title: A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.
abstract: BACKGROUND
  Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single-agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results.
  
  
  METHODS
  In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m(2)).
  
  
  RESULTS
  In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2).
  
  
  CONCLUSIONS
  Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.).
authors.affiliation: Department of Medical Oncology, Kyorin University Hospital, 6-20-2 Shinkawa, 181-8611, Mitaka, Tokyo, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kasuga
authors.affiliation: Department of Medical Oncology, Faculty of Medicine, Kinki University Hospital, 377-2, Ono-Higashi, 577-0818, Osakasayama City, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Department of Medical Oncology, Kyorin University Hospital, 6-20-2 Shinkawa, 181-8611, Mitaka, Tokyo, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Nagashima
authors.affiliation: Department of Medical Oncology, Faculty of Medicine, Kinki University Hospital, 377-2, Ono-Higashi, 577-0818, Osakasayama City, Osaka, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Medical Oncology, Kyorin University Hospital, 6-20-2 Shinkawa, 181-8611, Mitaka, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Naruge
authors.affiliation: Department of Medical Oncology, Faculty of Medicine, Kinki University Hospital, 377-2, Ono-Higashi, 577-0818, Osakasayama City, Osaka, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nishina
authors.affiliation: Department of Medical Oncology, Kyorin University Hospital, 6-20-2 Shinkawa, 181-8611, Mitaka, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitamura
authors.affiliation: Department of Medical Oncology, Faculty of Medicine, Kinki University Hospital, 377-2, Ono-Higashi, 577-0818, Osakasayama City, Osaka, Japan.
authors.forename: Takayasu
authors.initials: T
authors.lastname: Kurata
authors.affiliation: Department of Medical Oncology, Kyorin University Hospital, 6-20-2 Shinkawa, 181-8611, Mitaka, Tokyo, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Takasu
authors.affiliation: Department of Medical Oncology, Faculty of Medicine, Kinki University Hospital, 377-2, Ono-Higashi, 577-0818, Osakasayama City, Osaka, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Fujisaka
authors.affiliation: Department of Medical Oncology, Faculty of Medicine, Kinki University Hospital, 377-2, Ono-Higashi, 577-0818, Osakasayama City, Osaka, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Okamoto
authors.affiliation: Medicines Development, Oncology Therapeutic Area, GlaxoSmithKline K.K., 6-15, Sendagaya 4-chome, 151-8566, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Medicines Development, Oncology Therapeutic Area, GlaxoSmithKline K.K., 6-15, Sendagaya 4-chome, 151-8566, Tokyo, Japan.
authors.forename: Akihira
authors.initials: A
authors.lastname: Mukaiyama
authors.affiliation: Medicines Development, Oncology Therapeutic Area, GlaxoSmithKline K.K., 6-15, Sendagaya 4-chome, 151-8566, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Matsushita
authors.affiliation: Department of Medical Oncology, Kyorin University Hospital, 6-20-2 Shinkawa, 181-8611, Mitaka, Tokyo, Japan. jfuruse@ks.kyorin-u.ac.jp.
authors.forename: Junji
authors.initials: J
authors.lastname: Furuse
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D044466:Asian People; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D011728:Pyridones; D011744:Pyrimidinones; D003841:Deoxycytidine; C560077:trametinib; D000093542:Gemcitabine
keywords: Gemcitabine; Japanese; MEK inhibitor; Pancreatic cancer; Solid tumors; Trametinib