High Remission Rates in Relapsed/Refractory Acute Myeloid Leukemia with QHRD107 (CDK9 Inhibitor), Venetoclax, and Azacitidine Combination Therapy (107VA regimen) : Preliminary Results of a Phase 2a Study

Introduction: Cyclin-dependent kinase 9 (CDK9) plays a a crucial role in regulating gene transcription and the expression of oncogenes, including anti-apoptotic proteins essential for cancer cell survival. QHRD107, a potent CDK9 inhibitor, has demonstrated significant cytotoxic effects cross various human hematological malignancies. In a First-in-Human (FIH) study (CTR20190521), QHRD107 monotherapy showed clinically meaningful clinical responses and tolerable toxicity in patients with relapsed or refractory acute myeloid leukemia (r/r AML). Venetoclax (VEN) , a BCL-2 inhibitor, combined with azacitidine (AZA), a hypomethylating agent,has became the standard therapy for elderly or unfit AML patients. However, resistance and relapse are common. Given the observed synergistic anti-leukemic effects of QHRD107 combined with VEN and AZA in preclinical models, we aimed to explore this novel approach further. This study reports preliminary safety and efficacy data from a Phase 2a study (NCT06532058, CTR20232448) involving patients with r/r AML.

Methods: This Phase 2a, open-label, multicenter study evaluates the combination of QHRD107, VEN and AZA (107VA regimen) in pateints with r/r AML. The study consists of dose escalation and expansion phases. QHRD107 was administered orally twice daily at escalating doses (40 mg, 60 mg, and 80 mg). VEN was given orally once daily according to a ramp-up schedule to a maximum dose of 400 mg, and AZA was administered subcutaneously at 75mg/m² daily throughout the study. The dose escalation phase utilized a 3+3 design to determine the dose-limiting-toxicity (DLT), maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). The dose expansion phase planned to randomize 40 eligible patients1:1 to receive either 60 mg or 80 mg QHRD107 twice daily. Primary endpoints included overall response rate (ORR), defined as the sum of complete response (CR), complete response with partial hematological recovery (CRh), complete response with incomplete hematological recovery (CRi), morphologic leukemia-free state (MLFS), and partial response (PR), as well as composite complete remission rate (cCR), defined as CR + CRh + CRi. Blood samples were analyzed for pharmacokinetics (PK) and pharmacodynamics (PD).

Results: As of July 19, 2024, 28 patients were screened across 10 sites in China, with 24 treated with the 107VA regimen. Of these, 13 patients were enrolled in dose escalation phase and 11 in the expansion phase.

Median age was 58.5 years (IQR 47, 67.5), with 50% male, and a median 2 prior lines of therapy (IQR 1, 4); 62.5% had prior VEN-AZA therapy. According to the ELN 2022 classification, 70.8% of patients had intermediate or adverse-risk AML. No DLTs were observed in the dose escalation phase, establishing 80 mg of QHRD107 twice daily as the MTD . Due to high gastrointestinal toxicity, 60 mg and 80 mg doses were selected for the expansion phase.

Among 18 efficacy-evaluable patients, the ORR was 72.2% (CR: 5.6%, CRh: 11.1%, CRi: 16.7%, MLFS: 33.3%, PR: 5.6%), with a cCR rate of 33.3%. For patients who relapsed from VEN-AZA treatment, the ORR was 71.4% (CR: 7.1%, CRi: 14.3%, MLFS: 42.9%, PR: 17.1%). Measurable residual disease (MRD) negativity by flow cytometry was achieved as best response in 3 of the responding patients. Three patients with TP53 mutations previously treated with VEN-AZA achieved responses, including 1 case in CRi MRD- and 2 cases in MLFS.

Common non-hematologic treatment-related adverse effects (TRAE) included diarrhea (66.7%, 4.2% ≥ G3), hypokalemia (50.0%, 8.3% ≥ G3), hepatic injury (50.0%), vomiting (45.8%), nausea (33.3%), infection (41.7%, 25.0% ≥ G3), and lactate dehydrogenase increase (29.2%).

Conclusions: The 107VA regimen was well tolerated at tested doses and showed preliminarily activity in patients, with a high rate of cCR rate observed in those resistant to VEN-AZA therapy.