Acalabrutinib Elicits Early Activity in a Japanese Population With B-Cell Malignancies

Acalabrutinib elicited early antitumor activity with acceptable tolerability in a population of Japanese patients with relapsed/refractory B-cell malignancies.

Acalabrutinib (Calquence) elicited early antitumor activity with acceptable tolerability in a population of Japanese patients with relapsed/refractory B-cell malignancies, according to the results of a phase 1 study (NCT03198650) published in Cancer Science.1

Patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) who were treated with the agent achieved an overall response rate (ORR) of 89% (n = 8/9; 95% CI, 52%-100%), while those with relapsed/refractory mantle cell lymphoma (MCL) experienced an ORR of 62% (n = 8/13; 95% CI, 32%-86%). Moreover, the median progression-free survival (PFS) was not yet reached in the CLL/SLL cohort, while it was 7 months in the MCL cohort.

“This is the first clinical study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of the BTK inhibitor acalabrutinib in Japanese adults with relapsed/refractory B‐cell malignancies,” the study authors wrote. “We report that acalabrutinib was safe and well tolerated, and that treatment resulted in ORRs for relapsed/refractor CLL and relapsed/refractory MCL that were similar to those reported for non‐Japanese patient populations with relapsed/reractory B‐cell malignancies who were treated with acalabrutinib.”

BTK expression is known to be expressed in cells of hematopoietic origin, such as B cells, myeloid cells, mast cells, and platelets.2,3 BTK activation has been implicated in the pathogenesis of B-cell lymphomas and leukemias due to the fact that BTK-dependent signals are needed for their survival.4 These data support BTK inhibition in the treatment of patients with B-cell malignancies.

Although the potent, highly-selective, orally bioavailable small molecule BTK inhibitor acalabrutinib was approved in Japan in January 2021 for use in patients with relapsed/refractory CLL and SLL, it had not yet been evaluated in a Japanese patient population.5 To facilitate the approval process, investigators determined it necessary to conduct a study examining acalabrutinib in this population.

Investigators launched the multicenter, open-label, 3-part phase 1 study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of acalabrutinib in a Japanese population of adult patients with relapsed/refractory B-cell malignancies.

To be eligible for enrollment, Japanese patients needed to be aged 20 years or older at the time of enrollment with a measurable lymphadenopathy or extranodal lymphoid malignancy. Patients also needed to have an ECOG performance status of 0 to 2, acceptable hematologic and organ function, and a serum amylase of 1.5 times or lower than the upper limit of normal (ULN) or a serum lipase of 1.5 times or lower than the ULN.

Inclusion criteria related to diagnosis differed between part 1 and part 2 of the study. Part 1 enrolled patients with nongerminal center diffuse large B-cell lymphoma, MCL, or indolent non-Hodgkin lymphoma including follicular lymphoma, CLL/SLL, and Waldenström macroglobulinemia. Moreover, patients with CLL/SLL or MCL who had relapsed or become refractory following 1 or more prior therapies and had active disease, suboptimal response, or documented progressive disease following the most recent therapy (MCL) were eligible to participate in part 2 of the study.

Patients who had central nervous system involvement or who had received biologically- or immunologically-based therapies within 4 weeks of receiving the first dose of acalabrutinib were excluded. Moreover, patients for whom the time from the last dose of the most recent chemotherapy or experimental therapy to the first dose of study treatment was less than 5 times the half‐life of the previously administered agent(s) were also excluded. Other exclusion criteria included those who had previously received B‐cell receptor inhibitors like BTK or BCL‐2 inhibitors and those on ongoing immunosuppressive therapy.

The study was divided into 3 parts. The first part of the study focused on dose confirmation, the second part was the dose-expansion phase, and part 3 was the confirmation phase for the combination therapy. Study authors reported data from parts 1 and 2 of the trial.

The primary objective in part 1 was to assess the safety and tolerability of acalabrutinib and to identify dose-limiting toxicities (DLTs). Key secondary objectives included examination of antitumor activity, pharmacokinetics, and pharmacodynamics of the agent.

Patients enrolled to this part of the study were given a single 100-mg dose of oral acalabrutinib on day 1, which was followed by a washout period of 2 to 7 days; this was followed by a 28-day cycle of twice daily acalabrutinib at 100 mg. The dosing could be continued from cycle 2 onward until progressive disease or intolerable drug-related toxicity.

The second half of the study set out to further explore the safety and tolerability of acalabrutinib at a twice-daily dose of 100 mg in 2 cohorts: those with CLL/SLL and MCL. Both cohorts of patients were given a 28-day cycle of treatment, with administration of the agent continuing until progressive disease or unacceptable drug-related toxicity. Key secondary objectives included evaluation of antitumor activity and pharmacodynamics.

A total of 28 patients were enrolled to the study, 25 of whom were given treatment at 14 Japanese study centers. At a March 4, 2020 data cutoff, 64% of patients continued to receive treatment, while 36% of patients discontinued early due to death (n = 2) and progression (n = 7). Both patients who died while on study did so because of progressive or worsening disease.

Study participants had a median age of 71 years (range, 51-82) across all tumor types and all parts of the study, and the majority of patients were male (76.0%). MCL was the most common malignancy (52.0%), followed by CLL (20.0%) and SLL (16%). Additionally, patients underwent a median of 2.0 prior lines of therapy (range, 1-7).

Additional results showed that among those with CLL/SLL, 2 achieved a complete response (CR) with incomplete bone marrow recovery, while 6 experienced a partial response (PR). Among patients with MCL, 5 patients experienced a CR and 3 achieved a PR. Two patients with follicular lymphoma experienced a PR and 1 patients with Waldenström macroglobulinemia had a minor response to treatment.

Of those who responded to treatment in the CLL/SLL cohort, no one experienced progressive disease, while 3 of 8 responders in the MCL cohort experienced progression. In both cohorts, the median duration of response could not be estimated.

The median duration of treatment with acalabrutinib was 31 months for part 1 of the study, 20 months in the CLL/SLL cohort for both parts 1 and 2 of the trial and 7 months in the MCL cohort for both parts 1 and 2. No DLTs were observed during the study.

The most common adverse effects (AEs) observed with acalabrutinib included nasopharyngitis (36%), headache (32%), and rash (28%), with potential treatment-related AEs including headache (28%) and purpura (24%). Over half (56%) of all patients experienced grade 3 or higher toxicities, and 36% were considered to be related to acalabrutinib.

Twenty percent of patients experienced grade 4 AEs, which included lymphopenia, neutropenia, thrombocytopenia, hyperuricemia, decreased lymphocyte count, decreased neutrophil count, and decreased white blood cell count.

Eighty-eight percent of patients experienced AEs of clinical interest, 24% had serious AEs, and 16% reported serious AEs determined to be related to treatment. No AEs resulted in death, nor did any AEs or serious AEs lead to treatment discontinuation.

Notably, 1 patient developed interstitial lung disease that was related to treatment with acalabrutinib. Investigators interrupted the dose and the patient recovered without the need for steroids. Additionally, 3 patients developed serious AEs of grade 3 pneumonia, 2 of which were thought to potentially be related to study treatment.


  1. Izutsu K, Ando K, Ennishi D, et al. Safety and antitumor activity of acalabrutinib for relapsed/refractory B‐cell malignancies: a Japanese phase I study. Cancer Sci. Published online March 16, 2021. doi:10.111/cas.14886
  2. Mohamed AJ, Yu L, Bäckesjö CM, et al. Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009;228(1):58-73. doi:10.1111/j.1600-065X.2008.00741.x
  3. Bradshaw JM. The Src, Syk, and Tec family kinases: distinct types of molecular switches. Cell Signal. 2010;22(8):1175-84. doi:10.1016/j.cellsig.2010.03.001
  4. Buggy JJ, Elias L. Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. Int Rev Immunol. 2012;31(2):119-132. doi:10.3109/08830185.2012.664797
  5. Calquence approved in Japan for the treatment of relapsed or refractory chronic lymphocytic leukemia. News release. AstraZeneca. January 25, 2021. Accessed May 11, 2021.