A Phase I open-label study to assess the pharmacokinetics, safety, and tolerability of capivasertib alone or in combination with paclitaxel in Chinese patients with advanced solid tumors

TL;DR

This study evaluated the safety and absorption of capivasertib, alone or with paclitaxel, in Chinese patients with advanced tumors, finding it generally well-tolerated with manageable side effects.

Contribution

The study provides new pharmacokinetic and safety data for capivasertib in Chinese patients, supporting its further use in this population.

Findings

Capivasertib was rapidly absorbed with a half-life of about 10 hours.

Hyperglycemia, diarrhea, and rash were the most common adverse events, mostly mild to moderate.

25% of patients achieved partial response or stable disease, indicating some antitumor activity.

Abstract

Capivasertib is recommended, plus fulvestrant, for hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with PIK3CA/AKT1/PTEN alterations and is under development for further breast and prostate cancer indications. Pharmacokinetics in Western and Japanese patients have been previously characterized. We conducted a Phase I trial assessing the pharmacokinetics and safety of capivasertib, alone or plus paclitaxel, in Chinese patients with advanced solid tumors.

In this open-label, fixed-sequence Phase I trial, Chinese patients with advanced solid tumors refractory or resistant to standard therapy received capivasertib alone (Part A) and then plus paclitaxel (Part B). The primary endpoint comprised capivasertib pharmacokinetics after a single dose (480 mg), or multiple doses given alone (480 mg twice daily [4 days on, 3 days off]) or plus paclitaxel (capivasertib 400 mg twice daily [4 days on, 3 days off], paclitaxel 80 mg/m2 once weekly; both 3 weeks on, 1 week off). Safety was a secondary endpoint. Investigator-assessed best objective response was an exploratory endpoint.

Overall, 16 patients (median age 55.5 years, median weight 58.9 kg, 81.3% breast primary tumor location) received capivasertib alone in Part A and then capivasertib plus paclitaxel in Part B. The median time to maximum concentration, the geometric mean maximum plasma concentration, and the geometric mean area under the curve from time 0 to the last quantifiable concentration of capivasertib were: after a single dose (n = 16): 1.0 h, 1465 ng/mL, and 7243 h×ng/mL; after multiple doses (n = 15): 0.9 h, 2535 ng/mL, and 12,080 h×ng/mL; after multiple doses plus paclitaxel (n = 8): 1.9 h, 2467 ng/mL, and 12,830 h×ng/mL, respectively. After a single dose, the geometric mean terminal elimination half-life was 9.7 h. Hyperglycemia, diarrhea, and rash were the most common adverse events (reported for all patients). Most adverse events were Grade 1–2. Four (25.0%) patients achieved confirmed partial response and four (25.0%) stable disease as best objective response.

Consistent with previous findings, capivasertib was absorbed rapidly and eliminated with a half-life of approximately 10 h. The manageable safety profile and preliminary antitumor activity support further investigation of capivasertib-containing combinations in Chinese patients with advanced solid tumors.

The trial was registered at ClinicalTrials.gov with identifier no. NCT04742036. Date of registration: February 4, 2021.

The online version contains supplementary material available at 10.1186/s12885-025-14982-4.

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