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

• ClinicalTrials.gov Identifier: NCT03945162
• Recruitment Status: Recruiting
• First Posted: May 10, 2019
• Last Update Posted: May 1, 2023
• Sponsor: Theralase® Technologies Inc.
• Information provided by (Responsible Party): Theralase® Technologies Inc.

Tracking Information

• First Submitted Date: May 8, 2019
• First Posted Date: May 10, 2019
• Last Update Posted Date: May 1, 2023
• Actual Study Start Date: August 30, 2019
• Estimated Primary Completion Date: June 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 27, 2023)

Efficacy, evaluated by Complete Response ("CR"). [ Time Frame: Throughout Study II and up to the completion of the follow-up phase (15 month) ]

The primary endpoint of Study II is efficacy, evaluated by the Complete Response ("CR") at any time point in patients with Carcinoma In-Situ ("CIS") with resected papillary disease. Patient CR is defined as at least one of the following:

• Negative cystoscopy and negative (including atypical) urine cytology
• Positive cystoscopy with biopsy-proven benign or low-grade NMIBC and negative cytology
• Negative cystoscopy with malignant urine cytology, if urothelial cancer is present in the upper tract or prostatic urethra and random bladder biopsies are negative.

Original Primary Outcome Measures (submitted: May 8, 2019)

Efficacy, evaluated by the Complete Response (CR) rate. [ Time Frame: Throughout the study and up to the completion of the follow-up phase (12 month) ]

The primary endpoint of this Study is efficacy, evaluated by the Complete Response ("CR") rate in patients with Carcinoma In-Situ ("CIS") with or without resected papillary disease at 360 days post primary treatment. CR is defined as at least one of the following:

• Negative cystoscopy and negative (including atypical) urine cytology.
• Positive cystoscopy with biopsy-proven benign or low-grade NMIBC and negative cytology.
• Negative cystoscopy with malignant urine cytology, if cancer is found in the upper tract or prostatic urethra and random bladder biopsies are negative.

For patients who are lost to follow-up or withdraw from the Study before recurrence or death, the CR will be censored at last disease assessment; for patients who start new anti- cancer treatment (i.e.: chemotherapy, immunotherapy or radiotherapy) or undergo a cystectomy, the CR will be censored at the last disease assessment before the start of the new anti-cancer therapy or cystectomy.

Current Secondary Outcome Measures (submitted: April 27, 2023)

Efficacy, evaluated by the duration of CR [ Time Frame: Throughout study II and up to the completion of the follow-up phase (15 month) ]

Duration of CR at 12 months post initial CR.

Original Secondary Outcome Measures (submitted: May 8, 2019)

Safety, evaluated by the incidence and severity of Adverse Events. [ Time Frame: Throughout the study and up to the completion of the follow-up phase (12 month) ]

AE summaries will be provided showing the number and percentage of patients who experienced at least 1 AE. These summaries will be presented by body system and preferred term. AEs resulting in discontinuation will be summarized separately. Adverse Events (AEs) will be monitored from the time of signing the Informed Consent Form (ICF) until End of Study. The relationship of every AEs to the study drug will be determined and documented by the principal investigator whether considered treatment-related, and classified as related, unlikely, possibly, or probably related. All AEs should be treated appropriately. All AEs will be followed until resolution or stabilization or until End of Study (whichever comes first). The severity of each AE will be evaluated as mild, moderate, or severe.

Current Other Pre-specified Outcome Measures (submitted: April 27, 2023)

Safety, evaluated by the incidence and severity of Adverse Events. [ Time Frame: Throughout the study and up to the completion of the follow-up phase (15 month) ]

The tertiary endpoint of Study II is safety, evaluated by the incidence and severity of Adverse Events ("AEs"), Grade 4 or higher that do not resolve within 450 days post initial treatment; whereby: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening or disabling, Grade 5 = Death

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Intravesical Photodynamic Therapy ("PDT") in BCG-Unresponsive/Intolerant Non-Muscle Invasive Bladder Cancer ("NMIBC") Patients
• Official Title: A Phase II Clinical Study of Intravesical Ruvidar® in Patients With BCG-Unresponsive Non-Muscle Invasive Bladder Cancer ("NMIBC") Carcinoma In-Situ ("CIS") or Patients Who Are Intolerant to BCG Therapy ("Study II")
• Brief Summary: 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 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 within 12 months after finishing the second course of BCG therapy are considered BCG-Unresponsive. The Study will consist of approximately 100 to 125 patients who will undergo two (2) PDT treatments employing 0.70 mg/cm^2 of Ruvidar® (TLD-1433) at Day 0 and Day 180.

Detailed Description

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 approximately 100 to 125 patients who will receive PDT employing 0.70 mg/cm^2 (Therapeutic Dose).

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 45 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, 30, 60, 90, 180, 187, 210, 240, 270, 360 and 450 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 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 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 Treatment and data must be promptly transferred to the corresponding electronic Case Report Form ("eCRF") page.

Positioning 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 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

Two Study Treatments are planned, a primary Study Treatment at Day 0 and a maintenance Study Treatment at Day 180. Each Study Treatment is a single whole bladder intravesical PDT with Ruvidar® (TLD-1433) and 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 and will be treated with this Protocol.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non-Muscle Invasive Bladder Cancer ("NMIBC") Unresponsive/Intolerant to BCG

Intervention

Combination Product: Ruvidar® (TLD-1433) Bladder infusion and PDT

Ruvidar® (TLD-1433) is infused into the bladder and treatment of bladder wall with light activation.

Study Arms

Experimental: 0.7 mg/cm^2 Ruvidar® (TLD-1433) Bladder infusion and Photodynamic Therapy

A single instillation of Ruvidar® (TLD-1433) (at the therapeutic dose of 0.7 mg/cm^2) will be infused intravesically into the bladder for approximately 60 minutes. PDT treatment is performed after Ruvidar® (TLD-1433) has been rinsed from the bladder. Two Study Treatments will be performed, a primary Study Treatment at Day 0 and a maintenance Study Treatment at Day 180.

Intervention: Combination Product: Ruvidar® (TLD-1433) Bladder infusion and PDT

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 8, 2019): 125
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: June 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 via biopsy with/without resected papillary disease (Ta, T1) (high grade) using the 2004 World Health Organization ("WHO") / International Society of Urologic Pathology classification system. The most recent cystoscopy / TURBT must have been performed within 12 weeks of the Study Treatment date to confirm: histology, grade and stage.

4. Intolerant to BCG or 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, or
   • At least five of six doses of an initial induction course, plus at least two of six doses of a second induction course.
5. Are not candidates for cystectomy on medical grounds or refuse radical cystectomy.
6. Have an Eastern Cooperative Oncology Group ("ECOG") performance score of 0 to 2.
7. Have satisfactory bladder function. Ability to retain Study Drug for a minimum of 60 minutes.
8. Are available for the duration of the Study including follow-up (approximately 15 months).
9. 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 Study Treatment.
10. 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 Study Treatment. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >1 year.

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 Study II, starting with the screening visit through to two weeks following the second Ruvidar® (TLD-1433) instillation.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Arkady Mandel, MD, PhD, DSc; 416-699-5273 ext 242; amandel@theralase.com

• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT03945162
• Other Study ID Numbers: Ruvidar® (TLD-1433) NMIBC PDT
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Theralase® Technologies Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Theralase® Technologies Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Girish Kulkarni, MD, FRCSC; University Health Network, Toronto

• PRS Account: Theralase® Technologies Inc.
• Verification Date: April 2023