Phase Ib and pharmacokinetics study of alpelisib, a PIK3CA inhibitor, and capecitabine in patients with advanced solid tumors

作者：Ah Reum Lim, Boyeon Kim, Jwa Hoon Kim, Myung Han Hyun, Kyong Hwa Park, Yeul Hong Kim, Soo Hyun Lee · 发表于：Frontiers in Oncology · 年份：2024 · DOI：10.3389/fonc.2024.1390452 · 被引用次数：10 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Colorectal Cancer Treatments and Studies、Fibroblast Growth Factor Research

Background This phase Ib study was performed to determine the safety of combination capecitabine with alpleisib (phosphatidylinositol 3-kinase catalytic subunit p110α blockade) and determine the maximal tolerated dose (MTD) and recommended phase ll dose (RP2D) of this combination regimen in patients with advanced solid tumors refractory to standard therapy. The synergistic anti-tumor activity and pharmacokinetics (PK) were investigated. Methods Dose escalation phases were conducted in patients with advanced solid cancers who were refractory to standard therapy regardless of PIK3CA mutation. Patients were administered orally once daily alpelisib (200mg and 300mg) and twice daily capecitabine (850mg, 1000mg, 1250mg orally, days 1–14) every 3 weeks. Standard “3 + 3” dose escalation was used to define the MTD. The effect of alpelisib on the PK of capecitabine was assessed. Results Patients with 6 colorectal cancer (three PIK3CA mutation) and 6 breast cancer (all PIK3CA mutation) were enrolled. The first three patients in dose level 0 (alpelisib 200mg daily, capecitabine 1,000 mg/m2 twice daily) had no dose-limiting toxicities (DLTs). In dose level 1 (alpelisib increased to 300 mg daily, capecitabine 1,000mg twice daily), one of six patients had DLT (grade (Gr) 3 hyperglycemia). When dose level 2 (alpelisib 300mg daily, capecitabine 1,250 mg/m2 twice daily) was expanded to 3 patients, no patients had DLTs. The combination of alpelisib 300mg daily and capecitabine 1,250 mg/m2 twice...