title: Phase I trial of topotecan in combination with gemcitabine in refractory solid tumor patients.
abstract: OBJECTIVE
  To determine maximum tolerated dose (MTD) and evidence of antitumor activity of topotecan in combination with gemcitabine in refractory cancer patients.
  
  
  METHODS
  This was a Phase I, prospective, dose-escalation trial that employed a novel-dosing schema to investigate clinical safety. Patients were treated in six cohorts with topotecan (T)+gemcitabine (G). The doses of T and G were administered by 30-minute IV infusion, T on days one through five (0.3 mg/m2 to 1 mg/m2) and G on days one and 15 of a 28-day cycle (1000 mg/m2 to 1500 mg/m2). Toxicity was monitored.
  
  
  RESULTS
  Twenty-three cancer patients were enrolled (colorectal, n=5; lung, n=4; gastric, n=4; esophageal, n=2; other, n=8). Two of three patients developed grade 3 nonhematologic toxicity attributed to study regimen, thereby fulfilling dose limiting toxicity requirements at cohort 6 (T, 1 mg/m2, G, 1500 mg/m2). Maximum tolerated dose (MTD) was established at cohort 5 (T, 1 mg/m2, G, 1250 mg/m2). Ten patients were treated at cohort 5. Nonhematologic adverse effects (AEs) >grade 3 attributed to the study regimen were not observed. Hematologic toxicity was frequent. Twenty-five percent of patients in cohort 2 and 50% of patients in cohorts 4, 5, and 6 had a reduction of ANC to <500 mm3. All neutropenic episodes were less than one week in duration. Five of the patients in the last three cohorts required delay and/or dose-reduction of G. Nineteen of 23 enrolled patients were evaluable for response. Two patients achieved a minimal response.
  
  
  CONCLUSIONS
  The MTD was observed at a T dose of 1 mg/m2 administered on days 1 through 15, and a G dose of 1250 mg/m2 administered on days 1 and 15 via 30 minute intravenous (IV) infusion.
authors.affiliation: US Oncology, Dallas, Texas, USA. john.nemunaitis@usoncology.com
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
authors.forename: C Casey
authors.initials: CC
authors.lastname: Cunningham
authors.forename: Suetislava
authors.initials: S
authors.lastname: Vukelja
authors.forename: R L
authors.initials: RL
authors.lastname: Ruxer
authors.forename: Ned
authors.initials: N
authors.lastname: Adams
authors.forename: Dawn
authors.initials: D
authors.lastname: Rich
authors.forename: A Scott
authors.initials: AS
authors.lastname: Paulson
authors.forename: Jane B
authors.initials: JB
authors.lastname: MacEachern
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011446:Prospective Studies; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D019772:Topotecan; D000093542:Gemcitabine