• The maximum tolerated dose (MTD)
  

• The percentage increase or reduction in the area of marker lesions
  
• The number of patients with progressive disease
  
• The time to disease progression
  

This study is designed to assess the safety and preliminary efficacy of five different doses of DTA-H19 given as six intravesical infusions into the bladder of patients with superficial bladder cancer [stages Ta and carcinoma in situ (CIS)] who have failed intravesical therapy with Bacille Calmette-Guérin (BCG). The primary safety outcome measure is the maximum tolerated dose (MTD). DTA-H19 is a DNA plasmid that contains H19 gene regulatory sequences that drive the expression of an intracellular toxin [diphtheria toxin A (DTA) chain]. This is a Patient-Oriented, Targeted Therapy as DTA expression is triggered by the presence of H19 transcription factors found only in bladder tumor and not normal bladder cells.

A maximum of 18 patients with histologically confirmed H19 positive superficial bladder cancer with multiple or recurrent stage Ta tumors or CIS will be included in this study. Patients with any grade 3, or any stage T1 or higher stage, will be excluded. This is a multicenter, dose escalation study in which, after eligibility criteria have been met, patients in five groups of 3 patients each, will receive escalating doses of DTA-H19 intravesically over a seven-week period. Treatments will be given weekly for three weeks followed one week later by safety and disease assessments, then another 3 weekly instillations will be performed. Each dose cohort will receive the same dose for all treatments. The first dose cohort will receive 2 mg of DTA-H19 plasmid per intravesical treatment for all treatments. The next dose cohort of 3 patients will receive 4 mg, the next 6 mg, the next 12 mg,and then the final dose cohort will receive 20 mg of DTA-H19 plasmid DNA. All doses will be mixed with polyethylenimine (PEI) to improve transduction efficiency.

Doses will be escalated if none of the first three patients in the preceding dose cohort experience a dose limiting toxicity (DLT) after the first three weekly intravesical treatments. Clinical responses will be assessed 4, 8, and 12 weeks after the start of treatment. If the stage Ta marker lesion is still present at the week 12 assessment, it will be resected by transurethral resection (TUR). Patients whose disease has not progressed (i.e., no new lesions, increase in the size of the marker lesion, by at least 50%, or increase in stage or any grade 3) will be offered continued once monthly treatments and follow-up for up to one year