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Background <p>Capivasertib is recommended, plus fulvestrant, for hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with <i>PIK3CA</i>/<i>AKT1</i>/<i>PTEN</i> 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.</p> Methods <p>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&#xa0;days on, 3 days off], paclitaxel 80 mg/m<sup>2</sup> once weekly; both 3 weeks on, 1 week off). Safety was a secondary endpoint. Investigator-assessed best objective response was an exploratory endpoint.</p> Results <p>Overall, 16 patients (median age 55.5 years, median weight 58.9&#xa0;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 (<i>n</i> = 16): 1.0&#xa0;h, 1465 ng/mL, and 7243&#xa0;h×ng/mL; after multiple doses (<i>n</i> = 15): 0.9&#xa0;h, 2535 ng/mL, and 12,080&#xa0;h×ng/mL; after multiple doses plus paclitaxel (<i>n</i> = 8): 1.9&#xa0;h, 2467 ng/mL, and 12,830&#xa0;h×ng/mL, respectively. After a single dose, the geometric mean terminal elimination half-life was 9.7&#xa0;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.</p> Conclusions <p>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.</p> Trial registration <p>The trial was registered at ClinicalTrials.gov with identifier no. NCT04742036. Date of registration: February 4, 2021.</p>

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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

  • 期刊论文

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  • 发表日期：

    2025年10月14日

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  • Jian Zhang,
  • Xiaojun Liu,
  • Yiqun Du,
  • Yuxin Mu,
  • Yanchun Meng,
  • Yan Sun,
  • Ling Zhang,
  • Chris Chen,
  • Marie Cullberg,
  • Ethan Fan,
  • Xichun Hu

摘要

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.