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

Abstract

Abstract This phase Ib study was performed to determine the safety, the maximal tolerated dose (MTD), and recommended phase II dose (RP2D) of capecitabine with alpleisib in patients with advanced solid tumors. Regardless of PIK3CA mutation, patients were administered orally once daily alpelisib (200mg and 300mg) and twice daily capecitabine (850mg/m2, 1,000mg/m2, 1,250mg/m2, 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. 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, capecitabine 1,000 mg/m2) had no dose-limiting toxicities (DLTs). In dose level 1 (alpelisib increased to 300 mg), one of six patients had DLT (grade 3 hyperglycemia). At dose level 2 (capecitabine 1,250 mg/m2), no patients had DLTs, establishing it as the MTD/RP2D. The most common AE was grade 1-3 hyperglycemia (75.0%). Antitumor activity was observed in patients with PIK3CA mutant breast cancer (3 partial response and 3 stable disease). Alpelisib was unaffected by capecitabine (Cmax and AUC0-12). This combination is generally tolerated, and shows antitumor activity in patients with PIK3CA mutant advanced cancers.