Ceralasertib Plus Acalabrutinib Shows Early Activity in High-Risk Relapsed/Refractory CLL

The combination of ceralasertib (AZD6738) and acalabrutinib (Calquence) showed preliminary clinical activity with acceptable tolerability in patients with high-risk, relapsed/refractory chronic lymphocytic leukemia (CLL), according to data from a phase 1/2 trial (NCT03328273).¹ However, the use of ceralasertib alone resulted in limited clinical benefit, and the study has since been terminated due to the evolving treatment landscape.

Data, which were presented during the 2022 AACR Annual Meeting, showed that among the 3 patients who received the combination (arm B), the overall response rate (ORR) was 100% (80% CI, 48%-100%), with all patients experiencing partial responses. The median duration of response (DOR) was not yet reached in this arm. Among the 8 patients who received ceralasertib monotherapy (arm A), the ORR was 0%.

At a median follow-up of 15.9 months, the median progression-free survival (PFS) in arm A was 3.8 months (95% CI, 0.7-4.6) vs not reached (NR) in arm B. Moreover, the median overall survival (OS) in arm A was 16.9 months (95% CI, 6.6–not evaluable) vs NR in arm B.

“Ceralasertib monotherapy in BTK inhibitor–exposed, high-risk CLL patients showed limited clinical benefit,” lead study author Wojciech Jurczak, MD, PhD, of Maria Sklodowska-Curie National Institute of Oncology, and colleagues, wrote in a poster on the data. “Acalabrutinib plus ceralasertib was tolerable with preliminary clinical activity in patients with CLL and del(11q).”

Patients with CLL who relapse on B-cell receptor–targeted therapies have limited options available to them. Ceralasertib has been found to produce synthetic lethality, be able to overcome resistance to chemotherapy, and to induce synergistic activity with a BTK inhibitor in CLL cells that are TP53 and ATM defective.

Acalabrutinib has also improved progression-free survival (PFS) when used as a single agent and in combination with obinutuzumab (Gazyva) in patients with treatment-naïve CLL, including those with high-risk genomic features, according to data from the phase 3 ELEVATE-TN trial (NCT02475681).^2,3 The agent also significantly improved PFS in those with relapsed/refractory CLL.^4,5

Investigators initiated this phase 1/2 multicenter, nonrandomized, open-label trial to evaluate ceralasertib alone and in combination with acalabrutinib in those with relapsed/refractory CLL.

The trial was comprised of 2 arms. Those in arm A had relapsed/refractory disease and del(17p), TP53mutation, or del(11q) who had exhausted all available options. Those in arm B had relapsed/refractory disease and del(11q) mutations who were eligible for BTK inhibitors and ceralasertib, based on investigator judgment.

Arm A included 2 cohorts of patients; cohort 1 received continuous ceralasertib at a twice-daily dose of 160 mg and those in cohort 2 were given the same twice-daily dose on a 2-weeks-on and 2-weeks-off schedule. After those in cohort 1 experienced 2 or more dose-limiting toxicities (DLTs), they went included in cohort 2.

Those who comprised arm B received single-agent acalabrutinib at a twice-daily dose of 100 mg continuously in cycle 1. In cycle 2 and onward, patients were given acalabrutinib at a twice-daily, continuous dose of 100 mg in combination with ceralasertib at a twice-daily dose of 160 mg for a 1-week-on/1-week-off schedule.

The primary objectives of the study included safety and pharmacokinetics. The secondary objective of the trial was clinical activity in the form of ORR, complete response rate, DOR, PFS, and OS.

At a data cutoff date of September 7, 2021, the median range of treatment duration was 3.7 months (range, 0.5-9.5) for ceralasertib and 15.9 months (range, 9.7-18.4) for acalabrutinib.

The median age of all 11 patients was 64 years (53.0-74.0), and 91% were male. The majority of patients received 3 or more prior anticancer systemic regimens (73%) and had relapsed disease (82%). Fifty-five percent of patients had del(11q), 45% had TP53 mutations, and 27% had del(17p). All patients previously received an anti-CD20 monoclonal antibody. Other prior therapies included an alkylating agent (91%), a BTK inhibitor (64%), a purine analogue (91%), a BCL-2 inhibitor (36%), or an allogenic stem cell transplant (9%).

At the time of data cutoff, all patients had discontinued treatment with ceralasertib. All 3 patients on arm B received acalabrutinib, 2 of whom received it in combination with ceralasertib, and they were still on acalabrutinib.

Among those in arm A, 4 DLTs of grade 4 thrombocytopenia were experienced by 3 patients; 3 occurred in 2 patients enrolled to cohort 1 and 1 occurred in 1 patient in cohort 2. No DLTs were experienced in arm B. All patients in arm A experienced grade 3 or higher treatment-emergent adverse effects (TEAEs) vs no patients in arm B. Notably, no patients discontinued treatment because of toxicity in either arm. No fatal AEs were reported.

TEAEs included anemia, thrombocytopenia, cough, diarrhea, fatigue, nausea, upper repository tract infection, constipation, confusion, decreased appetite, dyspnea, epistaxis, insomnia, neutropenia, oropharyngeal pain, and vomiting. The most common grade 3 or higher TEAEs were anemia (55%) and thrombocytopenia (45%).

Serious AEs were experienced by 7 patients, which included 6 patients in arm A and 1 patient in arm B. In arm A, 63% of patients experienced a SAE of anemia and 38% experienced thrombocytopenia. These effects were determined to be associated with ceralasertib only in cohort 1 patients. In arm B, 1 patient experienced a SAE of COVID-19.

Five patients died, all of whom were in arm A. Four deaths were because of disease progression and 1 was from an unknown cause.

References

1. Jurczak W, Elmusharaf N, Fox CP, et al. Phase 1/2 results of ceralasertib as monotherapy or in combination with acalabrutinib in high-risk relapsed/refractory chronic lymphocytic leukemia. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT532.
2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naïve chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2
3. Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia. Leukemia. 2022;36(4):1171-1175. doi:10.1038/s41375-021-01485-x
4. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355
5. Jurczak W, Pluta A, Wach M, et al. Three-year follow-up of the Ascend trial: acalabrutinib vs rituximab plus idelalisib or bendamustine in relapsed/refractory chronic lymphocytic leukemia. Blood. 2021;138(suppl 1):393. doi:10.1182/blood-2021-146570