation therapy after the induction therapy.

47 subjects who meet the eligibility criteria will receive no more than 2 cycles (each cycle is 28 days) of induction therapy with sonrotoclax on day5-14 combined with the standard 3+7 intensive chemotherapy regimen (3+7 regimen) containing cytarabine, and daunorubicin or idarubicin. In cycle(C)1 of induction therapy, sonrotoclax will be administered orally once daily by a 4-day dose rump-up of 20mg on Day(D)5, 40mg on D6, 80mg on D7, and 160mg on D8-14. The first 6 subjects will be enrolled in a Safety Run-in period in C1 to assess tolerability and determine the final sonrotoclax regimen. Within 42 days or before the next cycle of therapy, if ≤1 of 6 subjects has dose-limiting toxicities (DLT), the study will be continued with the sonrotoclax dose regimen as above, and if ≥2 of 6 subjects have DLTs, the dose will be adjusted. Adjustment may include reducing the dose, shortening the duration of each cycle, or terminating the study, based on the DLTs' characteristics.

Subjects who achieve a composite complete remission (CRc) after induction therapy will receive further consolidation therapy, which regimen will be decided based on the ELN risk at diagnosis and MRD status detected by MFC after induction therapy.

After consolidation, subjects will receive once daily sonrotoclax orally combined with azacitidine (AZA) subcutaneously once daily alternating with AZA monotherapy every 2 cycles as maintenance therapy until unacceptable toxicity, 12 months, recurrence, death, withdrawal of informed consent, or study termination determined by investigators.

This single-armed study aims to investigate the safety and efficacy of a risk-stratified regimen of sonrotoclax in combination with intensive chemotherapy in subjects with newly diagnosed AML.

Inclusion Criteria:

1. Newly diagnosed untreated acute myeloid leukemia patients;

2. Age range from 18 to 75 years old;

3. The Eastern Cooperative oncology Group (ECOG) score is ≤ 2 points;

4. The following organ functional conditions must be met:

   • Liver function (bilirubin<2mg/dL, AST and/or ALT<3 x ULN)
   • Renal function (blood creatinine clearance rate ≥ 30 mL/min)
   • Cardiac function (left ventricular ejection fraction ≥ 50%)

5. If the age is ≥ 60 years old, the following conditions must be further met;

   • Charlson comorbidity index (CCI) ≤ 1
   • Activity of Daily Living Scale (ADL)>100
   • No cognitive impairment, Mini Mental State Examination (MMSE) ≥ 28
   • No impairment of living ability, Short Physical Performance Battery Protocol (SPPB) ≥ 9

6. Women with fertility must have a negative serum pregnancy test ≤ 7 days before the first administration. In addition, they must use efficient contraceptive methods before the first dose of study medication, during the study treatment period, and for ≥ 180 days after the last dose of study medication.

7. Non infertile males must use efficient contraceptive methods during the study treatment period and within ≥ 90 days after the last dose of the study medication. During this period, they are not allowed to donate sperm.

8. The patient fully understands this study, obtains an informed consent form (ICF) signed by the patient or their legal representative, and follows the research protocol and follow-up process.

9. The expected lifespan is greater than 12 weeks.

Exclusion Criteria:

1. Acute promyelocytic leukemia (APL)；
2. Malignant tumor in the past 2 years, except for cured localized skin cancer, superficial bladder cancer, cervical cancer or cancer in situ of breast cancer, and localized prostate cancer with Gleason score ≤ 6;
3. Uncontrolled concurrent diseases, including but not limited to: ongoing or active uncontrolled infections, cardiovascular or mental illnesses/social situations that may limit compliance with research requirements;
4. It is known that the subjects are positive for hepatitis B or hepatitis C infection, except those whose viral load cannot be detected within 3 months (Note: patients with HBcAb+but HBsAg - can only meet the condition if hepatitis B virus (HBV) DNA cannot be detected in the detection with sensitivity ≤ 20 IU/mL. In this case, patients should receive regular monitoring of HBV DNA and receive prophylactic antiviral drug treatment according to the central diagnosis and treatment routine; Patients with HCV antibody+are eligible only if they cannot detect HCV RNA and are willing to monitor HCV reactivation；
5. Receive any moderate or strong CYP3A4 inhibitor (7 days or 5 half-lives, whichever is longer) or moderate or strong CYP3A4 inducer (14 days or 5 half-lives, whichever is longer) treatment before the first use of Sonrotoclax；
6. Patients who are known to have hypersensitivity reactions to any component in the study protocol;
7. Known central nervous system involvement in AML;
8. Previously received organ, bone marrow, or peripheral blood organ transplantation；
9. Participate in another therapeutic clinical study simultaneously；
10. Pregnant or lactating women, or male and female patients planning to have children during the study period.