Phase I/II results of ceralasertib as monotherapy or in combination with acalabrutinib in high-risk relapsed/refractory chronic lymphocytic leukemia

Wojciech Jurczak; Nagah Elmusharaf; Christopher P Fox; William Townsend; Amanda G Paulovich; Jeffrey R Whiteaker; Fanny Krantz; Chuan-Chuan Wun; Graeme Parr; Shringi Sharma; Veerendra Munugalavadla; Richa Manwani; Emma Dean; Talha Munir

doi:10.1177/20406207231173489

Phase I/II results of ceralasertib as monotherapy or in combination with acalabrutinib in high-risk relapsed/refractory chronic lymphocytic leukemia

Ther Adv Hematol. 2023 May 30:14:20406207231173489. doi: 10.1177/20406207231173489. eCollection 2023.

Authors

Affiliations

¹ Maria Sklodowska-Curie National Institute of Oncology, Garncarska 11, 31-115 Krakow, Poland.
² University Hospital of Wales, Cardiff, UK.
³ Nottingham University Hospitals, Nottingham, UK.
⁴ NIHR Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK.
⁵ Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁶ AstraZeneca, South San Francisco, CA, USA.
⁷ Oncology R&D, AstraZeneca, Cambridge, UK.
⁸ St. James's University Hospital, Leeds, UK.

Abstract

Background: Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) have limited treatment options. Ceralasertib, a selective ataxia telangiectasia and Rad-3-related protein (ATR) inhibitor, demonstrated synergistic preclinical activity with a Bruton tyrosine kinase (BTK) inhibitor in TP53- and ATM-defective CLL cells. Acalabrutinib is a selective BTK inhibitor approved for treatment of CLL.

Objectives: To evaluate ceralasertib ± acalabrutinib in R/R CLL.

Design: Nonrandomized, open-label phase I/II study.

Methods: In arm A, patients received ceralasertib monotherapy 160 mg twice daily (BID) continuously (cohort 1) or 2 weeks on/2 weeks off (cohort 2). In arm B, patients received acalabrutinib 100 mg BID continuously (cycle 1), followed by combination treatment with ceralasertib 160 mg BID 1 week on/3 weeks off from cycle 2. Co-primary objectives were safety and pharmacokinetics. Efficacy was a secondary objective.

Results: Eleven patients were treated [arm A, n = 8 (cohort 1, n = 5; cohort 2, n = 3); arm B, n = 3 (acalabrutinib plus ceralasertib, n = 2; acalabrutinib only, n = 1)]. Median duration of exposure was 3.5 and 7.2 months for ceralasertib in arms A and B, respectively, and 15.9 months for acalabrutinib in arm B. Most common grade ⩾3 treatment-emergent adverse events (TEAEs) in arm A were anemia (75%) and thrombocytopenia (63%), with four dose-limiting toxicities (DLTs) of grade 4 thrombocytopenia. No grade ⩾3 TEAEs or DLTs occurred in arm B. Ceralasertib plasma concentrations were similar when administered as monotherapy or in combination. At median follow-up of 15.1 months in arm A, no responses were observed, median progression-free survival (PFS) was 3.8 months, and median overall survival (OS) was 16.9 months. At median follow-up of 17.2 months in arm B, overall response rate was 100%, and median PFS and OS were not reached.

Conclusion: Ceralasertib alone showed limited clinical benefit. Acalabrutinib plus ceralasertib was tolerable with preliminary activity in patients with R/R CLL, though findings are inconclusive due to small sample size.

Registration: NCT03328273.

Keywords: acalabrutinib; ceralasertib; chronic lymphocytic leukemia; molecular targeted therapy.

Associated data

ClinicalTrials.gov/NCT03328273

Abstract

Associated data

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