Trial Information

Phase 1/2a, Dose-Escalation, Safety and Proof of Concept Study of Intravesical DTA-H19 in Patients With Superficial Bladder Cancer

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