Evaluation of Padeliporfin Vascular Targeted Photodynamic Therapy in Low-Grade Upper Tract Urothelial Carcinoma: A Phase 3 Multicenter Study

The primary objective of this multicenter Phase 3 pivotal study is to demonstrate the **efficacy** and durability of effect following TOOKAD (padeliporfin) Vascular Targeted Photodynamic Therapy (VTP) on low-grade Upper Tract Urothelial Cancer (UTUC) tumors located in the calyces, renal pelvis, and ureter. This is clinically relevant as it aims to establish a novel therapeutic approach for managing low-grade UTUC, potentially offering a less invasive treatment option with sustained outcomes.

Secondary objectives include:

• Evaluating TOOKAD (padeliporfin) VTP related **safety** and tolerability in the treatment of low-grade UTUC tumors in the calyces, renal pelvis, and ureter.
• Exploring a potential link between UTUC cancer genomic markers and treatment-related clinical outcomes and disease progression.

The clinical trial involves a total of **70 participants** diagnosed with **Low Grade Upper Tract Urothelial Cancer**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their ability to understand and provide written informed consent, as well as their willingness to comply with all study-related tests and procedures. The trial specifically targets individuals with new or recurrent low-grade, non-invasive UTUC disease, confirmed through biopsy, with up to two biopsy-proven sites of low-grade involvement. The largest tumor, referred to as the index tumor, must measure between 5 mm and 15 mm in diameter and be located in the calyces, renal pelvis, or ureter of the ipsilateral kidney. Participants are required to have a Karnofsky Performance Status of 50% or higher and demonstrate adequate organ function at baseline. The study does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.

The clinical trial is designed to evaluate the **safety** and **efficacy** of TOOKAD (padeliporfin) Vascular Targeted Photodynamic Therapy in the treatment of low-grade upper tract urothelial cancer. This is a multicenter, Phase 3 pivotal study employing a randomized, double-blind, controlled trial design. The trial is expected to span from March 2021 to August 2028, with participant involvement lasting up to 12 months. The study will include several key visits: an initial screening visit to confirm eligibility, multiple follow-up visits to monitor treatment response and safety, and a final end-of-study visit to assess the primary and secondary endpoints.

Participants will be required to meet specific inclusion criteria, such as being 18 years or older, having biopsy-proven low-grade, non-invasive upper tract urothelial cancer, and demonstrating adequate organ function. The primary endpoint is the absence of tumors in the ipsilateral calyces, renal pelvis, and ureter, assessed through endoscopic evaluation. Secondary endpoints include the duration of response, overall renal functional outcome, and safety follow-up based on adverse event recording. Participants may be terminated early from the study if they experience significant adverse events or fail to comply with study procedures.

The investigational product, TOOKAD, is administered via **intravenous infusion** and is activated by a laser light delivery system. This system locally activates the drug in the circulation of the target tumor(s) through 753 nm illumination delivered via an optical fiber. The study aims to demonstrate the efficacy and durability of the treatment effect on low-grade tumors located in the calyces, renal pelvis, and ureter. The trial will ensure rigorous monitoring and data collection to evaluate the therapeutic potential of TOOKAD in this patient population.

The clinical trial involves the administration of **TOOKAD** 183 mg powder for solution for injection, which contains the active substance **padeliporfin**. This experimental medication is formulated as a powder that is reconstituted into a solution for injection. The route of administration is via **intravenous infusion**. The dosing regimen specifies a maximum daily dose of 3.66 mg/kg, with the same amount as the maximum total dose. The treatment period is limited to a maximum of 12 weeks. The drug is a derivative of bacteriochlorophyll, specifically **Palladium Bacteriopheophorbide Monolysotaurine**, and is chemically synthesized. The administration of TOOKAD is accompanied by a light delivery system, which is a medical device that activates the drug in the circulation of the target tumor(s) through 753 nm illumination delivered via an optical fiber. This fiber is positioned with the aid of a tumor/organ imaging system either near (intraluminal) or in the center of the tumor (interstitially).

In addition to the experimental treatment, the study may involve the use of standard-of-care therapies as deemed necessary by the clinical investigators. These therapies are not specified in the trial documentation and are administered according to the standard medical practice for the treatment of low-grade upper tract urothelial cancer. Participant compliance with the dosing schedule and administration protocol is monitored throughout the study to ensure adherence to the trial's requirements.

The efficacy of TOOKAD (padeliporfin) Vascular Targeted Photodynamic Therapy in the treatment of low-grade Upper Tract Urothelial Cancer (UTUC) will be assessed through a series of primary and secondary endpoints. The primary efficacy outcome is defined as the absence of UTUC tumors in the entire ipsilateral calyces, renal pelvis, and ureter, as determined by endoscopic evaluation. This outcome will be evaluated dichotomously, categorizing results as either a failure or success in achieving a **Complete Response**. A Complete Response is characterized by the absence of visual tumors on endoscopy, no evidence of tumors on biopsy (if feasible), and negative urinary cytology obtained through instrumented collection.

Secondary endpoints include the duration of response, which is defined as the absence of disease in the entire ipsilateral kidney and the specific Treatment Area. Additional secondary measures involve overall renal functional outcomes, kidney organ loss or preservation, and pathological evaluation of response in kidney tissue from patients undergoing surgical removal following at least one TOOKAD (padeliporfin) VTP treatment. Safety follow-up will be conducted through the recording of adverse events. These efficacy parameters will be collected and analyzed according to the study protocol, with specific details outlined in the protocol sections related to Primary and Secondary Endpoints/Estimands.