title: Phase 1/2 study of intravenous paclitaxel and oral cyclophosphamide in pretreated metastatic urothelial bladder cancer patients.
abstract: BACKGROUND
  To the authors' knowledge, no previous studies have been reported with the combination of paclitaxel and oral cyclophosphamide in patients with metastatic bladder cancer. A phase 1/2 study was conducted of paclitaxel in combination with oral cyclophosphamide for patients with advanced urothelial bladder cancer who had been previously treated with gemcitabine/cisplatin chemotherapy as first-line metastatic treatment.
  
  
  METHODS
  This was a single-arm phase 1/2 study. Patients were treated with paclitaxel and oral cyclophosphamide at 3-week intervals until disease progression or irreversible toxicity occurred. Primary endpoints were to determine the maximum tolerated doses (MTD) and objective response rate; secondary endpoints were safety, time to disease progression (TTP), and overall survival (OS).
  
  
  RESULTS
  Forty-four patients were enrolled. Dose levels of paclitaxel of 175 mg/m(2) (Day 1) and cyclophosphamide of 50 mg (Days 1-7 orally) (dose level I) of a 21-day cycle were tolerated without dose-limiting toxicities (DLTs). At a cyclophosphamide dose of 100 mg (dose level II) the MTD was exceeded; 3 of 6 patients experienced a DLT (grade 3 constipation and grade 4 neutropenia and thrombocytopenia [toxicities were graded using National Cancer Institute Common Toxicity Criteria (version 3.0)]). Dose level I was expanded and determined to be the MTD. A total of 32 patients were treated at dose level I in the phase 2 portion. Partial responses were observed in 31% of patients (10 of 32 patients; 95% confidence interval [95% CI], 17%-45%). Grade 1/2 vomiting, peripheral neuropathy, and neutropenia were the most common side effects, noted in 11 (34%), 8 (25%), and 10 (31%) patients, respectively. The median TTP was 5 months (95% CI, 2 months-7.5 months) and the median OS was 8 months (95% CI, 4 months-14 months).
  
  
  CONCLUSIONS
  The combination of paclitaxel and cyclophosphamide is well tolerated and associated with promising efficacy. Further trials are needed to confirm these preliminary results.
authors.affiliation: Department of Clinical and Molecular Oncology, Federico II University, Naples, Italy. giuseppedilorenzoncol@hotmail.com
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Lorenzo
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Montesarchio
authors.forename: Riccardo
authors.initials: R
authors.lastname: Autorino
authors.forename: Teresa
authors.initials: T
authors.lastname: Bellelli
authors.forename: Nicola
authors.initials: N
authors.lastname: Longo
authors.forename: Ciro
authors.initials: C
authors.lastname: Imbimbo
authors.forename: Emilio
authors.initials: E
authors.lastname: Morelli
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giannarini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mirone
authors.forename: Sabino
authors.initials: S
authors.lastname: De Placido
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D015996:Survival Rate; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D003520:Cyclophosphamide; D017239:Paclitaxel