P1141: ENCOURAGING COMPLETE RESPONSES (CRS) OBSERVED WITH CDK9 INHIBITOR AZD4573 IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY (R/R) PERIPHERAL T-CELL LYMPHOMA (PTCL): EARLY TRIAL ANALYSIS

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Patients with r/r PTCL have limited treatment options and poor outcomes to standard of care therapy. CDK9 regulates transcription elongation through phosphorylation of RNA polymerase II. AZD4573 is a highly potent and selective CDK9 inhibitor that downregulates short-lived transcripts and labile proteins such as MCL1, BFL1, and MYC, which are overexpressed in haematologic tumours, including T cell lymphoma. Based on preclinical experiments using T cell lines, and primary PTCL samples, AZD4573 demonstrated in vitro and in vivo activity against T cell lymphoma through caspase activation (Cidado, Clin Cancer Res 2020;26:922–34). In a phase 1, first-in-human study in pts with haematologic malignancies, the recommended phase 2 dose of AZD4573 monotherapy was 12 mg IV QW (Brümmendorf, ASH 2022, abs 1353). Aims: To determine the efficacy and safety of AZD4573 monotherapy in pts with r/r PTCL, in a phase 2a study (NCT05140382). Methods: Pts in this single-arm, open-label study were ≥18 years old, had ECOG PS ≤2, and ≥1 prior line of therapy including an alkylating agent and/or anthracycline. Pts with primary cutaneous or primary leukemic PTCL subtypes were excluded. Each pt received an intra-pt ramp-up of AZD4573: 6 mg on day 1, 9 mg on day 8, then the target dose of 12 mg on day 15, continuing weekly thereafter. The primary objective was efficacy by ORR per investigator assessment (Lugano criteria); secondary objectives included efficacy by complete response rate, duration of response, progression-free survival and overall survival; safety and tolerability; and pharmacokinetics (PK). Results: Eighteen pts received AZD4573; median age was 63.0 years (range 45–83), 66.7% were male and median number of prior regimens was 3.0 (range: 1–9). At the 1 Feb 2023 data cutoff, efficacy was evaluable in 12 pts who had received at least one 12 mg dose. The ORR rate was 3/12 (25.0%, all CRs) in the efficacy-evaluable set (Table). The CRs lasted 7.7 wks to 17.4+ wks. An additional CR was observed in a pt after an initial progressive disease (PD). Safety was evaluable in 18 pts who received ≥1 dose. Treatment-emergent adverse events (TEAEs) occurred in 16 pts (88.9%), all of which were Grade ≥3. Key Grade ≥3 TEAEs were neutropenia (55.6%) and increased aspartate aminotransferase (22.2%). Two pts had TEAEs leading to discontinuation (11.2%; hospitalisation and septic shock, n=1 each). Serious TEAEs were reported in 72.2% and were deemed treatment-related by investigators in 61.1%. Grade 5 treatment-related AEs were reported in 2 pts (11.1%, both septic shock). AZD4573 exhibited linear PK (half-life ~6 hrs) with dose-dependent increases in exposure (Cmax and AUC). Conclusion: Preliminary results show encouraging clinical activity with AZD4573 monotherapy in pts with r/r PTCL, including 3 CRs and one complete metabolic response after initial PD. The PK and safety profiles of AZD4573 monotherapy in PTCL are consistent with the previous phase 1 study with no unexpected findings, and the study continues to expand in the PTCL population.Keywords: Clinical trial, Phase II, relapsed/refractory, Peripheral T-cell lymphoma