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.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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