Abstract
2551 Background: Patients (pts) with ovarian cancer (OC) often develop resistance to standard medical treatment (Rx) with platinum-taxane chemotherapy. Preclinical studies have shown that intra-nuclear activation of AKT by DNA-dependent protein kinase inhibits cisplatin-mediated DNA damage in OC cell lines, which is reversible through AKT inhibition. The following study investigates whether the oral pan-AKT inhibitor afuresertib can restore sensitivity to platinum Rx and reverse acquired resistance to standard Rx in recurrent OC. Methods: In phase I, the maximum tolerated dose (MTD) was investigated; pts with recurrent OC were treated with afuresertib (orally qd) at doses escalating from 50 to 150 mg combined with paclitaxel (IV 175 mg/m2) and carboplatin (AUC 5) q3w for ≤ 6 cycles followed by afuresertib maintenance until progression/toxicity. Phase II investigated efficacy and safety of afuresertib at MTD plus paclitaxel and carboplatin followed by afuresertib maintenance. Pts were split into two cohorts: platinum resistant (PTR) or platinum refractory pts. Results: Phase I enrolled 29 pts; dose-limiting toxicities (DLTs) were reported in 1 pt from the 125 mg cohort (G3 rash [n = 1]) and 2 pts from the 150 mg cohort (G3 rash in both pts with concurrent G2 febrile neutropenia and G2 lip swelling in 1 pt). The MTD of afuresertib was established as 125 mg. Phase II enrolled 30 heavily pre-treated pts (median time since diagnosis = 2.1 y; median prior Rx lines = 3); 28 were PTR and 2 were platinum refractory. Tolerability of Rx was consistent with findings in phase I; G3/4 AEs included diarrhea (20%), fatigue (10%), rash (10%), vomiting (7%), and nausea (3%). Overall response rate (ORR) per RECIST v1.1 for pts in the platinum-resistant cohort was 32.1% (95% CI: 15.9–52.4) and median PFS was 7.1 months (95% CI: 6.3–9.0). ORR per GCIG CA125 in evaluable pts was 52.0% (n = 25; 95% CI: 31.3–72.2). Ad hoc analyses showed ORR to correlate with duration of sensitivity to prior platinum Rx and platinum-free intervals. Conclusions: An MTD of 125 mg afuresertib was established for the Rx of pts in combination with paclitaxel and carboplatin. Combination Rx was well tolerated and showed promising activity in pts with PTR OC. Clinical trial information: NCT01653912.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
