Abstract CT142: A single arm, single stage phase II trial of trametinib (GSK1120212) and GSK2141795 in persistent or recurrent cervical cancer
Authors: Matulonis Ursula A. , Wright Alexi , Campos Susana , Konstantinopoulos Panagiotis , Peralta Ariana , MacNeill Kimberley , Morrissey Stephanie , Whalen Christin , Liu Joyce 
Published: July 2017

Abstract
Introduction: In the US, invasive cervical cancer (CC) will affect 12,710 women/year with approximately 4,290 deaths. While screening has reduced cases in the developed world, CC remains a leading cause of cancer death globally with 275,000 women dying of CC/year. Though treatment options for recurrent/metastatic (met) CC have improved by adding bevacizumab to platinum-based chemotherapy, patients with met CC will eventually have cancer progression and therapies are few. PIK3CA and KRAS mutations are found in both adenocarcinomas and squamous cell cancers of the cervix. Thus, therapies targeting the PI3K/AKT and RAS-ERK pathways have rationale for treating metastatic CC; pre-clinical studies support dual PI3K inhibition and MEK inhibition given pathway redundancy and negative feedback loops. This phase II study tested a MEK and an AKT inhibitor combination.
Study Design: Trametinib (GSK1120212) is a reversible/selective inhibitor of MEK1 and MEK2. GSK2141795 is an AKT1-3 inhibitor. Objectives included RECIST 1.1 activity of trametinib and GSK2141795 in pts with recurrent CC (primary objective). Other objectives included toxicities and duration of response. Translational objectives included description of mutation and co-mutation rates of PI3K and RAS-ERK signaling pathway genes using hybrid-capture and massively parallel sequencing assay at Dana-Farber Cancer Institute. Eligibility: recurrent or met CC (any histology), receipt of 1 prior chemotherapy, and up to 1 additional regimen, no prior use of PI3K or RAS-ERK pathway inhibitor, ECOG PS 0-2, normal organ function, and availability of FFPE tissue. The treatment regimen was: trametinib 1.5 mg and GSK2141795 50 mg, both given PO daily; cycle length: 28 days. RR was assessed every 2 cycles. This study (NCT01958112) was approved and funded in part by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Novartis Pharmaceuticals Corporation.
Results: 16 pts were enrolled and 14 received study drug. The study was closed prior to accrual completion because of Novartis’ decision to stop 1) developing this combination because of lack of activity across several cancer types and observed toxicities and 2) manufacturing GSK2141795. Of the 14 patients who received study drug, one patient had a partial response lasting 108 days, 8 had stable disease, 3 had progression at their first evaluation and 2 pts were unevaluable. Related serious adverse events included a thromboembolic event (grade 3), acneiform rash (grade 3), retinal detachment (grade 2), and hypophosphatemia (grade 3). There were no grade 4 or 5 drug related toxicities.
Conclusions: This combination of an AKT and MEK inhibitor was tolerated by patients. Anti-cancer activity was minimal in the enrolled patients, but the study was terminated early due to discontinuation of the AKT inhibitor GSK2141795.
Citation Format: Ursula A. Matulonis, Alexi Wright, Susana Campos, Panagiotis Konstantinopoulos, Ariana Peralta, Kimberley MacNeill, Stephanie Morrissey, Christin Whalen, Joyce Liu. A single arm, single stage phase II trial of trametinib (GSK1120212) and GSK2141795 in persistent or recurrent cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT142. doi:10.1158/1538-7445.AM2017-CT142