Phase 1b/2a Study of AZD4573 (CDK9i) and Acalabrutinib in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (r/r DLBCL): Results from Dose-Escalation

Abstract

Background: Inhibition of Cyclin-dependent kinase 9 (CDK9), a transcriptional regulator, leads to short-term reduction of anti-apoptotic and oncogenic proteins. AZD4573, a potent and highly selective inhibitor of CDK9, triggers downregulation of MCL-1, BFL-1 and MYC, rapidly inducing apoptosis in human hematological cancer cell lines. The safety of AZD4573 as monotherapy was previously established in a Phase 1 trial in hematological malignancies (NCT03263637). Inhibition of Bruton tyrosine kinase with acalabrutinib increases expression of pro-apoptotic proteins such as Bim. Combining AZD4573 with acalabrutinib in DLBCL in in vitro models accelerates induction of cleaved Caspase-3, suggesting a synergistic mechanism that pushes malignant cells closer to their apoptotic threshold. Here, we report the dose-escalation of a multicenter, open-label, Phase 1b/2a study to assess safety and tolerability of AZD4573 with acalabrutinib in patients with r/r DLBCL (NCT04630756). Methods: Patients with r/r DLBCL with ≥2 prior lines of therapy (stem cell transplant or CAR-T allowed) were eligible. AZD4573 was given intravenously weekly and acalabrutinib 100 mg was given orally twice daily. In cycle 1, there was a weekly intrapatient dose ramp up of AZD4573 with a target dose of 9 mg in cohort 1 (3 mg, 6 mg, 9 mg) and 12 mg in cohort 2 (6 mg, 9 mg, 12 mg). Treatment was given until progressive disease/unacceptable toxicity. Responses were assessed by Lugano 2014 criteria and adverse events (AEs) were graded using CTCAE v5.0. The primary objective was to assess safety and determine the recommended phase 2 dose; pharmacokinetics and antitumor efficacy were secondary and exploratory endpoints, respectively. Results: As of August 2, 2022, 21 patients have been dosed. At data cutoff (DCO) on May 17, 2022, 13 patients were evaluable for safety (cohort 1, n=6; cohort 2, n=7) and 11 were evaluable for response (cohort 1, n=4; cohort 2, n=7). Median age was 61 years, 69.2% of patients were male, and median number of prior lines of treatment was 4 (range 2-8). The safety set included 8 DLBCL not otherwise specified (NOS), 1 high-grade B-cell lymphoma, 1 primary mediastinal B-cell lymphoma, and 3 patients with other subtypes, all T-cell rich. Cell of origin, determined locally, was reported in 10 patients (6 germinal center B-cell-like [GCB]; 4 non-GCB). At DCO, median duration of AZD4573 treatment was 4.0 weeks (range, 1-53) in cohort 1 and 12.6 weeks (range, 2-23) in cohort 2. AEs considered possibly related to either treatment occurred in 76.9% of patients and were grade ≥3 in 69.2% (Table 1). The most common AEs possibly related to AZD4573 were neutropenia (69.2%), thrombocytopenia (38.5%), alanine aminotransferase increased (38.5%) and aspartate aminotransferase increased (38.5%). Liver function test increases were short-lived with spontaneous resolution before subsequent weekly infusion. These findings were mainly due to down-modulation of hepatic transporter proteins and reduced clearance rather than hepatocellular impairment (based on clinical, in-vitro and in-silico assessments). Clinical tumor lysis syndrome (TLS) related to AZD4573 was not reported in cohort 1 and occurred in 1 of 7 patients in cohort 2 (TLS and transient 1.5xULN creatinine increase). No treatment-emergent AEs led to death. One patient in cohort 1 discontinued treatment due to grade 2 fatigue related to AZD4573. No dose limiting toxicities (DLTs) were observed in either cohort. The objective response rate (ORR) was 63.6% and the complete response (CR) rate was 36.4%. Of 4 response-evaluable patients in cohort 1, 1 had a CR and 1 had a partial response (PR), for an ORR of 50.0%. Of 7 evaluable patients in cohort 2, 3 had CRs and 2 had PRs, for an ORR of 71.4% (Table 2). Notably, 3/4 patients with prior CAR-T failure responded (2 CRs and 1 PR). Responses were seen in both GCB (1 CR/2 PRs in 5 evaluable patients) and non-GCB (2 CRs in 3 evaluable patients) subtypes. Conclusions: In this heavily pretreated population including CAR-T failures, the combination of AZD4573 and acalabrutinib resulted in high response rates (ORR 63.6%, CR rate 36.4%). No DLTs were detected, the combination was well tolerated with a manageable safety profile, and no new safety signals were identified. The study is currently enrolling in the Phase 2a expansion phase and updated data will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal