P1126: phase 1b/2a study of azd4573 (cdk9i) and acalabrutinib in patients (pts) with relapsed/refractory diffuse large b-cell lymphoma (r/r dlbcl)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Despite recent major advances in the treatment of DLBCL using CAR-T and bispecific T-cell engagers (TCEs), pts with r/r disease continue to have unmet medical needs. AZD4573, a potent and highly selective CDK9 inhibitor, rapidly induces apoptosis in human haematologic cancer cell lines. In a first-in-human trial, AZD4573 monotherapy had manageable safety in pts with r/r haematologic malignancies and signs of antitumour activity in those with DLBCL. In the current multicenter, open-label, Phase 1b/2a study (NCT04630756), initial results showed that the escalation of AZD4573 up to the monotherapy RP2D of 12 mg QW plus acalabrutinib 100 mg continuously PO BID had manageable safety (no dose-limiting toxicities) and encouraging response rates in pts with r/r DLBCL (Strati, ASH 2022). Aims: Here we report pooled data from the completed Phase 1b and the ongoing Phase 2a expansion. Methods: Eligible pts were ≥18 years old with ECOG PS ≤2, and had received ≥2 prior lines of therapy (stem cell transplant, TCEs and/or CAR-T were allowed). Following a 3-week intrapatient ramp-up in Cycle 1, pts received AZD4573 IV QW at target doses of 9 mg (Cohort 1) or 12 mg (Cohort 2). The dose-escalation used the mTPI-2 model. Treatment continued until progressive disease or unacceptable toxicity. Objectives included ORR, safety and PK. Responses were assessed by Lugano 2014 criteria and adverse events (AEs) graded using CTCAE v5.0. Results: As of December 2, 2022, 27 pts were treated: 8 in Cohort 1 and 19 in Cohort 2 (11 pts were in the escalation phase and 16 were in the expansion phase; pooled data from both phases is presented here by dose level). Median age was 60 yrs, 59.3% of pts were male, and median number of prior lines of treatment was 4 (range 2–6). Response was evaluable in 24 pts, 8 in Cohort 1 and 16 in Cohort 2. Of these 24 pts, 11 had prior CAR-T and 5 had prior TCE. The ORR for the total population was 50.0% (95% CI 29.1, 70.9) including 25% with CRs. Responses occurred in both Cohorts. Median duration of response was 6.8 months. Notably, 5/11 pts with prior CAR-T therapy responded to treatment (ORR 45.5%; 95% CI 16.7, 76.6), including 3 CRs in Cohort 2 and 2 PRs in Cohort 1. Responses were seen in both GCB (7 evaluable pts; 2 CRs/1 PR) and non-GCB (8 evaluable pts; 2 CRs/2 PRs) subtypes. AZD4573 showed linear PK (half-life ~6 hrs) with dose-dependent increases in exposure (Cmax and AUC) and target coverage (pSER2, cleaved caspase-3 activation). No DLTs were identified at either dose level and both were expanded. Median duration of AZD4573 treatment was 14.9 wks (range, 1–74) in Cohort 1 and 8.9 wks (range, 1–38) in Cohort 2. Safety was evaluable in 27 pts. The most common any-grade TEAEs were primarily laboratory-based and included neutropenia (92.6%), ALT increase, AST increase, thrombocytopenia and nausea (each 44.4%). Neutropenia was manageable with G-CSF; 4/27 pts (14.8%) had grade ≥3 infections. ALT/AST and bilirubin elevations were mainly due to down-modulation of hepatic transporter proteins and reduced enzyme clearance rather than direct hepatocellular injury; they were all short-lived with spontaneous resolution and did not cause any treatment delays. One pt discontinued AZD4573 due to Grade 2 fatigue related to AZD4573. Summary/Conclusion: AZD4573 plus acalabrutinib had a manageable safety profile with no new safety signals. The combination showed promising clinical activity with durable responses in this heavily pretreated population, including pts with prior CAR-T. The study is ongoing and more mature data will be presented at the conference.Keywords: Phase I/II, Diffuse large B cell lymphoma, relapsed/refractory, Clinical trial