Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	25	5	2019 Mar 01	1472-1478	Clin Cancer Res

URL

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
Afuresertib	Afuresertib	1	3

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Afuresertib		GSK2110183\|GSK-2110183	Akt Inhibitor (Pan) 21 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