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