title: A Phase I study of 9-nitrocamptothecin given concurrently with capecitabine in patients with refractory, metastatic solid tumors.
abstract: BACKGROUND
  9-Nitrocamptothecin (9-NC) is an orally available camptothecin analog with antineoplastic activity that results from the inhibition of DNA topoisomerase I. Previous studies have suggested that it has significant clinical efficacy. The primary toxicities of 9-NC include gastrointestinal upset, cystitis, and myelosuppression at the maximum tolerated dose (MTD) of 1.5 mg/m(2) per day. Capecitabine is a prodrug of 5-fluorouracil that is approved for use in patients with metastatic breast carcinoma and colorectal carcinoma, and it offers the convenience of oral administration. This trial examined the combination of these two oral agents in patients with metastatic solid tumors.
  
  
  METHODS
  Capecitabine was administered twice daily at a total daily dose of 1300 mg/m(2) per day for 14 days followed by a 1-week break. 9-NC was taken daily 5 days per week for 2 weeks in a dose-escalation scheme. The starting dose was 0.5 mg/m(2) per day, and cohorts of 3 patients were enrolled until the dose level reached 1.25 mg/m(2) per day.
  
  
  RESULTS
  Twenty-one patients were evaluable for toxicity and response, and nausea and emesis were the dose-limiting toxicities. Despite antiemetic prophylaxis with 5-hydroxytryptamine-3 antagonists, 2 of 3 patients at the 1.0 mg/m(2) per day dose level had Grade 2-3 nausea; while at the MTD of 0.75 mg/m(2) per day, 3 of 14 patients had Grade > or = 2 nausea. The incidence of hand-foot syndrome, stomatitis, diarrhea, and myelosuppression did not exceed that expected with capecitabine alone, suggesting that 9-NC does not exacerbate these side effects. No objective responses were seen. Stable disease was observed in 9 patients (43%) with a median duration of 11 weeks, including 3 patients with responses that lasted from 20 weeks to 40 weeks.
  
  
  CONCLUSIONS
  The combination of 9-NC and capecitabine with the current schedule was limited in dose by nausea and had minimal clinical efficacy in a group of patients with refractory solid tumors.
authors.affiliation: Department of Hematology/Oncology, Massachusetts General Hospital, Cox Building Room 640, 100 Blossom Street, Boston, MA 02114, USA. dmichaelson1@partners.org
authors.forename: M Dror
authors.initials: MD
authors.lastname: Michaelson
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.forename: Rocio
authors.initials: R
authors.lastname: Garcia-Carbonero
authors.forename: J
authors.initials: J
authors.lastname: Paul Eder
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000069287:Capecitabine; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D003841:Deoxycytidine; D000069287:Capecitabine; C079905:rubitecan; D005472:Fluorouracil; D002166:Camptothecin