title: Paclitaxel-hyaluronic acid for intravesical therapy of bacillus Calmette-Guérin refractory carcinoma in situ of the bladder: results of a phase I study.
abstract: OBJECTIVE
  Carcinoma in situ represents high grade anaplasia of the bladder mucosa. Intravesical immunotherapy with bacillus Calmette-Guérin is the gold standard treatment for patients with carcinoma in situ. Patients with carcinoma in situ refractory to bacillus Calmette-Guérin are candidates for major surgery such as radical cystectomy. We identified the maximum tolerated dose and the recommended dose, and evaluated the safety profile of paclitaxel-hyaluronic acid bioconjugate given by intravesical instillation to patients with carcinoma in situ refractory to bacillus Calmette-Guérin.
  
  
  METHODS
  A total of 16 patients with carcinoma in situ refractory to bacillus Calmette-Guérin were enrolled in a phase I, open label, single institution study. A minimum of 3 eligible patients were included per dose level. Paclitaxel-hyaluronic acid solution (ONCOFID-P-B™) was administered for 6 consecutive weeks. The primary objective was to identify the maximum tolerated dose and the recommended dose. As secondary objectives the safety profile of ONCOFID-P-B, the pharmacokinetic profile after each instillation and the tumor response were also evaluated.
  
  
  RESULTS
  No dose limiting toxicity occurred at any drug level evaluated. The plasma levels of the study drug were always below the lower limit of quantification at all tested doses after each instillation. A total of 11 adverse events were reported by 7 patients and 9 (60%) showed complete treatment response.
  
  
  CONCLUSIONS
  Intravesical instillation of ONCOFID-P-B for carcinoma in situ refractory to bacillus Calmette-Guérin showed minimal toxicity and no systemic absorption in the first human intravesical clinical trial to our knowledge. Finally, satisfactory response rates were observed.
authors.affiliation: Department of Urology, Catholic University School of Medicine, Rome, Italy.
authors.forename: P F
authors.initials: PF
authors.lastname: Bassi
authors.forename: A
authors.initials: A
authors.lastname: Volpe
authors.forename: D
authors.initials: D
authors.lastname: D'Agostino
authors.forename: G
authors.initials: G
authors.lastname: Palermo
authors.forename: D
authors.initials: D
authors.lastname: Renier
authors.forename: S
authors.initials: S
authors.lastname: Franchini
authors.forename: A
authors.initials: A
authors.lastname: Rosato
authors.forename: M
authors.initials: M
authors.lastname: Racioppi
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects; D000283:Administration, Intravesical; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001500:BCG Vaccine / Q000627:therapeutic use; D001707:Biopsy, Needle; D002278:Carcinoma in Situ / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D003558:Cystoscopy / Q000379:methods; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000009:adverse effects; D007558:Italy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D018579:Patient Selection; D016019:Survival Analysis; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D006820:Hyaluronic Acid; D017239:Paclitaxel