Phase IIa Study to Assess Safety and Efficacy in the Relapsed/Refractory Acute Myeloid Leukemia

Safety and Efficacy of QHRD107 Capsule Combined With Venclexta and Azacitidine in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia: a Single-arm, Open, Multicenter Phase IIa Study

The purpose of this study is to assess the safety and efficacy of QHRD107 capsule combined with Venclexta and azacitidine in the treatment of relapsed/refractory acute myeloid leukemia: a single-arm, open, multicenter Phase IIa study

This study is a single-arm, open, multicenter phase IIa clinical study, which is divided into two stages: the dose-increasing study phase and the dose-expanding exploration phase. The purpose of the dose-escalation phase is to explore the safety and tolerability of QHRD107 capsule（40mgBID,60mgBID and 80mgBID） combined with Venclexta and azacitidine, to evaluate the efficacy of the three-drug combination in subjects with relapsed/refractory acute myeloid leukemia (R/R-AML), and to explore the pharmacokinetic characteristics of the combination. The dose expansion stage aims to further evaluate the safety, efficacy, pharmacodynamics and pharmacokinetics of QHRD107 capsule（60mgBID and 80mgBID）combined with Venclexta and azacitidine on the basis of exploring the safe dose range determined in the dose escalation stage, and determine the recommended dose for subsequent clinical studies

Inclusion Criteria:

1. Understand and voluntarily sign informed consent;

2. Age 18 and above;

3. Subjects with confirmed International Consensus Classification (ICC) relapsed/refractory acute myeloid leukemia (R/R-AML) :

   Recurrence was defined as the recurrence of leukemia cells in peripheral blood or ≥5% of bone marrow original cells after complete response (except for other reasons such as bone marrow regeneration after consolidation chemotherapy) or the occurrence of extramedullary leukemia cell infiltration.

   Refractory is defined as meeting any of the following criteria:

   1. Initial treatment cases that failed after 2 courses of treatment with standard protocols;
   2. Relapse within 12 months after complete remission (CR) after consolidation and intensive treatment;
   3. Recurrence after 12 months but failed to respond to conventional chemotherapy;
   4. Two or more relapses.

4. ECOG evaluation ≤2 points;

5. Expected survival ≥3 months;

6. White blood cell (WBC) count <25×109 cells /L (hydroxyurea is allowed to control the white blood cell count before treatment);

7. Subjects must have adequate liver function: total bilirubin (TBIL) ≤1.5× upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN;

8. Subjects must have adequate renal function: creatinine clearance ≥50 mL/min (calculated using the Cockroft-Gault formula);

9. The subject has recovered from previous therapeutic toxicity to < grade 2 (according to CTCAE 5.0 criteria), excluding primary disease effects. The following are excluded: hair loss, fatigue, hyperpigmentation, stable hypothyroidism with hormone replacement therapy, peripheral nerve toxicity after chemotherapy;

10. Eluting period from the first administration of antitumor therapy: a) At least 2 weeks between the end of cytotoxic chemotherapy drug treatment; b) Non-cytotoxic drugs should be separated by at least 5 half-lives (if the duration of 5 half-lives exceeds 4 weeks, the washout period is still measured by 4 weeks), and the interval > 4 weeks shall prevail if the half-life is not clear; c) Anti-tumor Chinese medicine at least 2 weeks interval;

11. Ability to understand and conduct visits, treatments, laboratory tests, and other research procedures as planned;

12. Male/female subjects with reproductive potential must use effective contraception from the date of signing the informed consent until 6 months after the last trial medication. At the same time, male subjects with reproductive potential must refrain from sperm donation from signing their informed consent until six months after the last trial medication.

Exclusion Criteria:

1. Subjects previously treated with other CDK9 inhibitors;
2. Subjects who are allergic to the active ingredients and/or excipients of the investigational drugs (QHRD107, Veneckla, and azacytidine);
3. Subjects with a history of myeloproliferative tumors (MPN);
4. Subjects with a history of chronic myeloid leukemia (CML);
5. Subjects with Ph chromosome-positive or BCR-ABL fusion gene positive acute myeloid leukemia (AML);
6. Confirmed acute promyelocytic leukemia;
7. Patients with AML central nervous system infiltration;
8. Subjects with extramedullary leukemia (such as myeloid sarcoma, skin infiltration, etc.) (except extramedullary lesions such as liver, spleen, and lymph node involvement);
9. Human immunodeficiency virus (HIV) antibody positive subjects; Subjects with active HBV infection: hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive, and peripheral blood hepatitis B virus (HBV-DNA) higher than the upper limit of normal; Subjects with active HCV infection: HCV antibody positive, peripheral blood HCV RNA positive;
10. The subject has an active infection (including bacterial, viral, and fungal infections) that requires systemic antibiotic treatment as determined by the investigator to be clinically significant;
11. People with significant active cardiovascular disease within the previous 6 months, including but not limited to: ≥III Heart failure as defined by the New York Heart Association (NYHA); Angina pectoris requiring surgical treatment, unstable angina pectoris, myocardial infarction; Hypertension that remains poorly controlled after treatment (i.e., systolic ≥160 mmHg, diastolic ≥90 mmHg); Uncontrolled arrhythmias; The left ventricular function resting ejection fraction measured by echocardiography was less than 50%. QT interval: > 450 ms for men and > 470 ms for women (according to the QTcF formula), or are on medication known to lengthen the QT/QTc interval, or have other factors that may lengthen the QTc interval; Or for patients whose QT interval is still > 450 ms after QT interval prolongation treatment;
12. Patients who have received allogeneic hematopoietic stem cell transplantation within 60 days of their initial investigational treatment must discontinue all immunosuppressants during the investigational treatment;
13. Patients who have previously received CAR-T therapy;
14. The subject has a malabsorption syndrome or other comorbid condition that prevents him from swallowing the capsule or administering the drug through enteral channels;
15. A history of other malignancies in the past 5 years, excluding cured basal cell carcinoma of the skin, localized squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or carcinoma in situ of the breast;
16. Pregnant or lactating women, or subjects who are fertile and do not want to take effective contraceptive measures;
17. Any ill-controlled clinical problems (such as severe psychiatric, neurological, cardiovascular, respiratory, digestive, urinary, etc.) or other factors that the investigator believes prevented the subject from completing the study.