title: A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors.
abstract: BACKGROUND
  Afatinib, an irreversible ErbB family blocker, demonstrated synergistic inhibition of epidermal growth factor receptor-mutant cell growth with pemetrexed. This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of afatinib plus pemetrexed in patients with advanced solid tumors.
  
  
  METHODS
  In a 3 + 3 dose-escalation design, patients were given intravenous pemetrexed (500 mg/m(2)) on day 1 of a 21-day cycle (maximum 6 cycles), combined with continuous daily oral afatinib (schedule A [SA]; starting dose 30 mg, escalation to 50 mg) or pulsed-dose daily oral afatinib (schedule B [SB]; starting dose 50 mg, escalation to 70 mg) on days 1-6 of each 21-day cycle. Primary endpoint was determination of MTD based on dose-limiting toxicities (DLTs) in cycle 1.
  
  
  RESULTS
  Fifty-three patients were treated (SA: n = 23; SB: n = 30). Eight patients had DLTs in SA, 11 patients in SB; diarrhea and fatigue were the most common. MTD of afatinib was 30 mg in SA and 50 mg in SB. Six patients in SA and eight in SB completed 6 treatment cycles. One patient in each schedule had confirmed objective response; 18/53 patients had disease control (SA: n = 7; SB: n = 11). Most frequent drug-related adverse events were diarrhea, rash, fatigue, and stomatitis. No relevant pharmacokinetic interactions were observed.
  
  
  CONCLUSIONS
  Continuous- or pulsed-dose afatinib combined with pemetrexed exhibited a manageable safety profile. Pulsed dosing conferred no apparent safety or dose advantage. Continuous-dose afatinib 30 mg/day with pemetrexed is recommended for phase II studies.
authors.affiliation: Cross Cancer Centre, 11560 University Ave NW, Edmonton, Alberta, T6G 1Z2, Canada, quincy.chu@albertahealthservices.ca.
authors.forename: Quincy S
authors.initials: QS
authors.lastname: Chu
authors.forename: Randeep
authors.initials: R
authors.lastname: Sangha
authors.forename: Sebastien J
authors.initials: SJ
authors.lastname: Hotte
authors.forename: Gwen
authors.initials: G
authors.lastname: Sergenson
authors.forename: David
authors.initials: D
authors.lastname: Schnell
authors.forename: Vikram K
authors.initials: VK
authors.lastname: Chand
authors.forename: Hal W
authors.initials: HW
authors.lastname: Hirte
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000068437:Pemetrexed; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D066066:Response Evaluation Criteria in Solid Tumors
chemical_list: D005971:Glutamates; D011799:Quinazolines; D000068437:Pemetrexed; D000077716:Afatinib; D006147:Guanine