Summary

This is a phase 3, open label, single arm study of padeliporfin in the treatment of Upper
Tract Urothelial Carcinoma (UTUC). The ENLIGHTED study will recruit patients with
low-grade non-invasive upper tract urothelial carcinoma in either the kidney or the
ureter. Patients will be treated with padeliporfin VTP in two phases: an Induction
Treatment Phase and a Maintenance Treatment Phase and will be followed up for up to an
additional 48 months in the long term (non intervention) follow up phase with the
specific duration depending on the patient's response to treatment

Objectives

Induction Treament Phase: Patients entered in the study will undergo an induction
treatment phase consisting of 1-3 padeliporfin VTP treatments provided 4 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 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 padeliporfin VTP are permitted 28 +/- 3 days apart for a
total of up to 3 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
padeliporfin VTP the treatment will be considered unsuccessful and the patient will be
discontinued from the Treatment Phases.

Maintenance Treatment Phase: Patients achieving CR at the induction treatment phase will
be allowed into the maintenance treatment phase of the study. 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.

Repeated maintenance VTP treatments during this period will be provided for patients who
show evidence of tumor recurrence that is deemed treatable as defined by the following
criteria: low-grade tumors with the largest tumor (index tumor) betwen 5 mm and 15 mm in
diameter, in up to 2 anatomical locations in the calyces, renal pelvis or the ureter with
ureter involvement in one anatomical location with no more than 20 mm of contiguous
ureteral length). Patients with treatable tumor recurrence post Induction Treatment Phase
would be considered as no longer having 'complete response in the entire ipsilateral
kidney' and time to recurrence will be recorded. 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 and time to this event will be recorded.

Long Term Follow-up Phase: Patients 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 VTP treatment related adverse events with the specific duration
depending on the patient's response to treatment. No additional padeliporfin VTP
treatment will be administered during this phase. Patients completing the maintenance
phase of the study who are in CR in V3 will undergo additional assessments 18 and 24
months (+/- 1 month) post-PRE and annually thereafter and for up to 5 years post PRE or
until recurrence, progression, death or loss to follow up, to document safety and ongoing
response.

Eligibility

1. Male and female patients 18 years or older
2. Able to understand and provide written informed consent and willing to comply with all tests and procedures associated with the study
3. New or recurrent low-grade, non-invasive UTUC disease
4. Biopsy-proven disease . A concurrence of the central pathology reader will be required for eligibility.
5. Up to 2 biopsy-proven sites of low-grade involvement with the largest tumor (index tumor) between 5 mm and 15 mm in diameter (as measured by endoscopy), both located in the calyces,renal pelvis or in the ureter of the ipsilateral kidney, with an absence of high-grade cells on cytology. (Ureter involvement should be in one anatomical location with no more than 20 mm of contiguous ureteral length)
6. Karnofsky Performance Status = 50%
7. Adequate organ function defined at baseline as:
8. ANC =1,000/ µl,
9. Platelets =75,000/ µl, Hb =9 g/dl,
10. INR = 2
11. Estimated glomerular giltration rate (eGFR) =30 ml/min (using CKD-EPI Method)
12. Total serum bilirubin <3 mg/dL, AST/ALT =5× upper limit of normal

Treatment Sites in Georgia