Primary Outcome Measures:
- Assessment of Safety: Evaluation of the safety of TLD1433 will be assessed with the incidence and severity of Adverse Effects [ Time Frame: Up to the completion of follow-up phase (180 days) ]
Hematology, blood chemistry, and urinalysis for safety purposes will be performed at days 1, 3, 30, 60, 90 and 180 as well as at the time of premature discontinuation. Troponin testing will only be performed at day 1, 3, and 30.
CT scan will be performed at Day 30 and Day 180 to identify possible tissue reaction to PDT.
ECG will be performed at baseline, during the study treatment and Day 1 (24 hours) after study treatment. An additional ECG will be performed at 8 hours ± 15 minutes post-drug instillation to correspond with the 8 hour PK blood sample at Day 0.
Vital signs (blood pressure, heart rate, respiratory rate and temperature) will be recorded for safety purposes at every visit throughout treatment and at the end of study.
A comprehensive physical examination for safety purposes is required during Screening and at the Month 6/End of Study and End of Treatment.
Multiple measurements will be aggregated into number of abnormal results different from baseline for each subject.
Secondary Outcome Measures:
- Pharmacokinetics of TLD1433 in blood and urine (Cmax) [ Time Frame: Blood (prior to drug, 1h, 4h, 8h, 24h, and 72h post drug). Urine (prior to drug, 8h, 24h, and 72h post drug) ]
Pharmacokinetics (PK) of TLD1433 will be assessed with the maximum observed concentration (Cmax) in blood and urine.
- Pharmacokinetics of TLD1433 in blood and urine (area under curve) [ Time Frame: Blood (prior to drug, 1h, 4h, 8h, 24h, and 72h post drug). Urine (prior to drug, 8h, 24h, and 72h post drug) ]
Pharmacokinetics (PK) of TLD1433 will be assessed with the area under the curve from time zero to the last quantifiable concentration (AUC0-t) in blood and urine.
10.1 Overall Study Design and Plan: Description
This is a phase Ib, open-label, single-arm, single-center study conducted in Canada. Subjects with NMIBC (Non-muscle Invasive Bladder Cancer, Ta, T1, and/or Tis) who are not candidates for or have refused radical cystectomy will be eligible for participation in this study. BCG intolerance or refractory disease are defined as inability to tolerate or failure to achieve a tumour-free state after at least one induction (a minimum of 5 instillations) followed by either a second induction (a minimum of 5 instillations) or at least 2 maintenance instillations. Subjects experiencing disease relapse within 12 months or less after finishing the second course of BCG therapy are also considered refractory.
The study will consist of 2 phases. In the first phase, 3 subjects will receive PDT employing 0.35 mg/cm^2 (maximum recommended starting dose) TLD1433 and 90 J/cm^2 of green light delivered by TLC-3200. If treatment with the maximum recommended starting dose does not raise significant safety concerns as determined by the safety monitoring committee, an additional 6 subjects will receive PDT with 0.70 mg/cm^2 (therapeutic dose) TLD1433 and 90 J/cm^2 of green light delivered by TLC-3200.
10.2 Screening Period
Subjects will be qualified for study entry by review of inclusion and exclusion criteria during the Screening Period, which will last up to 2 weeks.
10.3 Maximum Recommended Starting Dose Treatment Phase
Three subjects will receive a single instillation of 0.35 mg/cm^2 TLD1433 followed by PDT (TLC-3200 System). If treatment with the maximum recommended starting dose doesn't raise safety concerns after 1 month of patient follow-up based on the judgment of the safety monitoring committee, the study will enroll an additional 3 subjects who will receive PDT at the maximum recommended starting dose.
10.4 Follow-Up Phase
All subjects enrolled, regardless of TLD1433 dose received, will be followed until the End of Study defined as completion of all required assessments after 6 months of follow-up or earlier due to early discontinuation or withdrawal of informed consent.
During the Follow-Up Phase, information on safety and efficacy will be collected. Assessments will be conducted at Day 7, Day 30 and monthly thereafter through Month 3, and every 3 months until End of Study.
10.6 Study Drug and PDT Administration
TLD1433 for intravesical administration is supplied as a lyophilizate for suspension in Sterile Water for Injection into the bladder and is packaged in the dark in amber borosilicate glass vials which can be stored at room temperature. Just before administration, it is reconstituted with Sterile Water for Injection to obtain the final clinical dilution.
TLD1433 will be supplied by Theralase Inc. Instillations cannot be done immediately following biopsy taken by TURBT. Investigators must wait a minimum of 7 days before dosing subjects 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, TLD1433 will be diluted to the proper concentration. On day 0 (treatment day), subjects will be asked to restrict fluid intake 12 hours before study drug instillation. Study drug must be instilled into the subject's empty bladder. Before instillation, a regular transurethral catheter should be inserted and the bladder drained. A single instillation of TLD1433 will be infused intravesically for 60 min (further TLD1433 will be instilled in case of leakage), followed by 3 washes with sterile water. Bladder will be distended using a fourth instillation of sterile water to prevent folds that prevent uniform light illumination. The laser technician worksheet must be completed during the procedure and data must be promptly transferred to the corresponding eCRF page. The optical fiber (with spherical diffuser) will be positioned in the center of the bladder with the aid of TLC-3200 and will be locked in place using an endoscope holder for continuous irradiation for the total exposure time. Exposure time will be calculated based on power (measured at the end of the optic fiber before inserting though a liquid-tight lock via catheter into the urethra) and bladder surface area to match the desired light dose at the bladder wall. Green laser light (wavelength = 532 nm, energy = 90 J/cm^2) will be irradiated using the spherical cavity diffuser.
10.6.1 Dosing Schedule
A single whole bladder intravesical PDT with TLD1433 and the TLC-3200 System is planned.
10.6.2 PDT Disruption
Only those patients in whom no papillary tumours remain after TURBT will be treated on this protocol. If one or more papillary tumours are seen at the time of cystoscopy for laser light application (maximum 6 weeks after TURBT), a patient must not be treated with the TLC-3200 System as scheduled, even though previously instilled with TLD1433. Procedures will be followed as though the tumour were first detected at the 90-day follow-up evaluation. The patient may then be treated in whatever manner the physician deems appropriate. However, such patients must be followed for collection of safety information for at least 30 days after TLD1433 instillation, even though alternate therapy may have been initiated during this time. Adverse experiences, weekly assessment of urinary symptoms, and the results of laboratory tests of blood and urine will be recorded. Full disclosure of the details of any alternate therapy or other medications given during the 30-day observation period (e.g., drug, dose, route, frequency and dates of administration) must be provided. After this 30-day period, an interim medical history will be taken and the patient will undergo a physical examination (including ECG), clinical laboratory tests, a Karnofsky Performance Status rating, and an assessment of urinary symptoms and adverse experiences. The patient will then be considered off study.