title: Phase I Results from a Study of Crizotinib in Combination with Erlotinib in Patients with Advanced Nonsquamous Non-Small Cell Lung Cancer.
abstract: This phase I trial was conducted to determine the safety, maximum tolerated dose (MTD)/recommended phase II dose, and efficacy of crizotinib plus erlotinib in patients with advanced NSCLC.
  
  
  
  Patients with NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 2 after failure of one or two prior chemotherapy regimens were eligible. Erlotinib, 100 mg, was given continuously once daily starting between day -14 and -7; crizotinib, 200 mg twice daily (dose level 1) or 150 mg twice daily (dose level -1), was added continuously beginning on day 1 of treatment cycle 1. Potential pharmacokinetic interactions between crizotinib and erlotinib were evaluated.
  
  
  
  Twenty-seven patients received treatment; 26 received crizotinib plus erlotinib. Frequent adverse events were diarrhea, rash, decreased appetite, and fatigue. Dose-limiting toxicities were dehydration, diarrhea, dry eye, dysphagia, dyspepsia, esophagitis and vomiting. The MTD was crizotinib, 150 mg twice daily, with erlotinib, 100 mg once daily. Crizotinib increased the erlotinib area under the concentration-time curve 1.5-fold (dose level -1) and 1.8-fold (dose level 1). The plasma level of crizotinib appeared to be unaffected by coadministration of erlotinib. Two patients whose tumors harbored activating EGFR mutations achieved confirmed partial responses, one at each crizotinib dose level.
  
  
  
  The MTD of the combination of crizotinib and erlotinib in patients with advanced NSCLC was crizotinib, 150 mg twice daily, with erlotinib, 100 mg once daily, which is less than the approved dose of either agent. The phase II portion of the study was not initiated.
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California at Irvine Medical Center, Orange, California. Electronic address: siou@uci.edu.
authors.forename: Sai-Hong Ignatius
authors.initials: SI
authors.lastname: Ou
authors.affiliation: Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Govindan
authors.affiliation: Seattle Cancer Care Alliance and the University of Washington, Seattle, Washington.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Eaton
authors.affiliation: Ohio State University Comprehensive Cancer Center and the James Cancer Hospital, Columbus, Ohio.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Otterson
authors.affiliation: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gutierrez
authors.affiliation: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.affiliation: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Argiris
authors.affiliation: Pfizer Oncology, Milan, Italy.
authors.forename: Nicoletta M
authors.initials: NM
authors.lastname: Brega
authors.affiliation: Pfizer Oncology, Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Usari
authors.affiliation: Pfizer Oncology, San Diego, California.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Tan
authors.affiliation: Pfizer Oncology, San Diego, California.
authors.forename: Steffan N
authors.initials: SN
authors.lastname: Ho
authors.affiliation: Birmingham Veterans Administration Hospital, Birmingham, Alabama; University of Alabama-Birmingham Comprehensive Cancer Center, Birmingham, Alabama.
authors.forename: Francisco
authors.initials: F
authors.lastname: Robert
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000188:drug therapy* / Q000556:secondary; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002291:Carcinoma, Papillary / Q000188:drug therapy* / Q000556:secondary; D000077547:Crizotinib; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D015996:Survival Rate; D014018:Tissue Distribution
chemical_list: D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D000069347:Erlotinib Hydrochloride
keywords: Crizotinib; EGFR inhibitor; Erlotinib; MET inhibitor; Phase I combination trial