title: A phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors.
abstract: BACKGROUND
  Tivantinib (ARQ 197) is an orally available, non-adenosine triphosphate competitive, selective c-MET inhibitor. The primary objective of this study was to evaluate the safety, tolerability and to establish the recommended phase II dose (RP2D) of tivantinib and gemcitabine combination.
  
  
  METHODS
  Patients with advanced or metastatic solid tumors were treated with escalating doses of tivantinib (120-360 mg capsules) in combination with gemcitabine (1000 mg/m(2) weekly for 3 of 4 weeks). Different schedules of administration were tested and modified based on emerging preclinical data. Tivantinib was given continuously, twice a day (b.i.d.) for 2, 3 or 4 weeks of a 28-day cycle or on a 5-day on, 2-day off schedule (the day before and day of gemcitabine administration).
  
  
  RESULTS
  Twenty-nine patients were treated with gemcitabine and escalating doses of tivantinib: 120 mg b.i.d. (n = 4), 240 mg b.i.d. (n = 6) and 360 mg b.i.d. (n = 19). No dose-limiting toxicities were observed in escalation. The RP2D was 360 mg b.i.d. daily, and 45 additional patients were enrolled in the expansion cohort. Grade ≥3 treatment-related toxicities were observed in 54 of 74 (73%) patients with the most common being neutropenia (43%), anemia (30%), thrombocytopenia (28%) and fatigue (15%). There was one treatment-related death due to neutropenia. Administration of gemcitabine did not affect tivantinib concentration. Fifty-six patients were assessable for response. Eleven (20%) patients achieved a partial response and 26 (46%) had stable disease (SD), including 15 (27%) who achieved SD for over 4 months. Ten of 37 patients with clinical benefit had prior exposure to gemcitabine.
  
  
  CONCLUSIONS
  The combination of tivantinib at its monotherapy dose and standard dose gemcitabine was safe and tolerable. Early signs of antitumor activity may warrant further development of this combination in nonsmall-cell lung cancer, ovarian, pancreatic and cholangiocarcinoma.
  
  
  BACKGROUND
  NCT00874042.
authors.affiliation: University of Oklahoma Health Sciences Center, Oklahoma City. Electronic address: shubham-pant@ouhsc.edu.
authors.forename: S
authors.initials: S
authors.lastname: Pant
authors.affiliation: Georgia Cancer Specialists, Atlanta.
authors.forename: M
authors.initials: M
authors.lastname: Saleh
authors.affiliation: SCRI, Tennessee Oncology, PLLC, Nashville.
authors.forename: J
authors.initials: J
authors.lastname: Bendell
authors.affiliation: SCRI, Tennessee Oncology, PLLC, Nashville.
authors.forename: J R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: SCRI, Tennessee Oncology, PLLC, Nashville.
authors.forename: S
authors.initials: S
authors.lastname: Jones
authors.affiliation: University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: C D
authors.initials: CD
authors.lastname: Kurkjian
authors.affiliation: University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: K M
authors.initials: KM
authors.lastname: Moore
authors.affiliation: Arqule, Inc., Woburn.
authors.forename: J
authors.initials: J
authors.lastname: Kazakin
authors.affiliation: Arqule, Inc., Woburn.
authors.forename: G
authors.initials: G
authors.lastname: Abbadessa
authors.affiliation: Arqule, Inc., Woburn.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: BioMarin Pharmaceutical, Inc., Novato.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Arqule, Inc., Woburn.
authors.forename: B
authors.initials: B
authors.lastname: Schwartz
authors.affiliation: St Luke's Medical Center, Houston, USA.
authors.forename: L H
authors.initials: LH
authors.lastname: Camacho
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011760:Pyrrolidinones / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage; D000093542:Gemcitabine
chemical_list: C551661:ARQ 197; D011760:Pyrrolidinones; D011804:Quinolines; D003841:Deoxycytidine; D019859:Proto-Oncogene Proteins c-met; D000093542:Gemcitabine
keywords: gemcitabine; phase I; tivantinib