Thermo reversible hydrogel based delivery of mitomycin C (UGN-101) for treatment of upper tract urothelial carcinoma (UTUC)

Background: There is an unmet need for an effective local treatment of upper tract urothelial carcinoma (UTUC). Drug delivery to the pyelocaliceal system and pursuant efficacy of intracavitary therapy is limited by urine production that washes the drug away, shortening dwell time and direct contact with the urothelium. Successful endoscopic management is often dictated by lesion size, grade, and focality. A thermo-reversible hydrogel formulation of Mitomycin C (UGN-101, formerly MitoGel) was developed and has demonstrated the safety and feasibility of increased time of the drug in the pyelocaliceal system resulting in chemoablation of tumors. Objectives: To examine the efficacy and safety of UGN-101 used for chemoablation of UTUC. Methods: There were 22 patients approved for compassionate use treatment at 14 institutions. Six-weekly instillations of UGN-101 were administered via ureteral catheter or percutaneous nephrostomy. Ureteroscopy was performed 2-6 weeks following treatment completion for response determination. Adverse events were recorded throughout treatment. Patients were followed up according to the standard of care of each center. Results: Median age of the cohort was 75 yrs., with 16 (73%) males. Eighteen patients had low-grade (LG) tumors, 2 highgrade (HG), and 2 had indeterminate grade. Median volume of UGN-101 instilled was 13.5cc with median Mitomycin dosage of 54 mg. Eight patients had complete response (36%) including 44% (8/18) of the patients with low grade tumors. Partial responses were observed in 23% and 28% of LG. Two patients had no response (9%) and 1 did not undergo ureteroscopy. Four patients could not complete 6 weeks due to adverse events (pyelonephritis, acute renal failure, pancytopenia, and unstable cardiac condition); 1 patient was diagnosed with a non-urothelial cancer during treatment; and 1 patient died prior to the third instillation due to suspected pulmonary embolus, determined to be unrelated to treatment with UGN-101. Out of the patients who had a complete response, 3 (37.5%) patients are recurrence free from 18-30 months. A total of 83 adverse events were recorded. Of these, 6 events related to UGN-101 were serious (requiring medical intervention), and 23 events related to UGN-101 were not serious. Conclusions: This compassionate use program of UGN-101 demonstrates proof of concept for chemoablation treatment of UTUC. A single arm Phase III multi-center registration trial to treat patients with low-grade low-volume renal pelvis tumors is open and enrolling patients (NCT02793128).