1. Overall Study Design and Plan: Description

   This is a phase II, open-label, single-arm, multi-center Study conducted in Canada, the United States and internationally. 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 100 patients who will receive PDT employing 0. 70 mg/cm^2 (Therapeutic Dose).

2. Screening Period

   Patients will be qualified for Study entry by review of inclusion and exclusion criteria during the Screening Period, which will last up to 28 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 12 months of follow-up post treatment or earlier 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, 30, 60, 90, 180, 187, 210, 240, 270 and 360.

4. Study Drug and PDT Administration

TLD-1433 for intravesical administration is supplied as a lyophilisate for suspension in Sterile Water for Injection into the bladder and is packaged in the dark in amber USP Type III glass vials which can be stored at room temperature. Up to 24 hours before administration, it is reconstituted with Sterile Water for Injection to obtain the final clinical dilution.

TLD-1433 will be supplied to each Study site by Theralase. Instillations cannot be done immediately following biopsy taken by 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 this Study.

Upon determination of the bladder volume (during the screening period) through a voiding diary or measuring instilled water volume, TLD-1433 to be instilled will be diluted to the proper concentration. On day 0 (treatment 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 TLD-1433 will be infused intravesically for approximately 60 minutes, followed by 3 washes with sterile water. The bladder will be distended using a fourth instillation of sterile water to prevent folds that may prevent uniform light illumination. The laser technician worksheet must be completed during the procedure and data must be promptly transferred to the corresponding electronic Case Report Form ("eCRF") page.

Insertion of the optical fiber with spherical diffuser into the bladder will be monitored under ultrasonic guidance. The optical fiber with spherical diffuser will be positioned 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. Exposure time will be calculated based on power emitted from the end of the optic fiber. The optic fiber is inserted through a liquid-tight lock via a catheter into the urethra. 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. The bladder volume may be monitored during the procedure and water instilled or drained, as required, to keep the bladder volume as consistent as possible.

4.1 Dosing Schedule

A single whole bladder intravesical PDT with TLD-1433 and the TLC-3200 System is planned. Two treatment procedures will be performed, a primary treatment at Day 0 and a secondary treatment at Day 180 post primary treatment.

4.2 PDT Disruption

Patients with NMIBC CIS with or without resected papillary disease (Ta, T1) that are considered 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 cystoscopy for laser light application (maximum 8 weeks after TURBT), a patient will be rescheduled for a TURBT procedure to resect the papillary tumour(s) and a new treatment procedure date will be set, even though previously instilled with TLD-1433.

Inclusion Criteria:

1. Be willing and able to provide a written Informed Consent Form ("ICF") for the Study.
2. Be > 18 years of age on day of signing ICF.

3. Have histologically confirmed NMIBC CIS with or without resected papillary disease (Ta, T1) (high grade) according to the 2004 World Health Organization ("WHO") / International Society of Urologic Pathology classification system up to 8 weeks prior to the treatment procedure.

   • Confirmation of histology, grade and stage will be performed by local review and must be completed prior to enrolment.

4. Patients with Ta, or T1 disease, must have undergone complete Trans-Urethral Resection of the Bladder Tumour ("TURBT") defined as the absence of resectable disease after at least 1 cystoscopy or TURBT procedure.

   • The most recent cystoscopy must have been performed no longer than 8 weeks prior to the treatment procedure.

5. Considered BCG-Unresponsive, which is at least one of the following:

   • At least five of six doses of an initial induction course, plus at least two of three doses of maintenance therapy
   • At least five of six doses of an initial induction course, plus at least two of six doses of a second induction course
   • Patients experiencing disease relapse less than 12 months after finishing the second course of BCG therapy are also considered BCG-Unresponsive.
6. Are not candidates for cystectomy on medical grounds or refuse radical cystectomy.
7. Have an Eastern Cooperative Oncology Group ("ECOG") performance score of 0 to 1.
8. Have satisfactory bladder function. Ability to retain Study Drug for a minimum of 1 hour.
9. Are available for the duration of the Study including follow-up (approximately 12 months).
10. Female patients of childbearing potential must have a negative Human Chorionic Gonadotropin ("HCG") pregnancy test taken during the screening visit and confirmed prior to the treatment procedure.
11. Female patients of childbearing potential must be willing to use 2 methods of birth control (i.e.: oral contraceptive, pills, diaphragm or condoms) or be surgically sterile, or abstain from heterosexual activity for two weeks after the treatment procedure. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >1 year.
12. Intolerance of BCG therapy

Exclusion Criteria:

1. Past or current muscle invasive (i.e.: T2, T3, T4) or metastatic urothelial carcinoma.

2. Has concurrent extravesical (i.e.: urethra, ureter, renal pelvis, prostate or prostatic ducts) non-muscle invasive transitional cell carcinoma of the urothelium. (confirmed by staging to exclude extravesical disease, which may include radiological imaging and/or biopsy) within 3 months of enrollment:

   If previous work up occurred more than 3 months prior to enrollment, staging for extravesical disease must be repeated prior to enrolment in order to determine eligibility.

3. Active gross hematuria.
4. Have a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, in situ cervical cancer or localized prostate cancer under active surveillance with Gleason 6 disease. A history of prostate cancer that was treated with definitive intent (surgically or through radiation therapy) is acceptable, provided that the following criteria are met: Stage T2N0M0 or lower; prostate-specific antigen (PSA) undetectable for 2 years while off androgen deprivation therapy or no more than 2 consecutive rising PSAs.
5. Have a history or current evidence of any condition, therapy, surgery or laboratory abnormality that, in the opinion of the PI, might confound the results of the Study, interfere with the patient's participation in the Study, or is not in the best interest of the patient to participate.
6. Currently receiving treatment with a prohibited concomitant therapy (refer to 12.2.1, Prohibited Medications).
7. Participated in a study with an investigational agent or device within 1 month from the first dose of current Study treatment.
8. Prior treatment with an intravesical chemotherapeutic agent within 1 month of the first dose of current Study Drug, with the exception of a single perioperative dose of chemotherapy immediately post-TURBT (not considered treatment).
9. Have an active infection requiring systemic therapy, including active or intractable Urinary Tract Infection ("UTI"), not resolved prior to the procedure.
10. Has any contraindication to general or spinal anesthesia.
11. Is pregnant or breastfeeding within the projected duration of the Study, starting with the screening visit through to two weeks following the second TLD-1433 instillation.

• University Health Network, Toronto
• Pharma eMarket