Evaluation of Nadofaragene Firadenovec Instillation in Renal Pelvis for Safety and Efficacy in Low-Grade Upper Tract Urothelial Carcinoma

Trial ID: 2024-514360-70-00
Protocol: 000425
Sponsor: Ferring Pharmaceuticals A/S

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Diseases & Conditions

Transitional cell carcinoma

Objectives

The primary objective is to assess the safety and tolerability of intrarenal pelvic instillation of nadofaragene firadenovec in adult patients with low-grade upper tract urothelial carcinoma, addressing the clinical need for organ‑preserving therapy, and to determine the efficacy of this approach by evaluating disease‑free survival and local tumor regression as measures of therapeutic benefit.

Participants

The trial enrolled 14 adult participants, both male and female, aged 18 years or older, who met laboratory and performance‑status requirements and had biopsy‑confirmed Low-grade upper tract urothelial carcinoma (LG‑UTUC) with at least one papillary lesion measuring 5–15 mm. Selection criteria included adequate hematologic and biochemical values, an estimated glomerular filtration rate of ≥45 mL/min/1.73 m², an Eastern Cooperative Oncology Group status of ≤2, a life expectancy exceeding two years, and the ability to provide written informed consent. Eligible subjects required a recent pathology report (≤2 months), measurable disease, and compliance with contraceptive requirements; those receiving anticoagulation were allowed if clinical discretion deemed laboratory results acceptable. No specific diet, physical activity, or habit restrictions were stipulated, indicating a generally healthy adult population with localized low‑grade disease.

Plans and Procedures

The study is a Phase 1/2, single‑arm, open‑label trial evaluating the safety, tolerability, and efficacy of ADSTILADRIN (nadofaragene firadenovec) administered as an intravesical suspension into the renal pelvis of adult subjects with Low‑grade upper tract urothelial carcinoma. The protocol prescribes an initial screening visit to obtain written informed consent, confirm biopsy‑proven disease within two months, and assess laboratory eligibility criteria. Eligible participants receive the first instillation at the baseline visit, followed by scheduled follow‑up assessments at approximately 3 months, 6 months, and regular intervals thereafter to monitor adverse events, laboratory values, urine cytology, and ureteroscopic findings. The end‑of‑study visit occurs at the end of an 18‑month observation period after the first dose, at which time final safety and efficacy data are collected. Participant involvement therefore spans a minimum of 18 months. The trial recruitment period is planned from February 1 2026 to June 30 2029. Early termination of a participant’s involvement may occur in cases of significant treatment‑emergent adverse events, protocol non‑compliance, withdrawal of consent, or loss to follow‑up.

Treatment

The investigational product, designated ADSTILADRIN, contains the active substance nadofaragene firadenovec in an intravesical suspension. The formulation is administered by instillation into the renal pelvis (route classified as “other use”). The specific dose volume and concentration are defined in the study protocol, and the product is delivered according to the schedule outlined for each subject. Administration is performed by qualified clinical personnel, and each instillation is documented to ensure adherence to the dosing regimen.

No comparator, placebo, or standard‑of‑care therapy is administered within this single‑arm, open‑label trial; participants receive only the investigational product. Compliance monitoring consists of recording the date, time, and completeness of each instillation, as well as any deviations from the prescribed schedule.

Efficacy

Efficacy will be evaluated based on the occurrence of a complete response at either the 3‑month or 6‑month assessment. A complete response is defined as the absence of any upper‑tract urothelial carcinoma in the renal pelvis, demonstrated by a negative urine cytology for high‑grade urothelial carcinoma (centrally assessed) together with either a lack of suspicious lesions on ureteroscopy (investigator assessed) or a negative for‑cause biopsy (centrally assessed).

Urine samples will be collected for cytologic examination at the specified timepoints, and ureteroscopic inspection will be performed by the treating investigator. When indicated, tissue biopsies will be obtained and evaluated centrally. All assessments will be conducted at the 3‑month and 6‑month visits to determine the presence or absence of disease, thereby establishing the efficacy outcome for each subject.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Aged ≥18 years at the time of signing informed consent.
Able to give written informed consent.
Have biopsy-proven low-grade upper tract urothelial cancer (LG-UTUC) confirmed by a pathology report ≤2 months prior to enrolment.
Have ≥1 measurable papillary low-grade tumour (5-15 mm in maximum diameter), evaluated visually above the ureteropelvic junction before enrolment. • Subjects with low-grade tumour larger than 15 mm will be eligible if endoscopic downsizing of the tumour to 5-15 mm in maximum diameter has been performed before enrolment.
Willing to be available for at least 18 months after first dosing.
Have life expectancy >2 years, in the opinion of the investigator.
Have an Eastern Cooperative Oncology Group (ECOG) status of 2 or less.
Females of reproductive potential must have a negative highly sensitive urine or serum pregnancy test upon entry into this trial and be willing to use highly effective contraception during treatment with the investigational medicinal product (IMP) and for 6 months following the last dose. Otherwise, female subjects must be post-menopausal (no menstrual period for a minimum of 12 months, confirmed by follicle-stimulating hormone levels) or surgically sterile. Highly effective methods of contraception include: combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, and sexual abstinence.
Male subjects must use highly effective contraception and a condom during sexual contact regardless of partner’s childbearing potential, until 3 months following the last trial drug administration. Effective contraception is specified in inclusion criterion #‎8.
Adequate laboratory values: • haemoglobin ≥10 g/dL • white blood cells (WBC) ≥4000/µL • absolute neutrophil count (ANC) ≥2000/µL • platelet count ≥100,000/µL • international normalized ratio (INR)* below institutional upper limit of normal (ULN) • activated partial thromboplastin time (aPTT)* below institutional ULN • aspartate aminotransferase (AST) ≤1.5 x ULN • alanine aminotransferase (ALT) ≤1.5 x ULN • total bilirubin ≤1.5 x ULN • sodium >135 mmol/L • potassium between 3.6 and 5.0 mmol/L * It is accepted that subjects receiving anticoagulation therapy would not have INR and aPTT results that fall within ‘normal limits’. It is not intended to exclude these subjects and therefore medical discretion is permitted for subjects who have clinically acceptable results regarding their current concomitant anticoagulant therapy.
Have an estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 (for inclusion in the safety lead-in the eGFR must be ≥60 mL/min/1.73 m2 [see exclusion criteria #‎20‎20]).

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Exclusion Criteria

UTUC characterised by one or more of the following: • High-grade cytology or high-grade histology • Multi-focal UTUC - Exception: Subjects with low-grade multi-focal tumours will be eligible if any ureteral tumours can be ablated before enrolment and if the total diameter of the multifocal tumours above the ureteropelvic junction is not exceeding 15 mm in diameter. • Bilateral disease - Exception: Subjects who have had bilateral disease are eligible (not in the safety lead-in) if one renal unit is removed or rendered disease-free by endoscopic ablation before enrolment.
Suspected and/or a medical history of hypersensitivity to nadofaragene firadenovec, interferon-α2b (IFN α2b) and/or adenovector medications.
Urinary tract infection or bacterial cystitis (once satisfactorily treated, subjects can enter the trial).
Clinically significant and unexplained elevated liver or renal function tests at screening.
Women who are pregnant (highly sensitive urine or serum pregnancy test at screening) or breastfeeding.
Any other significant disease or other clinical findings which in the opinion of the investigator would prevent trial entry.
History of malignancy in any other organ system than the upper urinary tract within the past 5 years prior to screening. However, subjects with the following exceptions will be allowed inclusion in the trial: • Treated basal cell carcinoma or squamous cell carcinoma of the skin. • History of ≤pT2 upper tract urothelial carcinoma, at least 24 months after radical nephroureterectomy (RNU). • Cervical intraepithelial carcinoma (CIN) without evidence of invasive carcinoma. • Prostate cancer that is under active surveillance or urothelial cancer. All other genitourinary cancers are excluded.
Inability to deliver IMP to the pyelocaliceal system.
Previous BCG treatment during 6 months before the initiation of treatment.
Any immunosuppressive therapy within 3 months prior to screening.
Subjects who are immunocompromised or immunodeficient at screening.
Current or previous evidence of carcinoma in situ, of muscle invasive (muscularis propria) urothelial cancer in the urogenital tract presented at the screening visit.
Subjects with solitary kidney and/or an eGFR <60 mL/min/1.73 m2 (only applicable for subjects in the safety lead-in period).
Concomitant lower tract urothelial carcinoma and/or concomitant or prior urothelial carcinoma within the prostatic urethra.
History of high grade papillary urothelial cancer within 2 years prior to screening.
Current or prior treatment with mitomycin gel and/or any investigational drug for the treatment of UTUC.
Current systemic chemo- or immunotherapy for bladder cancer or any other malignancy.
Current or prior investigational treatment for Bacillus Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) or any other investigational drug within 1 month prior to screening.
Current or prior retroperitoneal external beam radiotherapy within 5 years of screening.
Prior treatment with adenovirus-based drugs including use of other adenovirus vector medications, including COVID-19 vaccines, within 2 weeks before instillation.
Hypersensitivity to contrast media used for pyelography.