Efficacy and Safety of Multi-Instillations of Apaziquone in Patients With Non-Muscle Invasive Bladder Cancer
Efficacy and Safety of Multi-Instillations of Apaziquone in Patients With Non-Muscle Invasive Bladder Cancer
This is an international, multicenter, double-blind, placebo-controlled, randomized study.
 All eligible patients entering the open label phase of the study will receive a single
 immediate instillation of apaziquone (4 mg in 40 mL diluent), post transurethral
 resection-bladder tumor (TURBT). Following Central Pathology review of histology and Double
 Blind Phase qualification, patients with confirmed eligibility will be randomized to receive
 either 6 weekly intravesical instillations of apaziquone or matching placebo and undergo
 cystoscopic and safety assessments every 3 months for 24 months from randomization. Patients
 with histologic evidence of recurrent disease during the study will be treated according to
 current treatment guidelines or local standard of care. Safety and efficacy assessments will
 be performed at 3 month intervals for all randomized patients throughout the study. Patients
 who receive single dose of apaziquone immediately following TURBT and are not eligible for
 randomization will be followed for 3 months by cystoscopic exam and safety assessments.
Inclusion Criteria:

 Open Phase Inclusion Criteria:

 1. Has the patient given written informed consent and is the patient willing and able to
 abide by the protocol?

 2. Is the patient 18 years old or above?

 3. If the patient is a female of childbearing potential, is she using an
 acceptable/effective method of contraception?

 4. Does the female patient of childbearing potential have a negative serum pregnancy test
 at screening?

 5. Does the patient with clinically apparent primary or recurrent low grade Ta NMIBC have
 :

 -  multiple tumors (2-7)

 -  No single Tumor > 3 cm

 -  No history / evidence of Tis

 Or does the patient with clinically apparent primary or recurrent high grade Ta NMIBC
 have:

 -  A single tumor that is ≤ 3 cm

 -  No history / evidence of Tis

 6. Is the patient able to retain bladder instillations for a minimum of 60 minutes?

 7. Did the patient have upper urinary tract evaluation to exclude urothelial carcinoma,
 hydronephrosis or renal cell carcinoma or other renal cancers in the 6 months prior to
 study screening?

 8. Is patient's urethra (including prostatic urethra in men) endoscopically free of any
 visible TCC?

 9. For patients with recurrent tumor, did the patient have at least a 6-month
 cystoscopically-confirmed tumor-free interval between the last tumor recurrence and
 the time of screening?

 10. Has the male patient with a prostate specific antigen (PSA) between 4 and 10 ng/mL had
 a diagnostic evaluation that reasonably excludes the diagnosis of prostate cancer in
 the opinion of the Investigator?

 Double-Blind Phase Inclusion Criteria:

 1. Was all visible tumor resected at the initial TURBT?

 2. Does Central Pathology review of the patient's bladder tumor confirm:

 -  Low grade Ta disease for multiple tumors (2 - 7) or

 -  High Grade Ta disease for single tumor

 -  No microscopic evidence of lymphovascular invasion and/or evidence of tumor
 thromboemboli

 Exclusion Criteria:

 Open Phase Exclusion Criteria:

 1. Has the patient received any previous pelvic radiotherapy (includes external beam
 and/or brachytherapy)?

 2. Has the patient ever received apaziquone?

 3. Has the patient received an induction course (completed 5 of 6 scheduled weekly
 instillations) of intravesical BCG (± interferon) with the last dose given less than
 12 months ago?

 4. Has the patient had any prior intravesical chemotherapy, exclusive of single-dose
 adjuvant intravesical chemotherapy immediately post-TURBT?

 5. Does the patient have a history of urinary retention or a post void residual ≥ 250 cc
 by bladder scan or ultrasound (post void residual test may be repeated up to 3 times)?

 6. Does the patient have or has the patient had any bladder tumor with histology other
 than transitional cell carcinoma?

 7. Does the patient have or has the patient had micro-papillary transitional cell
 carcinoma?

 8. If the patient has recurrent papillary disease of the bladder, has the pathology been
 anything other than pTa in the past?

 9. Does the patient have an active urinary tract infection confirmed by culture or a
 documented history of recurrent UTI (≥ 6 for females and ≥2 for males per year) in the
 prior 2 years?

 10. Does the patient have a bleeding disorder or a screening platelet count < 50 x 109/L?

 11. Does the patient have a screening hemoglobin < 10 mg/dL?

 12. Does the male patient have a serum PSA > 10 ng/mL?

 13. Does the patient have a history of Acquired Immunodeficiency Syndrome or HIV positive?

 14. Does the patient have a condition or a concurrent severe and/or uncontrolled medical
 or psychiatric disease (e.g., uncontrolled diabetes, decompensated congestive heart
 failure, myocardial infarction within 6 months of study, unstable and uncontrolled
 hypertension, or an active uncontrolled infection), which could compromise
 participation, compliance with scheduled visits and/or completion of the study?

 15. Has the patient participated in an investigational protocol within the past 90 days?

 16. Is the patient pregnant or breast feeding?

 17. Does the patient have a life expectancy of <3 years?

 18. Has the patient had any other malignancy or received therapy for any malignancy in the
 last five years except

 -  non-melanoma skin tumors

 -  stage 0 (in situ) cervical carcinoma

 -  undetectable PSA for ≥1 year following definitive therapy for localized prostate
 cancer?

 19. Does the patient have documented vesicoureteral reflux or an indwelling ureteral
 stent?

 20. Does the patient have tumor in a bladder diverticulum?

 21. Does the patient have a known allergy to red color food dye?