Phase 2b, Trial of Intravesical DTA-H19/PEI in Patients With Intermediate-Risk Superficial Bladder Cancer

DTA-H19, is a doubled stranded DNA plasmid that carries the gene for the diphtheria toxin A
(DT-A) chain under the regulation of the H19 promoter sequence. This is a Patient-Oriented,
Targeted Therapy as DT-A chain expression is triggered by the presence of H19 transcription
factors that are upregulated in tumor cells. The selective initiation of toxin expression
results in selective tumor cell destruction via inhibition of protein synthesis in the tumor
cell, enabling highly targeted cancer treatment.

Inclusion Criteria:

To be eligible to participate in this study, patients must:

1. Provide written informed consent.

2. Have intermediate-risk recurrent superficial TCC of the bladder defined as Stage Ta
(low or high grade) or T1 (but with penetration into no more than ½ of the lamina
propria), low grade (grade 1 or grade 2), as confirmed by histopathology, and have
not recurred within 3-months of a complete course of a prior acceptable therapy
(i.e., 6-weekly intravesical administrations of BCG or standard adjuvant treatment
with thiotepa, doxorubicin, epirubicin, valrubicin, or mitomycin C).

3. Have complete resection of all papillary tumors with the exception of a single
superficial papillary tumor that is appropriate to be a marker tumor (<1 cm in
diameter).

4. Have ≥ 2 tumor and ≤ 7 tumors visible during cystoscopy and no tumor larger than 3
cm in diameter. If only one tumor is present, it must be large enough to obtain a
biopsy specimen adequate to determine the tumor stage and grade and leave a marker
tumor.

5. Have at least one tumor specimen resected before the start of the study that was
positive for H19 expression by ISH. H19 expression positive is defined as >= 60 % of
the tumor cells in the specimen expressing H19 at a moderate staining intensity.

6. Have failed at least one prior standard intravesical treatment including chemotherapy
with mitomycin C, thiotepa, valrubicin, doxyrubicin, or epirubicin, or immunotherapy
with BCG. Failure after treatment with chemotherapy is defined as recurrent disease
after at least one intravesical instillation of drug. Failure after treatment with
BCG is defined as intolerance to treatment such that treatment was discontinued or
after having received 6 or more BCG instillations there is recurrent or persistent
disease 3 or more months after initiation of BCG treatment.

7. Have a Karnofsky's performance status of greater than or equal to 60%.

8. Have adequate bone marrow reserve: Hemoglobin > 10 g/dL, WBC greater than or equal
to 3000/mm3, and platelets > 100,000 /mm3.

9. Have adequate renal function with serum creatinine < 1.5 x the laboratory upper limit
of normal (ULN).

10. Have adequate liver function with serum biliru¬bin, AST/SGOT and ALT/SGPT < 2 times
the laboratory ULN.

11. Be at least 18 years of age.

12. If male, agree to use a condom, if sexually active, and if female, agree to practice
one of the acceptable methods of birth control or be surgically sterile or
postmenopausal (greater than 1 year post last menstrual cycle.

Exclusion Criteria:

To be eligible to participate in this study, patients must not:

1. Have current diagnosis or history of Stage T1 (high grade) or Stage T2 or higher or
CIS.

2. Have severe concomitant disease that might limit compliance or completion of the
protocol.

3. Have a tumor in a diverticulum, in the prostatic urethra, or covering the ureteral
orifice.

4. Have any other malignancy that might impact 5-year survival or might be potentially
confused with TCC.

5. Have congenital or acquired immune deficiencies.

6. Be receiving cytotoxic drugs or corticosteroids.

7. Have received intravesical therapy within 8 weeks prior to study entry.

8. Have received radiation therapy for their bladder cancer at any time or any other
conditions including pelvic irradiation for any condition within 4 months prior to
study entry.

9. Have active infections (including urinary tract infections) defined as viral,
bacterial, or fungal infections requiring therapy, HIV-positive status, concurrent
febrile illness, or gross hematuria.

10. Have biopsy, TUR, or traumatic catheterization within 14 days of start of treatment.

11. If female, be pregnant or breast feeding.

12. Have participated in any therapeutic research study within the last 8 weeks.

13. Have participated in any other gene therapy study including patients who have
received DTA-H19/PEI in the past.