Multicenter Phase III Pivotal Study to Evaluate the Safety and Efficacy of TOOKAD (Padeliporfin) Vascular Targeted Photodynamic Therapy in the Treatment of Low Grade Upper Tract Urothelial Cancer

Drug: Experimental: TOOKAD VTP Patients entered in the study will undergo an induction treatment phase consisting of 1-3 TOOKAD VTP treatments provided 4 weeks (28 +/-3 days) apart. Patients achieving CR at the induction treatment phase will be allowed into the maintenance treatment phase. The patients will be followed over a period of 12 months post PRE, to assess the duration of response and its safety, and to provide planned maintenance treatment. Repeated maintenance VTP treatments during this period will be provided for patients who show evidence of tumor recurrence that is deemed treatable as defined: Up to 2 low-grade tumors with the largest tumor (index tumor) betwenn 5 mm and 15 mm in diameter, in up to 2 anatomical locations in the calyces, renal pelvis or the ureter (with ureter involvement should be in one anatomical location with no more than 20 mm of contiguous ureteral length). Drug: TOOKAD VTP During treatment, placement at the target area of an optical light fiber, through the working channel of the ureteroscope. Intravenous administration of TOOKAD (padeliporfin) at the dose of 3.66 mg/kg infused over 10 minutes. Each target area will be illuminated for 10 minutes. The patients will then be followed over a period of 12 months post PRE, to assess the duration of response and its safety, and to provide planned maintenance treatment. Pts are being treated with padeliporfin VTP in two phases: Induction and Maintenance treatment Phases (ITP and MTP). ITP consists of 1-3 VTPs every 28 days. If CR is not achieved after 1st VTP, up to 2 additional VTPs are allowed. If CR is achieved in the ITP, pts are allowed into the MTP (12 mos). In the MTP VTPs can be provided every 3 mos for pts with recurrent tumor that is deemed treatable, defined as LG with the largest tumor (index) 5 -15 mm, in up to 2 locations in the kidney or one ureter location ≤20 mm. Long Term FU Phase: Pts completing the MTP, will be followed for safety for 48 mos with no VTPs. ASCO 2023: MTD of laser light fluence was established at 150 mW/cm for ureter and 200 mW/cm for kidney 14 (74%) patients received the MTD of 200mW/cm, 2 (11%) of whom experienced DLTs (flank pain grade 2 and 3). Response rate at 30 days was 94% (50% CR, 44% PR). 8 (42%) patients received 2nd VTP, with a final observed 68% complete response (CR) rate. Most frequent adverse events: transient flank pain (79%) and hematuria (84%). No treatment- associated ureteral strictures were reported. No patient experienced severe kidney disease (eGFR<30mL/min) at any point during follow-up. Renal function was well maintained in patients following VTP. All patients had preserved kidney at the 6-months follow up 4 Weeks Patients are treated in two phases: Induction(ITP) and Maintenance Treatment Phases (MTP). ITP consists of 1-3 VTPs provided at 4-week intervals until achieving complete response (CR) or treatment failure. The study consists of two parts - an Induction Treatment Phase (ITP) and Maintenance Treatment Phase (MTP) - across which Padeliporfin, a photosensitizing drug, is administered intravenously and VTP therapy is performed, via an outpatient endoscopy which applies a laser fiber illumination for 10 minutes in the proximity of the tumor, leading to local activation of Padeliporfin in the tumor. ITP consists of one-to-three treatments with VTP therapy at four-week intervals or until a complete response (CR) is achieved; MTP follows with standard-of-care treatment alongside VTP therapy administered every three months for up to 12 months. CTIS: Period details NumberPeriod titlePeriod DescriptionAllocation methodBlinding usedRoles blindedBlinding implementation detailsArm details 1Induction Treatment PhasePatients entered in the study will undergo an induction treatment phase consisting of 1-3 TOOKAD (padeliporfin) VTP treatments provided four weeks (28 +/-3 days) apart. The goal of this induction treatment phase will be to achieve Complete Response (CR) in the involved ipsilateral tract system. During this phase, patients will be treated with TOOKAD (padeliporfin) VTP to visually identified tumor sites in the calyces, renal pelvis and/or ureter and subsequently examined endoscopically at 28 +/- 3 days post treatment to determine whether the treatment was successful. If CR is not achieved, an additional two treatments of TOOKAD (padeliporfin) VTP are permitted 28 +/- 3 days apart for a total of up to three treatments during the induction treatment phase. The Primary Response Evaluation (PRE) will be performed 28 +/- 3 days after the last VTP treatment, to determine if the treatment was successful at achieving CR defined as absence of visible tumor on endoscopy, negative urinary cytology by instrumented collection, and no evidence of tumor on biopsy (if feasible). Patients undergoing extirpative surgery of any part of the ipsilateral kidney or ureter for indications related to urothelial cancer will be considered as no longer having CR. If CR is not achieved after 3 treatments with TOOKAD (padeliporfin) VTP the treatment will be considered unsuccessful and the patient will be discontinued from the Treatment Phases and will be followed up to 12 months after PRE (Visit 2).Not ApplicableNone 1. Induction Treatment Phase: 1-3 TOOKAD (padeliporfin) VTP treatments provided four weeks (28 +/-3 days) apart. If CR is not achieved, an additional two treatments of TOOKAD padeliporfin) VTP are permitted 28 +/- 3 days apart for a total of up to three treatments during the induction treatment phase. 2Maintenance Treatment PhasePatients achieving CR at the induction treatment phase will be allowed into the maintenance treatment phase of the study. The patients will be followed over a period of 12 months post PRE, to assess the duration of response and its safety, and to provide planned maintenance treatment. Repeated maintenance VTP treatments during this period will be provided every 3 months +/- 3 weeks post PRE for patients who show evidence of tumor recurrence.Not ApplicableNone 1. Maintenance treatment phase: Repeated VTP treatments will be allowed for patients who show evidence of tumor recurrence 3Long Term Follow-up PhasePatients completing the 12 months of the maintenance treatment phase of the study, could be followed for an additional 48 months to monitor for disease related outcomes and padeliporfin VTP treatment related adverse events with the specific duration depending on the patient’s response to treatment.Not ApplicableNone 1. Long Term Follow-up Phase: non-interventional phase, no additional TOOKAD (padeliporfin) VTP treatment will be administered