Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 May 30:14:20406207231173489.
doi: 10.1177/20406207231173489. eCollection 2023.

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

Wojciech Jurczak  1 , Nagah Elmusharaf  2 , Christopher P Fox  3 , William Townsend  4 , Amanda G Paulovich  5 , Jeffrey R Whiteaker  5 , Fanny Krantz  6 , Chuan-Chuan Wun  6 , Graeme Parr  7 , Shringi Sharma  6 , Veerendra Munugalavadla  6 , Richa Manwani  7 , Emma Dean  7 , Talha Munir  8
Affiliations

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

Wojciech Jurczak et al. Ther Adv Hematol. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: WJ: Contract/grant – AstraZeneca, Janssen, and Lilly. NE: Conference registration grants – AbbVie; speakers fees – Roche and AstraZeneca. CPF: Consultancy and honoraria – AbbVie, Acerta Pharma/AstraZeneca, Atara Biotherapeutics, Celgene/BMS, GenMab, Gilead/Kite, Incyte, Lilly, Janssen, MorphoSys, Ono, Roche, and Takeda; research funding – BeiGene. WT: Consultancy and honoraria – BMS, Gilead, Incyte, and Roche; travel expenses – Gilead and Takeda. AGP: Consultancy – CellCarta; founder – Precision Assays. JRW: Consultancy – CellCarta. FK: Employment and stock ownership – AstraZeneca. CW: Employment – AstraZeneca. GP: Employment and stock ownership – AstraZeneca. SS: Employment and stock ownership – AstraZeneca. VM: Employment and stock ownership – AstraZeneca (a family member is an employee and stock owner of Gilead). RM: Employment and stock ownership – AstraZeneca. ED: Employment and stock ownership – AstraZeneca. TM: Honoraria – AstraZeneca, Alexion, Gilead, Novartis, Roche, Janssen, AbbVie; advisory board – AstraZeneca, AbbVie, Janssen, MorphoSys, Alexion.

Figures

Figure 1.
Figure 1.
Plasma concentration by visit for ceralasertib. n represents the total number of patients. Circles represent mean (±SD) concentrations (monotherapy) and the squares represent individual plasma concentrations (combination). C, cycle; D, day; h, hour; SD, standard deviation. aDay 1 represents C1D1 for monotherapy and C2D1 for combination treatment. bDay 7 (onward) represents C1D15, C1D22, and C2D15 for monotherapy and C2D7 for combination treatment.
Figure 2.
Figure 2.
Mean plasma concentration for acalabrutinib (a) and ACP-5862 (b) compared with historical data. For acalabrutinib and ACP-5862, n represents the total number of PK assessments available in a total of two patients at C1D7. Historical data are from PK assessments at C1D1 from the ELEVATE-TN study (data on file, AstraZeneca). The data represent mean (±SD) concentrations. C, cycle; CLL, chronic lymphocytic leukemia; D, day; h, hour; PK, pharmacokinetics; SD, standard deviation.
Figure 3.
Figure 3.
BTK target occupancy of samples from patients receiving acalabrutinib plus ceralasertib in arm B. BTK, Bruton tyrosine kinase; C, cycle; D, day. aAcalabrutinib monotherapy was administered during C1. bAcalabrutinib + ceralasertib were administered during C2.
Figure 4.
Figure 4.
PD changes in blood with ceralasertib monotherapy. Normalized light: heavy ratio measures endogenous (light) peptide relative to the stable isotope-labeled internal standard (heavy) peptide spiked into each sample. BID, twice daily; C, cycle; D, day; DBL, double baseline; pATM, phosphorylated ataxia telangiectasia mutated; PCNA, proliferating cell nuclear antigen; PD, pharmacodynamic. aPatient with del(11q)/del(17p) and TP53 and C481S mutation was treated with ceralasertib 160 mg BID continuously. bPatient with del(11q)/del(17p) was treated with ceralasertib 160 mg BID continuously. cPatient with TP53 and C481S mutation was treated with ceralasertib 160 mg BID for 2 weeks on and 2 weeks off.
Figure 5.
Figure 5.
Telomere length for patients on ceralasertib monotherapy. BID, twice daily; I, intermediate; S, short; w, week.
See this image and copyright information in PMC

References

    1. Hallek M, Cheson BD, Catovsky D, et al.. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 2018; 131: 2745–2760. - PubMed
    1. Forconi F, Lanham SA, Chiodin G. Biological and clinical insight from analysis of the tumor b-cell receptor structure and function in chronic lymphocytic leukemia. Cancers 2022; 14: 663. - PMC - PubMed
    1. Dreger P, Ghia P, Schetelig J, et al.. High-risk chronic lymphocytic leukemia in the era of pathway inhibitors: integrating molecular and cellular therapies. Blood 2018; 132: 892–902. - PubMed
    1. Hallek M, Al-Sawaf O. Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures. Am J Hematol 2021; 96: 1679–1705. - PubMed
    1. Kwok M, Davies N, Agathanggelou A, et al.. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells. Blood 2016; 127: 582–595. - PubMed

Associated data