Carboplatin + Ipatasertib

The combination of carboplatin and ipatasertib is an investigational treatment that has been studied primarily for metastatic triple-negative breast cancer (mTNBC). This combination brings together a platinum-based chemotherapy agent (carboplatin) with a selective pan-AKT inhibitor (ipatasertib). Ipatasertib is designed to block AKT, an enzyme involved in cancer cell growth, while carboplatin works by damaging DNA in cancer cells, preventing them from dividing. The combination has been evaluated in clinical trials to determine its safety profile and efficacy, particularly in patients with mTNBC. A Phase I trial evaluated different dosing regimens and combinations, including: - Ipatasertib plus carboplatin - Ipatasertib plus carboplatin/paclitaxel - Ipatasertib plus capecitabine/atezolizumab The recommended Phase 2 dose (RP2D) for ipatasertib plus carboplatin was established as ipatasertib 400 mg daily with carboplatin AUC2 on days 1, 8, and 15 of a 28-day cycle. For the ipatasertib plus carboplatin/paclitaxel combination, the RP2D was ipatasertib 300 mg daily with carboplatin AUC2 and paclitaxel 80 mg/m² on days 1, 8, and 15 of a 28-day cycle. The combination showed modest clinical activity in patients with mTNBC. In the Phase I trial, the overall response rates at the recommended Phase 2 dose were: - 25% for ipatasertib plus carboplatin - 29% for ipatasertib plus carboplatin/paclitaxel - 33% for ipatasertib plus capecitabine/atezolizumab Progression-free survival was 3.9 months for ipatasertib plus carboplatin and 4.8 months for ipatasertib plus carboplatin/paclitaxel. Interestingly, patients with tumors harboring PIK3CA/AKT/PTEN alterations showed an overall response rate of 33% (including one complete response), suggesting potential biomarkers for treatment selection. The most common grade 3-4 adverse events at the recommended Phase 2 dose for ipatasertib plus carboplatin were diarrhea (17%) and lymphopenia (25%). For ipatasertib plus carboplatin/paclitaxel, the most common grade 3-4 adverse events were neutropenia (29%), diarrhea (14%), oral mucositis (14%), and neuropathy (14%). Overall, continuous dosing of ipatasertib with chemotherapy was found to be safe and well-tolerated.