Phase IB dose-escalation and expansion study of AKT kinase inhibitor afuresertib with carboplatin and paclitaxel in recurrent platinum-resistant ovarian cancer

Journal article

Purpose: Preclinically, AKT kinase inhibition restores drug sensitivity in platinum-resistant tumors.Here the pan-AKT kinase inhibitor afuresertib was given in combination with paclitaxel and carboplatin (PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum refractory ovarian cancer (PPROC).

Experimental Design: Part I was a combination 3+3 dose-escalation study for recurrent ovarian cancer. Patients received daily continuous oral afuresertib at 50-150 mg/day with three-weekly intravenous paclitaxel (175 mg/m2) and carboplatin (AUC5) for 6 cycles followed by maintenance afuresertib at 125mg/day until progression or toxicity. Part II was a single arm evaluation of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients received oral afuresertib at the maximum tolerated dose (MTD) defined in Part I in combination with PC for 6 cycles, followed by maintenance afuresertib. Primary endpoints were safety and tolerability of afuresertib in combination with PC (Part I, dose-escalation), and investigator-assessed overall response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Part II).

Results: Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities (DLTs) of grade 3 rash were observed, one at 125mg and two at 150mg afuresertib. The MTD of afuresertib in combination with PC was therefore identified as 125 mg/day. The most common (≥ 50%) drug-related adverse events observed in Part I of the study were nausea, diarrhea, vomiting, alopecia, fatigue and neutropenia and, in Part II, were diarrhea, fatigue, nausea and alopecia. The Part II ORR in the intention to treat (ITT) patients was 32% (95% CI: 15.9–52.4) by RECIST 1.1 and 52% (95% CI: 31.3–72.2) by GCIG CA125 criteria. Median progression-free survival was 7.1 months (95% CI: 6.3–9.0 months).

Conclusion: Afuresertib plus PC demonstrated efficacy in recurrent PROC with the MTD of afuresertib defined as 125 mg/day.

Authors: Blagden, S; Hamilton, A; Mileshkin, L; Wong, S; Michael, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Association for Cancer Research
• Journal: Clinical Cancer Research
• Volume: 25
• Issue: 5
• Pages: 1472-1478
• Publication date: 2018-12-18
• Acceptance date: 2018-11-30
• DOI: 10.1158/1078-0432.ccr-18-2277
• EISSN: 1557-3265
• ISSN: 1078-0432
• Language: English