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 bacillus Calmette-Guerin (BCG)-Unresponsive or who are intolerant to BCG therapy. BCG-Unresponsive 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; OR, 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. The Study will consist of 100 patients who will undergo two (2) PDT treatments employing 0.70 mg/cm^2 of TLD-1433 at Day 0 and Day 180.
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
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
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
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.
|Overal Status||Start Date||Phase||Study Type|
|Recruiting||August 30, 2019||Phase 2||Interventional|
Primary Outcome 1 - Measure: Efficacy, evaluated by the Complete Response (CR) rate.
Primary Outcome 1 - Time Frame: Throughout the study and up to the completion of the follow-up phase (12 month)
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
9. Are available for the duration of the Study including follow-up (approximately 12
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
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
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,
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.
Minimum Age: 18 Years
Maximum Age: N/A
Healthy Volunteers: No
Name: Girish Kulkarni, MD, FRCSC
Role: Principal Investigator
Affiliation: University Health Network, Toronto
Name: Shawn Shirazi, Ph.D
|Site 02008 - MidLantic Urology
Bala-Cynwyd, Pennsylvania 19087
|Site 02006 - Carolina Urologic Research Center
Myrtle Beach, South Carolina 29572
|Site 02007 - Urology Associates, P. C
Nashville, Tennessee 37209
|Site 02010 - Urology San Antonio P. A
San Antonio, Texas 78229
|Site 02009 - Virginia Urology
Richmond, Virginia 23235
|Site 02011 - University of Wisconsin Health
Madison, Wisconsin 53705
|Site 01005 - The Vancouver Prostate Centre - Diamond Health Care Centre
Vancouver, British Columbia V5Z 1M9
|Site 01004 - Nova Scotia Health Authority - Centre for Urology Research
Halifax, Nova Scotia
Natasha Duggan, B.A.
|Site 01002- London Health Sciences Centre
|Site 01001 - University Health Network
Toronto, Ontario M5G 2C4
|Site 01003 - McGill University Health Centre