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Ref Type Journal Article
PMID (30563934)
Authors Blagden SP, Hamilton AL, Mileshkin L, Wong S, Michael A, Hall M, Goh JC, Lisyanskaya AS, DeSilvio M, Frangou E, Stronach EA, Gopalakrishna P, Meniawy TM, Gabra H
Title Phase IB Dose Escalation and Expansion Study of AKT Inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-resistant Ovarian Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 25
Issue 5
Date 2019 Mar 01
Abstract Text 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).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 intravenous paclitaxel (175 mg/m2) and carboplatin (AUC5) every 3 weeks for six cycles followed by maintenance afuresertib at 125 mg/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 MTD defined in Part I in combination with PC for six 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 RECIST version 1.1 (Part II).Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities of grade 3 rash were observed, one at 125 mg and two at 150 mg 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 patients was 32% [95% confidence interval (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).Afuresertib plus PC demonstrated efficacy in recurrent PROC with the MTD of afuresertib defined as 125 mg/day.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Afuresertib GSK2110183|GSK-2110183 Akt Inhibitor (Pan) 19 AKT Inhibitor (Pan) - ATP competitive 7 Afuresertib (GSK2110183) is a pan-AKT, ATP-competitive inhibitor, which may result in inhibition of the PI3K/AKT signaling pathway and tumor cell proliferation, and induction of tumor cell apoptosis (PMID: 25075128, PMID: 30563934).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown ovary epithelial cancer not applicable Afuresertib + Carboplatin + Paclitaxel Phase I Actionable In a Phase Ib trial, the combination of Afuresertib (GSK2110183) , Paraplatin (carboplatin), and Taxol (paclitaxel) was well-tolerated and demonstrated preliminary efficacy in patients with platinum-resistant epithelial ovarian cancer, resulting in an overall response rate in the dose-expansion part of the trial (Part II) of 32% (9/28) and a median progression-free survival of 7.1 months (PMID: 30563934; NCT01653912). 30563934