A Randomized Phase I Study of Abemaciclib in Chinese Patients with Advanced and/or Metastatic Cancers

Abstract

Background Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, is approved in combination with endocrine therapy or as monotherapy for hormone receptor-positive and human epidermal growth factor receptor-2-negative (HR+/HER2−) advanced breast cancer outside of China. Objective To evaluate the safety, tolerability, and pharmacokinetic (PK) profile of abemaciclib in Chinese patients with advanced and/or metastatic cancers. Patients and methods A multicenter, open-label, phase I trial of abemaciclib in Chinese patients with advanced and/or metastatic cancers was conducted. Patients were randomized (1:1) to oral abemaciclib 150 or 200 mg every 12 h on a 28-day cycle. Safety analyses (primary outcome) included all patients receiving at least one dose of abemaciclib. PK and antitumor activity were also assessed. Results Of the 26 patients randomized, 25 received abemaciclib 150 mg ( n = 12) or 200 mg ( n = 13). All 25 patients reported ≥ 1 treatment-emergent adverse event (TEAE). The majority of TEAEs were Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2 in severity. The most frequent TEAEs of Grade ≥ 3 were neutropenia (32%) and thrombocytopenia (24%). Four patients (16%) discontinued treatment due to AEs. Abemaciclib exhibited slow absorption and clearance at single dose, with maximum concentrations achieved after around 6 h and an elimination half-life of approximately 24 h. No complete response was observed, two patients (8%) achieved partial response, with one confirmed responder, and the disease control rate was 68% ( n = 17). Conclusions Abemaciclib was well tolerated and the safety and PK profiles in Chinese patients were comparable to those previously reported in non-Chinese populations. Preliminary antitumor activity was observed. ClinicalTrials.gov identifier NCT02919696.

A narrative review of the clinical development of CDK4/6 inhibitor abemaciclib in breast cancer

“…An open-label phase I trial was conducted in Chinese patients with advanced malignancies ( 29 ) to evaluate the safety, tolerability, and PK characteristics of abemaciclib. A total of 26 patients were randomly assigned 1:1 to abemaciclib 150 mg (n=12) or 200 mg (n=13).…”

Therapeutic Drug Monitoring of Protein Kinase Inhibitors in Breast Cancer Patients

“…Neutropenia represented the most common adverse event developed in 83.3% of Chinese patients (n=10), followed by diarrhea, leukopenia, and decreased appetite in 75% of the patients (n=9) in phase I abemaciclib study. The mean steady-state C trough of 202 ng/ml (CV = 72%) was observed in 7 patients suffering from tumour diseases, including breast cancer, treated with a standard dose of 150 mg twice daily (Zhang et al, 2021). However, it appears that neutropenia is related to C max of abemaciclib and its metabolites (Groenland et al, 2020).…”