Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study
John H. Farley,William E. Brady,Vinod Vathipadiekal,Heather A. Lankes,Robert L. Coleman,Mark A. Morgan,Robert S. Mannel,S. Diane Yamada,David G. Mutch,William H. Rodgers,Michael J. Birrer,David M. Gershenson +11 more
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TLDR
Selumetinib is well tolerated, and is active in the treatment of recurrent low-grade serous carcinoma of the ovary or peritoneum, and the findings suggest that inhibitors of the MAPK pathway warrant further investigation in these patients.Abstract:
Summary Background Low-grade serous carcinoma of the ovary is chemoresistant but mutations in the MAPK pathway could be targeted to control tumour growth. We therefore assessed the safety and activity of selumetinib, an inhibitor of MEK1/2, for patients with this cancer. Methods In this open-label, single-arm phase 2 study, women (aged ≥18 years) with recurrent low-grade serous ovarian or peritoneal carcinoma were given selumetinib (50 mg twice daily, orally) until progression. The primary endpoint was the proportion of patients who had an objective tumour response according to RECIST version 1.1, assessed for all the treated patients. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00551070. Findings 52 patients were enrolled between Dec 17, 2007, and Nov 23, 2009. All were eligible for analyses. Eight (15%) patients had an objective response to treatment—one patient had a complete response and seven had partial responses. 34 (65%) patients had stable disease. There were no treatment-related deaths. Grade 4 toxicities were cardiac (one), pain (one), and pulmonary events (one). Grade 3 toxicities that occurred in more than one patient were gastrointestinal (13), dermatological (nine), metabolic (seven), fatigue (six), anaemia (four), pain (four), constitutional (three), and cardiac events (two). Interpretation Selumetinib is well tolerated, and is active in the treatment of recurrent low-grade serous carcinoma of the ovary or peritoneum. The findings suggest that inhibitors of the MAPK pathway warrant further investigation in these patients. Funding National Cancer Institute.read more
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Kristine M. Cornejo,Ediz F. Cosar,Gladell P. Paner,Ping Yang,Keith Tomaszewicz,Xiuling Meng,Vikas Mehta,Sahussapont Joseph Sirintrapun,Güliz A. Barkan,Lloyd Hutchinson +9 more
TL;DR: UAC and BAC have overlapping but distinct mutation profiles and these differences may aid in separating these 2 entities and next-generation sequencing to identify therapeutic targets or resistance markers may aid treatment decisions.
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Heterogeneous alteration of the ERBB3–MYC axis associated with MEK inhibitor resistance in a KRAS-mutated low-grade serous ovarian cancer patient
Ilaria Colombo,Swati Garg,Arnavaz Danesh,Jeffrey Bruce,Patricia Shaw,Qian Tan,Rene Quevedo,Marsela Braunstein,Amit M. Oza,Trevor J. Pugh,Trevor J. Pugh,Stephanie Lheureux +11 more
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Genetic and pharmacologic inhibition of Tpl2 kinase is protective in a mouse model of ventilator-induced lung injury
Evangelos Kaniaris,Katerina Vaporidi,Eleni Vergadi,Emmanuel E. Theodorakis,Eumorfia Kondili,Eleni Lagoudaki,Christos Tsatsanis,Dimitris Georgopoulos +7 more
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References
More filters
Journal ArticleDOI
New Guidelines to Evaluate the Response to Treatment in Solid Tumors
Patrick Therasse,Susan G. Arbuck,Elizabeth Eisenhauer,Jantien Wanders,Richard Kaplan,Larry Rubinstein,Jaap Verweij,Martine Van Glabbeke,Allan T. van Oosterom,Michaele C. Christian,S. Gwyther +10 more
TL;DR: A model by which a combined assessment of all existing lesions, characterized by target lesions and nontarget lesions, is used to extrapolate an overall response to treatment is proposed, which is largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines.
Journal ArticleDOI
Recurrent Epithelial Ovarian Carcinoma: A Randomized Phase III Study of Pegylated Liposomal Doxorubicin Versus Topotecan
TL;DR: The comparable efficacy, favorable safety profile, and convenient dosing support the role of PLD as a valuable treatment option in patients with epithelial ovarian carcinoma that recurred after or didn't respond to first-line, platinum-based chemotherapy.
Journal ArticleDOI
BRCA Mutation Frequency and Patterns of Treatment Response in BRCA Mutation–Positive Women With Ovarian Cancer: A Report From the Australian Ovarian Cancer Study Group
Kathryn Alsop,Sian Fereday,Cliff Meldrum,Anna deFazio,Catherine Emmanuel,Joshy George,Alexander Dobrovic,Michael J. Birrer,Penelope M. Webb,Colin J.R. Stewart,Michael Friedlander,Stephen B. Fox,David D.L. Bowtell,Gillian Mitchell +13 more
TL;DR: The data supports the recommendation that germ-line BRCA1/2 testing should be offered to all women diagnosed with nonmucinous, ovarian carcinoma, regardless of family history, and supports the advent of poly(ADP-ribose) polymerase inhibitor trials.
Journal ArticleDOI
Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial.
M K B Parmar,Jonathan A. Ledermann,Nicoletta Colombo,Bois A Du,J. F. Delaloye,G.B. Kristensen,S Wheeler,Ann Marie Swart,Wendi Qian,Valter Torri,Irene Floriani,Gordon C Jayson,Alan Lamont,Claes G. Tropé +13 more
TL;DR: Paclitaxel plus platinum chemotherapy seems to improve survival and progression-free survival among patients with relapsed platinum-sensitive ovarian cancer compared with conventional platinum-based chemotherapy.
Journal ArticleDOI
Mutations in BRAF and KRAS Characterize the Development of Low-Grade Ovarian Serous Carcinoma
Gad Singer,Robert J. Oldt,Yoram Cohen,Brant G. Wang,David Sidransky,Robert J. Kurman,Ie Ming Shih +6 more
TL;DR: The apparent restriction of these BRAF and KRAS mutations to low-grade serous ovarian carcinoma and its precursors suggests that low- grade and high-grade ovarian serous carcinomas develop through independent pathways.
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