Phase 1b/2a Study of Azd4573 (cdk9i) and Acalabrutinib in Patients (pts) With Relapsed/refractory Diffuse Large B‐cell Lymphoma (r/r Dlbcl)
Year: 2023
Type: article
Abstract: Introduction: AZD4573, a potent and highly selective CDK9i, 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 cancers and antitumour activity in those with DLBCL. In the current multicenter, open-label, Phase 1b/2a study (NCT04630756), initial results showed that AZD4573 up to 12 mg QW IV + acalabrutinib 100 mg continuously PO BID had manageable safety (no dose-limiting toxicities [DLTs]) and encouraging activity in pts with r/r DLBCL (Strati, ASH 2022, abs 2962). Here we report pooled data from the completed Phase 1b and ongoing Phase 2a expansion. Methods: Pts were ≥18 years old with ECOG PS ≤2, and had received ≥2 prior lines of therapy (stem cell transplant, T cell engagers [TCEs] and/or CAR-T were allowed). Following a 3-wk intra-pt ramp-up, pts received AZD4573 QW at target doses of 9 mg (Cohort 1) or 12 mg (Cohort 2). Dose escalation used the mTPI-2 model. 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 2 December 2022, 27 pts were treated: 8 in Cohort 1 and 19 in Cohort 2 (11 pts in escalation, 16 pts in expansion; pooled data is presented by dose). Median age was 60 yrs, 59.3% of pts were male, and median number of prior lines of treatment was 4 (range 2–6). 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. Response was evaluable in 24 pts, 8 in Cohort 1 and 16 in Cohort 2; 11/24 had prior CAR-T and 5/24 had prior TCE. The ORR was 50.0% (95% CI 29.1, 70.9) and the CR rate was 25%. Responses occurred in both Cohorts. Median duration of response was 6.8 mos. Responses were noted in 5/11 pts with prior CAR-T (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 PK was linear (half-life ∼6 hrs) with dose-dependent increases in exposure (Cmax and AUC) and target coverage. No DLTs were identified and both doses were expanded. Safety was evaluable in 27 pts. The most common TEAEs were primarily laboratory-based. ALT/AST and bilirubin increases were mainly due to down-modulation of hepatic transporter proteins and reduced enzyme clearance, not direct hepatocellular injury; all were short-lived with spontaneous resolution and caused no treatment delays. Neutropenia occurred in 92.6% of pts but was manageable with G-CSF; 4/27 pts (14.8%) had Grade ≥3 infections. One pt discontinued due to AZD4573-related Grade 2 fatigue. Conclusions: AZD4573 + acalabrutinib had manageable safety with no new signals. Clinical activity was promising with durable responses in heavily pretreated pts, including those with prior CAR-T. More mature data will be presented at the conference. Encore Abstract—previously submitted to EHA 2023 The research was funded by: AstraZeneca Keywords: aggressive B-cell non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract A. Danilov Consultant or advisory role: AbbVie, AstraZeneca, Bayer Oncology, BeiGene, Bristol Myers Squibb, Genentech, GenMab, Incyte, Lilly Oncology, Nurix, Oncovalent, Pharmacyclics and TG Therapeutics Research funding: AbbVie, AstraZeneca, Bayer Oncology, Bristol Myers Squibb, Cyclacel, Lilly Oncology, MEI Pharma, Nurix and Takeda Oncology G. P. Gregory Consultant or advisory role: Merck, Roche, Janssen, Novartis, BMS, Link Clinigen Honoraria: Roche, Merck Research funding: BeiGene, AbbVie, Janssen, Merck F. Morschhauser Consultant or advisory role: Genmab, Novartis, Gilead, Roche C. Y. Cheah Consultant or advisory role: Roche, Janssen, Gilead, AstraZeneca, Lilly, TG therapeutics, BeiGene, Novartis, Menarini, Dizal, AbbVie, Genmab, BMS Honoraria: Roche, Janssen, Gilead, AstraZeneca, Lilly, TG therapeutics, BeiGene, Novartis, Menarini, Daizai, AbbVie, Genmab Research funding: BMS, Roche, AbbVie, MSD, Lilly H. Shah Consultant or advisory role: Seattle Genetics, AstraZeneca Research funding: Epizyme, AstraZeneca, Seattle Genetics, ADC Therapeutics W. Jurczak Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Lilly, Roche, Takeda Research funding: AbbVie, AstraZeneca, BeiGene, Janssen, Lilly, Merck, Morphosys, Roche, Takeda D. Olabode Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca S. Meyer Employment or leadership position: AstraZeneca J. L. Yoon Employment or leadership position: AstraZeneca S. Arduini Employment or leadership position: AstraZeneca J. Saeh Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca R. F. Olsson Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca P. Strati Consultant or advisory role: Roche-Genentech, Kite-Gilead, Hutchinson MediPharma, AstraZeneca-Acerta, ADC Therapeutics, Sobi and TG Therapeutics Research funding: AstraZeneca-Acerta, ALX Oncology and ADC Therapeutics
Source: Hematological Oncology
DOI: 10.1002/hon.3163_87
Institutions: City Of Hope National Medical Center, City of Hope, Monash Health, Monash University, Centre Hospitalier Universitaire de Lille, Hôpital Claude Huriez, The University of Western Australia, Sir Charles Gairdner Hospital, University of Utah, Huntsman Cancer Institute, The Maria Sklodowska-Curie National Research Institute of Oncology, AstraZeneca (United States), AstraZeneca (United Kingdom), AstraZeneca (Sweden), The University of Texas MD Anderson Cancer Center
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4380082894