Background: Localized treatment of upper tract urothelial carcinoma (UTUC) is technically challenging which limits the ability to provide organ-sparing therapies to preserve renal function and representing a serious unmet need. Vascular-targeted photodynamic therapy (VTP) using intravascular photosensitizing agent padeliporfin (WTS11) has demonstrated preclinical safety and effective tumoricidal activity. Endoluminal application of this therapy offers a promising alternative to radical surgery for patients with upper tract cancers seeking to avoid extirpative surgery. Herein we present early results from a phase I dose-finding study of padeliporfin VTP for UTUC. Methods: Fourteen patients with recurrent UTUC were treated with up to 2 sessions of endoscopic padeliporfin VTP treatment. Eligibility included residual or recurrent urothelial carcinoma of the ureter or renal pelvis failing prior endoscopic treatment in patients who were unable or unwilling to undergo surgical management by resection of the involved ureter or kidney. WST-11 was administered at 4mg/kg and infused over 10 minutes. An intermedic diode laser was used to illuminate tumors with light at a wavelength 753 nm through a flexible ureteroscope. A light dose escalation model was employed with increasing light fluence from 100mW/cm up to a maximally tolerated dose of 200mW/cm. The primary endpoint was the determination of maximally tolerated laser light fluence rate, with the secondary objective to evaluate treatment efficacy defined by absence of visible tumor and negative urine cytology following treatment. Results: Among 14 treated patients, complete response and tumor recurrence rates at 30 days after treatment were 64% and 29%, respectively. A second VTP treatment was performed in 6 (43%) patients. The efficacy rates were comparable among patients who received the intermediate and highest light fluence and between the first and second treatment. At the last follow-up (mean: 11.5 months), 13 patients (93%) had maintained their affected kidney and renal function was not significantly affected. Graded adverse events related to treatment were rigorously evaluated prospectively as the primary endpoint of the trial to be reported separately in detail. Treatment related toxicities were limited, and no ureteral strictures were identified with the procedure. No evidence of increased toxicity was identified among patients who received a second VTP treatment. Conclusions: WST11-VTP shows promising evidence of therapeutic treatment effect in low- and high-grade upper tract urothelial tumors with limited treatment related toxicity. These early results provide support for further investigation to evaluate the curative potential for this therapy in a planned multicenter trial. Clinical trial information: NCT03617003