Intravesical Photodynamic Therapy ("PDT") in BCG-Unresponsive/Intolerant Non-Muscle Invasive Bladder Cancer ("NMIBC") Patients

1. Overall Study Design and Plan: Description

   This is a phase II, open-label, single-arm, multi-center Study conducted in Canada and the United States. Patients with NMIBC CIS (with or without resected papillary disease (Ta, T1)) that are considered BCG-Unresponsive or are intolerant to BCG therapy that meet the inclusion and exclusion criteria will be enrolled and treated. The Study will consist of 90 patients who will receive one (1) Study Procedure, with up to two (2) additional re-induction Study Procedures based on patient response.

2. Screening Period

   Patients will be qualified for Study II entry by review of inclusion and exclusion criteria during the Screening Period, which will last up to 60 days.

3. Follow-Up Phase

   All patients enrolled and treated by the treatment procedure will be followed until the End of Study defined as completion of all required assessments after 15 months of follow-up post primary study treatment or due to early discontinuation or withdrawal of informed consent.

   During the Follow-Up Phase, information on efficacy and safety will be collected. Assessments will be conducted at Day 0, 7, 90, 180, 270, 360 and 450 days.

   Survival surveillance for all patients who achieve a CR or Indeterminate Response ("IR") (negative cystoscopy and positive urine cytology, without confirmatory negative bladder cancer biopsies) at four hundred and fifty (450) days and remain in Study II will be monitored for up to one thousand and eighty (1080) days post primary Study II Treatment, recording: efficacy, safety and incidence of radical cystectomy every ninety (90) days for the first seven hundred and twenty (720) days, then every one hundred and eighty (180) days, until one thousand and eighty (1080) days.

4. Study Drug and PDT Administration

Ruvidar® (TLD-1433) for intravesical administration is supplied as a lyophilisate for suspension in Sterile Water For Injection ("SWFI") into the bladder and is packaged in the dark in amber USP Type III glass vials, which are stored at 3 to 8 degree Celsius. Up to 24 hours before administration, it is reconstituted with SWFI to obtain the final clinical dilution.

Ruvidar® (TLD-1433) will be supplied to each Study II site by Theralase®. Instillations cannot be done immediately following biopsy taken by Trans-Urethral Resection of Bladder Tumour ("TURBT"). Investigators must wait a minimum of 7 days before dosing patients after a TURBT/biopsy, and/or until any bladder wall integrity issues have resolved. Dose/volume reductions are not allowed during Study II.

Upon determination of the bladder volume (during the screening period) through a self-recorded voiding diary, Ruvidar® (TLD-1433) will be diluted with SWFI to the proper concentration. On day 0 (Primary Study Procedure day), patients will be asked to restrict fluid intake 12 hours before Study Drug instillation. Study Drug must be instilled into the patient's empty bladder. Before instillation, a regular transurethral catheter should be inserted and the bladder drained. A single instillation of Ruvidar® (TLD-1433) will be infused intravesically for approximately 60 minutes, followed by 1 wash with SWFI. The bladder will be distended using a second instillation of SWFI to prevent folds that may prevent uniform light illumination. The Computer Operator worksheet must be completed during the Study Procedure and data must be promptly transferred to the corresponding electronic Case Report Form ("eCRF") page.

The optical fiber with spherical diffuser will be positioned through the cystoscope in the geometric center of the bladder with the aid of TLC-3200 and will be locked into place using an endoscope holder for continuous irradiation for the total exposure time. The optical power and treatment time will be determined to provide the correct dose of laser light to the bladder surface area. Green laser light (wavelength = 532 nm, energy = 90 J/cm2) will be irradiated from the emitter optical fiber via the spherical diffuser.

4.1 Dosing Schedule

One Study Procedure is planned, with up to two additional re-induction Study Procedures based on patient response. Each Study Procedure is a single whole bladder intravesical Ruvidar® (TLD-1433) instillation followed by PDT with the TLC-3200 System.

4.2 PDT Disruption

Patients with persistent or recurrent NMIBC CIS alone (or with recurrent Ta/T1 (noninvasive papillary disease/tumour invades the subepithelial connective tissue)) disease within 12 months of completion of BCG therapy (BCG-Unresponsive) or who are intolerant to BCG therapy will be treated with this Protocol. If one or more papillary tumours are seen at the time of Study Treatment (maximum 12 weeks after TURBT), the patient will be resected via TURBT and will be treated with this Protocol.