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Phase IB Dose-Escalation and Expansion Study of AKT kinase inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-Resistant Ovarian Cancer.

Blagden, SP; Hamilton, AL; Mileshkin, L; Wong, S; Michael, A; Hall, M; Goh, JC; ... Gabra, H; + view all (2019) Phase IB Dose-Escalation and Expansion Study of AKT kinase inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-Resistant Ovarian Cancer. Clinical Cancer Research 10.1158/1078-0432.CCR-18-2277. (In press).

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Abstract

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. (etc -see manuscript for full version).

Type: Article
Title: Phase IB Dose-Escalation and Expansion Study of AKT kinase inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-Resistant Ovarian Cancer.
Location: United States
DOI: 10.1158/1078-0432.CCR-18-2277
Publisher version: https://doi.org/10.1158/1078-0432.CCR-18-2277
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
URI: http://discovery.ucl.ac.uk/id/eprint/10065629
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