title: Phase I study of a 3-drug regimen of gemcitabine/cisplatin/pemetrexed in patients with metastatic transitional cell carcinoma of the urothelium.
abstract: OBJECTIVE
  Gemcitabine (G) plus cisplatin (C) is standard care for metastatic transitional cell carcinoma (TCC) of the urothelium. Pemetrexed (P), alone or in combination with G, is active in metastatic TCC. However, the safety and efficacy of P combined with GC therapy is unknown. This phase I trial was designed to determine the maximum tolerated dose (MTD) of GC followed by P+G in patients with metastatic TCC.
  
  
  METHODS
  Cohorts of 3 to 6 patients received escalating doses 28-day cycles (maximum 6 cycles): G 800-1,000 mg/m2 on days 1 and 15; P 400-500 mg/m2 on day 15; and C 50-70 mg/m2 on day 1. All patients received folic acid, vitamin B12, and full supportive care. The 3+3 standard phase I escalation rule was used to determine MTD.
  
  
  RESULTS
  Fifteen patients registered: 13/15 white males; median age 70 years (range, 53-82); 11/15 had KPS>or=90. At dose level 0, 2/4 patients experienced unrelated DLTs, and 1 patient was replaced (completed<1 cycle). Dose escalation proceeded to dose level 1. At level 1, 4/6 patients experienced DLTs; dosing decreased to level 0 and 4/5 patients experienced DLTs. The MTD was not determined. The 2 patients that completed 6 cycles both had partial responses. Grades 3-4 hematologic toxicities included neutropenia (60%), leukopenia (20%), and febrile neutropenia (13%).
  
  
  CONCLUSIONS
  Adding P to the standard GC regimen as first-line therapy for metastatic TCC produced no benefit. The MTD exceeded therapeutic gemcitabine and cisplatin doses for urothelial cancer and thus the study was aborted.
authors.affiliation: US Oncology Research, Inc., Genitourinary Oncology Program, Houston, TX, USA. Thomas.Hutson@usoncology.com
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: Svetislava
authors.initials: S
authors.lastname: Vukelja
authors.forename: Daniel
authors.initials: D
authors.lastname: Atienza
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
authors.forename: Robert
authors.initials: R
authors.lastname: Delaune
authors.forename: Margaret
authors.initials: M
authors.lastname: Deutsch
authors.forename: Philip Y
authors.initials: PY
authors.lastname: Dien
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gregory
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kolodziej
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Muscato
authors.forename: Robert N
authors.initials: RN
authors.lastname: Raju
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ruxer
authors.forename: Stephanie
authors.initials: S
authors.lastname: Mull
authors.forename: Des
authors.initials: D
authors.lastname: Ilegbodu
authors.forename: Karen
authors.initials: K
authors.lastname: Hood
authors.forename: Steven
authors.initials: S
authors.lastname: Nicol
authors.forename: William
authors.initials: W
authors.lastname: Berry
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000068437:Pemetrexed; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D019459:Urothelium / Q000187:drug effects* / Q000473:pathology; D014805:Vitamin B 12 / Q000627:therapeutic use; D014803:Vitamin B Complex / Q000627:therapeutic use; D000093542:Gemcitabine
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D003841:Deoxycytidine; D014803:Vitamin B Complex; D006147:Guanine; D005492:Folic Acid; D014805:Vitamin B 12; D002945:Cisplatin; D000093542:Gemcitabine