Phase I Study Demonstrates Favorable Pharmacokinetics and Safety Profile of Capivasertib in Chinese Patients with Advanced Solid Tumors
Key Insights
A Phase I trial in 16 Chinese patients with advanced solid tumors (search) showed capivasertib was rapidly absorbed with a median time to maximum concentration of approximately 1 hour and eliminated with a half-life of 9.7 hours.
The study demonstrated manageable safety profile with hyperglycemia (search), diarrhea (search), and rash as the most common adverse events, occurring in all patients but mostly Grade 1-2 severity.
Preliminary efficacy results showed 25% of patients achieved confirmed partial response and 25% achieved stable disease when treated with capivasertib plus paclitaxel combination therapy.
A Phase I clinical trial has provided comprehensive pharmacokinetic and safety data for capivasertib, an oral AKT (search) inhibitor, in Chinese patients with advanced solid tumors (search). The open-label, fixed-sequence study evaluated capivasertib both as monotherapy and in combination with paclitaxel, addressing a critical gap in understanding the drug's behavior in this patient population.
Study Design and Patient Population
The trial enrolled 16 Chinese patients with a median age of 55.5 years, with 81.3% having breast cancer (search) as the primary tumor location. All patients had advanced solid tumors (search) refractory or resistant to standard therapy. The study followed a two-part design: Part A assessed capivasertib monotherapy (480 mg twice daily, 4 days on, 3 days off), while Part B evaluated the combination with paclitaxel (capivasertib 400 mg twice daily plus paclitaxel 80 mg/m² weekly).
Pharmacokinetic Profile Confirms Rapid Absorption
The pharmacokinetic analysis revealed capivasertib was rapidly absorbed across all dosing scenarios. After a single 480 mg dose, the median time to maximum concentration was 1.0 hour, with a geometric mean maximum plasma concentration of 1,465 ng/mL and area under the curve of 7,243 h×ng/mL. The geometric mean terminal elimination half-life was 9.7 hours.
Multiple dosing demonstrated approximately two-fold accumulation of capivasertib, with geometric mean maximum plasma concentrations reaching 2,535 ng/mL after multiple doses alone and 2,467 ng/mL when combined with paclitaxel. The pharmacokinetic profile remained consistent whether capivasertib was administered as monotherapy or in combination with paclitaxel.
Safety Profile Shows Manageable Tolerability
The safety analysis encompassed all treatment cycles from both study parts. Hyperglycemia (search), diarrhea (search), and rash emerged as the most common adverse events, occurring in all 16 patients (100%). However, most adverse events were Grade 1-2 in severity. The most frequent Grade ≥3 adverse events were neutrophil count decreased (75.0% of patients) and white blood cell count decreased (62.5% of patients).
Despite the high incidence of adverse events, the safety profile proved manageable. No patients discontinued treatment due to adverse events, and no deaths were attributed to adverse events. Adverse events led to dose interruptions in 87.5% of patients for capivasertib and 75.0% for paclitaxel, while dose reductions were required in 31.3% of patients for both drugs.
Preliminary Efficacy Signals
The study provided encouraging preliminary efficacy data. Among the 16 patients treated with capivasertib plus paclitaxel combination, four patients (25.0%) achieved confirmed partial response, while another four patients (25.0%) experienced stable disease as their best objective response. Seven patients (43.8%) had progressive disease, and one patient's response was not evaluable.
Consistency with Global Population Data
The pharmacokinetic parameters observed in Chinese patients aligned closely with previous studies in Western and Japanese populations. The rapid absorption, biphasic elimination pattern, and approximately 10-hour half-life were consistent across ethnic groups. This consistency supports the conclusion that no a priori dose adjustments are needed for capivasertib based on ethnicity.
The study's findings complement the broader capivasertib development program, which includes the successful Phase III CAPItello-291 trial demonstrating improved progression-free survival when capivasertib was combined with fulvestrant in hormone receptor-positive/HER2-negative advanced breast cancer (search) patients with PIK3CA/AKT1 (search)/PTEN (search) alterations.
Clinical Implications
These results support the continued investigation of capivasertib in Chinese patients with advanced solid tumors (search). The manageable safety profile, combined with preliminary evidence of antitumor activity, provides a foundation for larger studies in this population. The consistency of pharmacokinetic parameters across ethnic groups strengthens the rationale for global development strategies without population-specific dose modifications.
The study contributes valuable data to the growing body of evidence supporting capivasertib's role in targeting the PI3K (search)/AKT (search) pathway, a critical signaling cascade dysregulated in many human malignancies. With multiple Phase III trials ongoing across various cancer types, including breast and prostate cancers, these Chinese population data enhance the global understanding of capivasertib's clinical profile.