Phase IB Dose Escalation and Expansion Study of AKT Inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-resistant Ovarian Cancer

Purpose: Preclinical studies have shown that AKT kinase inhibition can restore drug sensitivity in platinum-resistant tumors. This study evaluates the combination of the pan-AKT kinase inhibitor afuresertib with paclitaxel and carboplatin (PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum-refractory ovarian cancer (PPROC).

Patients and Methods: Part I of the study was a 3+3 dose escalation trial for recurrent ovarian cancer, where patients received daily continuous oral afuresertib (50-150 mg/day) alongside intravenous paclitaxel (175 mg/m²) and carboplatin (AUC5) every 3 weeks for six cycles. Maintenance therapy with afuresertib at 125 mg/day continued until disease progression or intolerable toxicity. Part II was a single-arm assessment of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients in Part II received the maximum tolerated dose (MTD) of afuresertib as determined in Part I, combined with PC for six cycles, followed by maintenance afuresertib. The primary endpoints were safety and tolerability (Part I, dose escalation) and overall response rate (ORR) assessed by the investigator per RECIST 1.1 (Part II).

Results: A total of 29 patients were enrolled in Part I, and 30 in Part II. Three dose-limiting toxicities of grade 3 rash were observed—one at 125 mg and two at 150 mg of afuresertib. Therefore, the MTD of afuresertib in combination with PC was established as 125 mg/day. The most common drug-related adverse events (≥50%) in Part I included nausea, diarrhea, vomiting, alopecia, fatigue, and neutropenia, while in Part II, the most frequent adverse events were diarrhea, fatigue, nausea, and alopecia. The ORR in the intention-to-treat population in Part II was 32% (95% CI, 15.9-52.4) by RECIST 1.1 and 52% (95% CI, 31.3-72.2) by GCIG CA125 criteria. The median progression-free survival was 7.1 months (95% CI, 6.3-9.0).

Conclusions: The combination of afuresertib and PC demonstrated promising efficacy in recurrent PROC, with the MTD of afuresertib established as 125 mg/day.