title: A phase I trial investigating pulsatile erlotinib in combination with gemcitabine and oxaliplatin in advanced biliary tract cancers.
abstract: Advanced biliary tract cancers (ABTC) are among the deadliest malignancies with limited treatment options after progression on standard-of-care chemotherapy, which includes gemcitabine (GEM) and oxaliplatin (OX). The epidermal growth factor receptor inhibitor erlotinib has been explored in ABTC with modest efficacy. Erlotinib given continuously may antagonize the action of chemotherapy against cycling tumor cells, but pulsatile dosing of erlotinib with chemotherapy may improve efficacy. The purpose of this study was to assess the safety of pulsatile erlotinib with GEMOX. This was a single-institution phase Ib study that enrolled adult patients with unresectable or metastatic biliary tract, pancreas, duodenal, or ampullary carcinomas that have not received any prior treatment for their disease. Dose escalation followed a standard 3 + 3 design, and dose-limiting toxicities (DLTs) were any treatment-related, first course non-hematologic grade ≥ 3 toxicity, except nausea/vomiting, or grade 4 hematologic toxicity. A dose expansion cohort in ABTC was treated at the MTD. Twenty-eight patients were enrolled and 4 dose levels were explored. The MTD was erlotinib 150 mg + GEM 800 mg/m2+ OX 85 mg/m2. DLTs were diarrhea and anemia. Most frequent toxicities were nausea (78 %), fatigue (71 %), neuropathy (68 %), and diarrhea (61 %), predominantly grade 1-2. In the ABTC patients, the objective response and disease control rates were 29 % and 94 %, respectively, and median overall survival was 18 months. Erlotinib plus GEMOX was well tolerated. Encouraging anti-tumor activity was seen as evidenced by a high disease control rate and longer median OS than standard chemotherapy in the patients with ABTC.
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA. Laura.goff@vanderbilt.edu.|Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Laura.goff@vanderbilt.edu.
authors.forename: Laura W
authors.initials: LW
authors.lastname: Goff
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA.|Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Dana B
authors.initials: DB
authors.lastname: Cardin
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Whisenant
authors.affiliation: Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.|Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.|Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Koyama
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Dahlman
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA.
authors.forename: Safia N
authors.initials: SN
authors.lastname: Salaria
authors.affiliation: Vanderbilt-Ingram Cancer Center at Cool Springs, Franklin, TN, USA.
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Young
authors.affiliation: Ohio State University, Columbus, OH, USA.
authors.forename: Kristen K
authors.initials: KK
authors.lastname: Ciombor
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA.|Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Gilbert
authors.affiliation: Vanderbilt-Ingram Cancer Center at Cool Springs, Franklin, TN, USA.
authors.forename: Stephen James
authors.initials: SJ
authors.lastname: Smith
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA.|Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, PRB 777, Nashville, TN, 37232, USA.|Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Berlin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000077150:Oxaliplatin; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016896:Treatment Outcome; D014746:Vimentin / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C513384:CDH1 protein, human; D015820:Cadherins; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D014746:Vimentin; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D000093542:Gemcitabine
keywords: Biliary tract cancers; Gemcitabine and oxaliplatin; Phase Ib trial; Pulsatile erlotinib