title: Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus Calmette-Guérin.
abstract: OBJECTIVE
  Evaluate the efficacy and safety of valrubicin for bacillus Calmette-Guérin (BCG)-refractory carcinoma in situ (CIS) of the bladder based on updated phase III pivotal trial efficacy data together with efficacy and safety data from a supportive phase II/III study.
  
  
  METHODS
  In a phase II/III open-label study (A9303), BCG refractory/intolerant adults with CIS (≥ 1 previous course of BCG or could not complete a BCG course owing to toxicity or contraindication) were randomized to receive 6 or 9 weekly intravesical valrubicin (800 mg) instillations. In the pivotal phase III open-label study, BCG-refractory/recurrent adults with CIS (≥ 2 previous courses of intravesical therapy, including ≥ 1 BCG course) received 6 weekly intravesical valrubicin (800 mg) instillations. Patients with muscle-invasive disease were excluded. Patients underwent a primary disease evaluation (PDE) at 3 months (≈ 6 weeks after last dose) that included cytoscopy, biopsy, and cytology. Disease recurrence was monitored at 3-month intervals. Complete response (CR) was defined as no evidence of disease at the PDE (month 3) and follow-up (month 6). Efficacy data from the pivotal trial reflect updated information based on US Food and Drug Administration review. Safety assessments in A9303 included local bladder adverse events (LBAEs) and other adverse events (AEs).
  
  
  RESULTS
  Eighty patients enrolled and 78 completed treatment and underwent the PDE in study A9303; in the pivotal trial, the respective numbers were 90 and 87 patients. In study A9303, 39% of patients had received ≥ 2 previous courses of BCG and 11% had received ≥ 3 courses vs. 70% and 28%, respectively, in the pivotal trial. In both studies, the CR rate was 18%. In A9303, LBAEs were the most common AEs, reported by 86% of patients during treatment and 45% during follow-up; most treatment-related LBAEs were mild to moderate. 2 serious AEs in 1 patient (azotemia/reflux nephropathy) were judged as definitely or possibly treatment related; none of the patient deaths were judged to be related to valrubicin.
  
  
  CONCLUSIONS
  Two trials of valrubicin in patients with CIS demonstrate a consistent degree of efficacy in highly pretreated patients (pivotal trial; BCG-refractory patients) and those with fewer previous therapies (A9303; BCG-refractory/intolerant patients).
authors.affiliation: University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: cdinney@mdanderson.org.
authors.forename: Colin P N
authors.initials: CP
authors.lastname: Dinney
authors.forename: Richard E
authors.initials: RE
authors.lastname: Greenberg
authors.forename: Gary D
authors.initials: GD
authors.lastname: Steinberg
mesh_terms: D015746:Abdominal Pain / Q000139:chemically induced; D000283:Administration, Intravesical; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001500:BCG Vaccine / Q000627:therapeutic use*; D002278:Carcinoma in Situ / Q000188:drug therapy*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D000075202:Contraindications; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D053159:Dysuria / Q000139:chemically induced; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care / Q000379:methods; D016032:Randomized Controlled Trials as Topic; D017211:Treatment Failure; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D014552:Urinary Tract Infections / Q000139:chemically induced
chemical_list: D001500:BCG Vaccine; C016163:valrubicin; D004317:Doxorubicin