A Study of Intravesical Apaziquone as a Surgical Adjuvant in Patient Undergoing TURBT

This is a Phase 3, randomized, multicenter, multi-arm, placebo-controlled, double-blind study
of apaziquone in patients with ≤4 non-muscle invasive bladder tumors, ≤3.5 cm in diameter,
all of which must have been fully resected at TURBT.

In addition to Screening, patients will undergo an assessment of urothelial carcinoma of the
bladder via cystoscopy for clinically apparent tumor Ta, G1-G2.

Following TURBT on Day 1, eligible patients will be randomized to one of three treatment arms
in a 1:1:1 ratio :

Arm 1 : One Dose of Apaziquone:

- Day 1: administration of 4 mg of apaziquone 60±30 minutes post-TURBT

- Day 15 (±5 days): administration of placebo

Arm 2 : Two Doses of Apaziquone :

- Day 1 : administration of 4 mg of apaziquone 60±30 minutes post-TURBT

- Day 15 (±5 days): administration of 4 mg of apaziquone

Arm 3: Placebo :

- Day 1 : administration of placebo 60±30 minutes post-TURBT

- Day 15 (±5 days) : administration of placebo

Once randomized, Day 1 study drug instillation will occur 60 ±30 minutes post TURBT. Patients
will return on Day 15 (±5 days) for a second instillation unless their pathology results are
available and show non Ta, G1-G2 histology; in the absence of local pathology results by the
Day 15 visit, patients will receive a second instillation of study drug. All histology
specimens will be reviewed by a local pathology laboratory and all clinical treatment
decisions and study analyses will be based on the local pathology review. Patients whose
pathology is other than Ta, G1-G2 will be followed for safety at Day 35 (±5 days) from the
last dose of study drug and then discontinued from the study.

Patients with pathology confirmed Ta, G1-G2 disease will be followed according to the
schedule below :

- Cystoscopic examination and urine cytology every 90 days (±10 days) (calculated from
date of TURBT) through 24 months for tumor recurrence and progression.

- If at any time during the 24 month follow up period there is a tumor recurrence, the
patient will continue on study with follow-up cystoscopic examination and urine cytology
every 90 days (±10 days) (calculated from date of TURBT) through the end of 24 months.
Patients with a recurrence are permitted to have a follow-up TURBT.

- If at any time during the 24 month follow up period there is a tumor recurrence and/or
patient is started on another therapy, the patient will be followed by telephone, for
safety every 90 days (±10 days) (calculated from date of TURBT) through the end of 24
months.

Duration of Study: The duration of the study for each patient will be approximately 24 months
including:

- Screening Period : 30-days

- Treatment Period : Day 1 and Day 15 (±5 days)

- Safety and Follow-up Period: 24-months

Inclusion Criteria:

1. Patient must have a diagnosis with urothelial carcinoma of the bladder with clinically
apparent tumor Ta, G1-G2.

2. Patient will have ≤4 tumors, none of which exceeds 3.5 cm in diameter.

3. Patient must be willing to give written informed consent and must be able to adhere to
dosing and visit schedules, and meet all study requirements.

4. Patient is at least 18 years of age at randomization.

5. Patient must be willing to practice two forms of contraception, one of which must be a
barrier method, from study entry until at least 35 days after the last dose of the
study drug.

6. Females of childbearing potential must have a negative pregnancy test within 30 days
prior to randomization. Females who are postmenopausal for at least 1 year (defined as
more than 12 months since last menses) or are surgically sterilized do not require
this test.

Exclusion Criteria:

1. Patient has an active concurrent malignancy/life-threatening disease. If there is a
history of prior malignancies/life-threatening diseases, the patient is to be disease
free for at least 5 years. Patients with other prior malignancies less than 5 years
before study entry may still be enrolled if they have received treatment resulting in
complete resolution of the cancer and currently have no clinical, radiologic, or
laboratory evidence of active or recurrent disease.

2. Patient has positive urine cytology for malignancy at Screening.

3. Patient has an active uncontrolled infection, including a urinary tract infection,
underlying medical condition, or other serious illness that would impair the ability
of the patient to receive protocol treatment.

4. Patient has used any investigational drugs, biologics, or devices within 30 days prior
to study treatment or plans to use any of these during the course of the study.

5. Patient has had any prior intravesical chemotherapy, immunotherapy, or previous
exposure to apaziquone.

6. Patient has or has ever had

- Upper tract Transitional Cell Carcinoma (TCC).

- Urethral tumor (prostatic urethra included).

- Any invasive bladder tumor known to be other than tumor Ta, G1-G2.

- Any evidence of lymph node or distant metastasis.

- Any bladder tumor with histology other than TCC.

- Carcinoma in situ (CIS).

7. Patient has a tumor in a bladder diverticulum.

8. Patient has received any pelvic radiotherapy (including external beam and/or
brachytherapy.)

9. Patient has a bleeding disorder or a screening platelet count <100×109/L.

10. Patient has screening hemoglobin <10 mg/dL.

11. Patient has any unstable medical condition that would make it unsafe to undergo TURBT.

12. Patient has a history of interstitial cystitis.

13. Patient has a history of allergy to red color food dye.

14. For patients with recurrent tumor, the patient had at least a 6-month
cystoscopically-confirmed tumor-free interval between the last tumor recurrence and
screening cystoscopic examination.

15. Patient is pregnant or breast-feeding.