AZD8186 in Combination With Paclitaxel in Patients With Advanced Gastric Cancer: Results From a Phase Ib/II Study (KCSG ST18-20)

BACKGROUND: Loss of PTEN function leads to increased PI3Kβ signaling. AZD8186, a selective PI3Kβ/δ inhibitor, has shown anti-tumor activity in PTEN-deficient preclinical models. This phase 1b/2 study was conducted to determine the safety and efficacy of AZD8186 and paclitaxel combination in patients with metastatic or recurrent gastric cancer (MRGC). METHODS: In the phase Ib dose-escalation, subjects with advanced solid tumors received oral AZD8186 (60 mg or 120 mg; twice daily (BID); 5 days on/2 days off) plus intravenous paclitaxel (70 mg/m(2) or 80 mg/m(2); days 1, 8, and 15) every 4 weeks. In the phase II part, MRGC patients with PTEN loss or PTEN/PIK3CB gene abnormality were enrolled and received recommended phase II dose (RP2D) of AZD8186 plus paclitaxel. Primary endpoints were to determine maximum tolerated dose (MTD) and RP2D in phase Ib and 4-month progression-free survival (PFS) rate in phase II. RESULTS: In phase Ib, both MTD and RP2D were determined at paclitaxel 80 mg/m(2) and AZD8186 120 mg BID. In phase II, 18 patients were enrolled [PTEN loss (n = 18) and PIK3CB mutation (n = 1)]. The 4-month PFS rate was 18.8% (3 of 16 evaluable patients) and further enrollment stopped due to futility. CONCLUSION: Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed. ClinicalTrials.gov Identifier: NCT04001569.