Robert L Coleman1, Michael W Sill2, Premal H Thaker3, David P Bender4, Daron Street5, William P McGuire6, Carolyn M Johnston7, Jacob Rotmensch8. 1. Dept. of Gynecologic Oncology & Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030. Electronic address: rcoleman@mdanderson.org. 2. NRG Oncology Statistics & Data Management Center; Roswell Park Cancer Institute, Buffalo, NY 14263. Electronic address: msill@gogstats.org. 3. Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, MO 63110. Electronic address: thakerp@wudosis.wustl.edu. 4. University of Iowa; Gyn/Onc Division; Iowa City, IA 52242. Electronic address: david-bender@uiowa.edu. 5. Cancer Care Associates; Tulsa, OK 74136. Electronic address: daron.street@tciok.org. 6. Franklin Square Hospital; Medical Oncology; Baltimore, MD 21237. Electronic address: wmcguire52@aol.com. 7. Division. of Gynecologic Oncology; University of Michigan; Ann Arbor, MI 48109. Electronic address: johnstob@med.umich.edu. 8. Rush-Presbyterian St. Lukes Med. Center; Chicago, IL 60612. Electronic address: jacob_rotmensch@rush.edu.
Abstract
BACKGROUND: Activation of the mitogen activated protein kinase pathway plays a pivotal role in cell proliferation and is frequently activated in endometrial cancer. We sought to evaluate the efficacy/safety of selumetinib, a selective MEK-1/2 inhibitor in women with recurrent endometrial cancer. METHODS: This was a phase II, single-arm, open-label study evaluating response and 6-month event-free survival (EFS) as primary endpoints. Eligible patients had measurable disease, 1-2 prior cytotoxic regimens, and performance status 0-2. Selumetinib 75mg PO BID was administered daily until progression or intolerance. One cycle was 28days. RESULTS: Fifty-four patients were enrolled; 2 were excluded due to improper pre-study treatment (1) and never treated (1), leaving 52 evaluable for efficacy/safety. Median age was 62; histology included endometrioid (58%), serous (17%) and mixed (23%). Seventeen patients (33%) had 2 prior cytotoxic regimens. The median number of cycles administered was 2 (1-34). Three (6%) patients had objective response (1 CR, 2 PR); 13 had SD as best response. The proportion of patients with 6-month EFS was 12%. Median EFS, progression-free and overall survival was 2.1, 2.3, and 8.5months, respectively. Drug-attributed grade 3/4 adverse events were observed (≥5%) were fatigue (15%), anemia (10%), pain (10%), extremity edema (8%), and dyspnea (6%). There was 1 grade 4 infection (renal), 1 grade 4 anemia, and 1 death due to hemorrhage (rectum). CONCLUSIONS: Selumetinib was tolerable in this population but did not meet pre-trial specifications for clinical efficacy.
BACKGROUND: Activation of the mitogen activated protein kinase pathway plays a pivotal role in cell proliferation and is frequently activated in endometrial cancer. We sought to evaluate the efficacy/safety of selumetinib, a selective MEK-1/2 inhibitor in women with recurrent endometrial cancer. METHODS: This was a phase II, single-arm, open-label study evaluating response and 6-month event-free survival (EFS) as primary endpoints. Eligible patients had measurable disease, 1-2 prior cytotoxic regimens, and performance status 0-2. Selumetinib 75mg PO BID was administered daily until progression or intolerance. One cycle was 28days. RESULTS: Fifty-four patients were enrolled; 2 were excluded due to improper pre-study treatment (1) and never treated (1), leaving 52 evaluable for efficacy/safety. Median age was 62; histology included endometrioid (58%), serous (17%) and mixed (23%). Seventeen patients (33%) had 2 prior cytotoxic regimens. The median number of cycles administered was 2 (1-34). Three (6%) patients had objective response (1 CR, 2 PR); 13 had SD as best response. The proportion of patients with 6-month EFS was 12%. Median EFS, progression-free and overall survival was 2.1, 2.3, and 8.5months, respectively. Drug-attributed grade 3/4 adverse events were observed (≥5%) were fatigue (15%), anemia (10%), pain (10%), extremity edema (8%), and dyspnea (6%). There was 1 grade 4 infection (renal), 1 grade 4 anemia, and 1 death due to hemorrhage (rectum). CONCLUSIONS:Selumetinib was tolerable in this population but did not meet pre-trial specifications for clinical efficacy.
Authors: T S Lewis; J B Hunt; L D Aveline; K R Jonscher; D F Louie; J M Yeh; T S Nahreini; K A Resing; N G Ahn Journal: Mol Cell Date: 2000-12 Impact factor: 17.970
Authors: P Therasse; S G Arbuck; E A Eisenhauer; J Wanders; R S Kaplan; L Rubinstein; J Verweij; M Van Glabbeke; A T van Oosterom; M C Christian; S G Gwyther Journal: J Natl Cancer Inst Date: 2000-02-02 Impact factor: 13.506
Authors: Carol Aghajanian; Michael W Sill; Kathleen M Darcy; Benjamin Greer; D Scott McMeekin; Peter G Rose; Jacob Rotmensch; Mack N Barnes; Parviz Hanjani; Kimberly K Leslie Journal: J Clin Oncol Date: 2011-05-02 Impact factor: 44.544
Authors: Tammie C Yeh; Vivienne Marsh; Bryan A Bernat; Josh Ballard; Heidi Colwell; Ron J Evans; Janet Parry; Darin Smith; Barbara J Brandhuber; Stefan Gross; Allison Marlow; Brian Hurley; Joe Lyssikatos; Patrice A Lee; James D Winkler; Kevin Koch; Eli Wallace Journal: Clin Cancer Res Date: 2007-03-01 Impact factor: 12.531
Authors: Jieru Meng; Henry Peng; Bingbing Dai; Wei Guo; Li Wang; Lin Ji; John D Minna; Christine M Chresta; Paul D Smith; Bingliang Fang; Jack A Roth Journal: Cancer Biol Ther Date: 2009-11-18 Impact factor: 4.742
Authors: Ana M Mendes-Pereira; Sarah A Martin; Rachel Brough; Afshan McCarthy; Jessica R Taylor; Jung-Sik Kim; Todd Waldman; Christopher J Lord; Alan Ashworth Journal: EMBO Mol Med Date: 2009-09 Impact factor: 12.137
Authors: Nicole Concin; Carien L Creutzberg; Ignace Vergote; David Cibula; Mansoor Raza Mirza; Simone Marnitz; Jonathan A Ledermann; Tjalling Bosse; Cyrus Chargari; Anna Fagotti; Christina Fotopoulou; Antonio González-Martín; Sigurd F Lax; Domenica Lorusso; Christian Marth; Philippe Morice; Remi A Nout; Dearbhaile E O'Donnell; Denis Querleu; Maria Rosaria Raspollini; Jalid Sehouli; Alina E Sturdza; Alexandra Taylor; Anneke M Westermann; Pauline Wimberger; Nicoletta Colombo; François Planchamp; Xavier Matias-Guiu Journal: Virchows Arch Date: 2021-02 Impact factor: 4.064
Authors: Shannon N Westin; Michael W Sill; Robert L Coleman; Steven Waggoner; Kathleen N Moore; Cara A Mathews; Lainie P Martin; Susan C Modesitt; Sanghoon Lee; Zhenlin Ju; Gordon B Mills; Russell J Schilder; Paula M Fracasso; Michael J Birrer; Carol Aghajanian Journal: Gynecol Oncol Date: 2019-10-15 Impact factor: 5.482
Authors: Vicky Makker; Virginia L Filiaci; Lee-May Chen; Christopher J Darus; James E Kendrick; Gregory Sutton; Katherine Moxley; Carol Aghajanian Journal: Gynecol Oncol Date: 2015-04-16 Impact factor: 5.482