PMID- 29785570
OWN - NLM
STAT- MEDLINE
DCOM- 20190610
LR  - 20191210
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Linking)
VI  - 36
IP  - 6
DP  - 2018 Dec
TI  - Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced 
      or metastatic biliary tract cancer.
PG  - 1037-1043
LID - 10.1007/s10637-018-0600-2 [doi]
AB  - Background The MAPK pathway plays a central role in regulation of several 
      cellular processes, and its dysregulation is a hallmark of biliary tract cancer 
      (BTC). Binimetinib (MEK162), a potent, selective oral MEK1/2 inhibitor, was 
      assessed in patients with advanced BTC. Patients and Methods An expansion cohort 
      study in patients who received </=1 line of therapy for advanced BTC was conducted 
      after determination of the maximum tolerated dose in this Phase 1 trial. Patients 
      received binimetinib 60 mg twice daily. The primary objectives were to 
      characterize the safety profile and pharmacokinetics of binimetinib in advanced 
      BTC. Secondary objectives included assessment of clinical efficacy, changes in 
      weight and lean body mass, and pharmacodynamic effects. Tumor samples were 
      assessed for mutations in relevant genes. Results Twenty-eight patients received 
      binimetinib. Common adverse events (AEs) were mild, with rash (82%) and nausea 
      (54%) being most common. Two patients experienced grade 4 AEs, one generalized 
      edema and the other pulmonary embolism. The pharmacokinetics in this patient 
      population were consistent with those previously reported (Bendell JC et al., Br 
      J Cancer 2017;116:575-583). Twelve patients (43%) experienced stable disease and 
      two had objective responses (1 complete response, 1 partial response) per 
      Response Evaluation Criteria in Solid Tumors and stable metabolic disease by 
      positron emission tomography/computed tomography. Most patients (18/25; 72%) did 
      not have KRAS, BRAF, NRAS, PI3KCA, or PTEN mutations, nor was there correlation 
      between mutation status and response. The average non-fluid weight gain was 1.3% 
      for lean muscle and 4.7% for adipose tissue. Conclusion Binimetinib was well 
      tolerated and showed promising evidence of activity in patients with BTC. 
      Correlative studies suggested the potential for binimetinib to promote muscle 
      gain in patients with BTC.
FAU - Finn, R S
AU  - Finn RS
AD  - Department of Medicine, University of California Los Angeles Medical Center, 2020 
      Santa Monica Blvd, Santa Monica, CA, 90404, USA.
FAU - Ahn, D H
AU  - Ahn DH
AD  - Department of Medicine, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ, 85054, USA.
FAU - Javle, M M
AU  - Javle MM
AD  - Department of Gastrointestinal Medical Oncology, The University of Texas MD 
      Anderson Cancer Center, 1515 Holcombe Blvd, Unit #426, Houston, TX, 77030, USA.
FAU - Tan, B R Jr
AU  - Tan BR Jr
AD  - Department of Medicine, Washington University School of Medicine, 660 S Euclid 
      Ave, Campus Box 8056, St. Louis, MO, 63110, USA.
FAU - Weekes, C D
AU  - Weekes CD
AD  - Department of Medicine, University of Colorado Cancer Center, 12801 E 17th Ave, 
      Aurora, CO, 80045, USA.
FAU - Bendell, J C
AU  - Bendell JC
AD  - Drug Development Program, Sarah Cannon Research Institute/Tennessee Oncology, 250 
      25th Ave N, Nashville, TN, 37203, USA.
FAU - Patnaik, A
AU  - Patnaik A
AD  - START - South Texas Accelerated Research Therapeutics, 4383 Medical Dr, San 
      Antonio, TX, 78229, USA.
FAU - Khan, G N
AU  - Khan GN
AD  - Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI, 48202, USA.
FAU - Laheru, D
AU  - Laheru D
AD  - Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 401 N 
      Broadway, Baltimore, MD, 21287, USA.
FAU - Chavira, R
AU  - Chavira R
AD  - Array BioPharma Inc., 3200 Walnut St, Boulder, CO, 80301, USA.
FAU - Christy-Bittel, J
AU  - Christy-Bittel J
AD  - Array BioPharma Inc., 3200 Walnut St, Boulder, CO, 80301, USA.
FAU - Barrett, E
AU  - Barrett E
AD  - Array BioPharma Inc., 3200 Walnut St, Boulder, CO, 80301, USA.
FAU - Sawyer, M B
AU  - Sawyer MB
AD  - Cross Cancer Institute Department of Medical Oncology, University of Alberta, 
      11560 University Ave, Edmonton, AB, T6G 1Z2, Canada.
FAU - Bekaii-Saab, Tanios S
AU  - Bekaii-Saab TS
AD  - Department of Medicine, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ, 85054, USA. 
      bekaii-saab.tanios@mayo.edu.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20180522
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Benzimidazoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 181R97MR71 (binimetinib)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Benzimidazoles/adverse effects/pharmacokinetics/pharmacology/*therapeutic use
MH  - Biliary Tract Neoplasms/*drug therapy/*pathology
MH  - DNA Mutational Analysis
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Muscles/drug effects/pathology
MH  - Neoplasm Metastasis
MH  - Neoplasm Staging
MH  - Organ Size/drug effects
MH  - Protein Kinase Inhibitors/pharmacology/*therapeutic use
MH  - Subcutaneous Fat/drug effects/pathology
MH  - Treatment Outcome
OTO - NOTNLM
OT  - Biliary tract cancer
OT  - Binimetinib
OT  - Cachexia
OT  - Cholangiocarcinoma
OT  - Clinical trial
OT  - MEK inhibitor
EDAT- 2018/05/23 06:00
MHDA- 2019/06/14 06:00
CRDT- 2018/05/23 06:00
PHST- 2018/02/09 00:00 [received]
PHST- 2018/04/03 00:00 [accepted]
PHST- 2018/05/23 06:00 [pubmed]
PHST- 2019/06/14 06:00 [medline]
PHST- 2018/05/23 06:00 [entrez]
AID - 10.1007/s10637-018-0600-2 [pii]
AID - 10.1007/s10637-018-0600-2 [doi]
PST - ppublish
SO  - Invest New Drugs. 2018 Dec;36(6):1037-1043. doi: 10.1007/s10637-018-0600-2. Epub 
      2018 May 22.