In short
Nadofaragene firadenovec (also called Adstiladrin) is being studied in clinical trials for some types of urothelial cancer, especially non-muscle invasive bladder cancer (NMIBC). These trials look at how well it works when placed into the bladder every few months, how long responses last, and how it compares with observation or other standard treatments. Some studies also test it in the upper urinary tract (the renal pelvis) for low-grade upper tract urothelial carcinoma.
Key points
- Nadofaragene firadenovec (Adstiladrin) is being studied as a gene therapy treatment for urothelial cancers, especially non-muscle invasive bladder cancer. Several trials give it directly into the bladder every 3 months and measure complete response and how long that response lasts. One randomized trial in intermediate-risk NMIBC compares the drug against observation with close surveillance. Another trial compares nadofaragene firadenovec to other standard treatments used in usual care for NMIBC. A separate phase 1/2 study tests delivery into the renal pelvis for low-grade upper tract urothelial carcinoma while closely tracking safety and signs of response.
At a glance
- Main cancers studied
- Non-muscle invasive bladder cancer (including CIS ± high-grade Ta/T1), intermediate-risk NMIBC, and low-grade upper tract urothelial carcinoma (renal pelvis)
- How it is given in trials
- Placed into the bladder (intravesical instillation), often every 3 months; also studied as instillation into the renal pelvis
- Key outcomes measured
- Complete response, durability of response, recurrence-free survival, progression to muscle-invasive disease, cystectomy outcomes, adverse events
- Types of trial designs in the data
- Open-label single-arm and multi-center trials, randomized controlled trials, and comparative effectiveness trials versus observation or usual care
- Combinations studied
- Nadofaragene firadenovec alone, or combined with intravesical gemcitabine + docetaxel, or with pembrolizumab (IV)
What nadofaragene firadenovec is
Nadofaragene firadenovec (also called Adstiladrin or ADSTILADRIN in the trial records) is studied as a treatment for urothelial cancers in the urinary system.
In multiple trials, it is described as a vector-based gene therapy designed to increase (amplify) the activity of interferon alfa-2b (IFN-α2b), a protein involved in immune responses, to help produce a durable anti-tumor effect.
One trial description explains that it is a non-replicating (replication-deficient) recombinant adenovirus serotype 5 vector that carries a gene (transgene) encoding the human IFN-α2b gene.
Which diseases are being studied
Across the provided trial data, nadofaragene firadenovec is studied mainly for non-muscle invasive bladder cancer (NMIBC), including carcinoma in situ (CIS) with or without high-grade Ta/T1 disease.
It is also being studied for intermediate risk non-muscle invasive bladder cancer in a randomized controlled trial comparing treatment versus observation (surveillance).
A separate phase 1/2 study evaluates nadofaragene firadenovec for low-grade upper tract urothelial carcinoma (LG-UTUC) when administered into the renal pelvis.
How the treatment is given (bladder and renal pelvis)
Several trials use intravesical instillation, meaning the medicine is placed directly into the bladder.
In one phase 4 study of reinduction, treatment is instilled quarterly (every 3 months) and followed by quarterly disease assessments.
In a randomized phase 3b intermediate-risk NMIBC trial, participants in the treatment arm receive quarterly instillations for 24 months, with disease evaluation visits within 2 weeks before instillation visits.
In the COMPARE IT trial, patients randomized to nadofaragene firadenovec receive it as normal saline instilled intravesically every 3 months for up to 12 months.
For low-grade upper tract urothelial carcinoma, one trial studies repeat dosing of nadofaragene firadenovec instilled into the renal pelvis (part of the kidney collecting system).
Types of clinical trials and what they compare
The provided data includes different study designs, which affects what questions the trial can answer.
- Open-label studies: both the care team and the participant know which treatment is being given, and the main focus may be response and safety in a real-world style setting.
- Randomized controlled trials: participants are assigned to a treatment group or a comparison group (such as observation), helping researchers compare outcomes more fairly between groups.
- Comparative effectiveness trials against “usual care”: one study compares nadofaragene firadenovec with other standard treatment options used for NMIBC (for example gemcitabine with or without docetaxel, mitomycin, re-treatment with BCG, or pembrolizumab).
Main outcomes researchers measure
Trials measure whether the cancer disappears, how long it stays away, and whether it progresses to more serious disease.
- Complete response (CR): in high-grade NMIBC settings, CR is defined as absence of high-grade recurrence, and trials may look at CR at month 3 and beyond.
- Durability of CR: how long CR lasts, such as evaluations at months 6, 9, and 12 after retreatment in one reinduction trial.
- Recurrence-free survival (RFS): time from randomization to recurrence, progression, or death (depending on the study definition), used as a primary outcome in an intermediate-risk NMIBC trial.
- High-grade recurrence-free survival: time from treatment start to detection of high-grade bladder cancer recurrence (including biopsy-proven intravesical recurrence or distant metastasis), used as the primary outcome in the COMPARE IT trial.
- Progression-free survival: time without progression to muscle-invasive disease (≥T2), lymph node or distant metastasis, or death without documented progression, used as a secondary outcome in the COMPARE IT trial.
- Muscle-invasive progression and cystectomy outcomes: some studies track whether disease becomes muscle-invasive and whether bladder removal surgery happens, including time to cystectomy and pathology staging at cystectomy.
Reinduction (retreatment) after no complete response
A phase 4, multi-center, open-label trial evaluates reinduction with nadofaragene firadenovec in people with NMIBC CIS (with or without high-grade Ta/T1) who did not respond to their first dose of nadofaragene firadenovec (commercial Adstiladrin) received before entering the trial.
In this study, eligible subjects receive quarterly instillations into the bladder, followed by quarterly disease assessments.
The primary outcome is complete response achieved at month 3 after retreatment.
Secondary outcomes include whether CR is maintained at months 6, 9, and 12, and durability defined as no evidence of CIS and/or high-grade Ta/T1 at those time points.
The trial also measures muscle-invasive progression up to month 12 and tracks cystectomy outcomes such as incidence, time to cystectomy, and pathological staging at cystectomy.
Intermediate-risk NMIBC: treatment vs observation
A phase 3b randomized controlled trial compares nadofaragene firadenovec versus observation in participants with intermediate-risk NMIBC.
In the treatment arm, participants receive quarterly instillations for 24 months, with evaluations scheduled near dosing visits.
In the observation arm, subjects are followed using a quarterly surveillance schedule based on AUA/SUO guideline surveillance during the 24-month period.
The primary outcome is recurrence-free survival, defined as time from randomization to recurrence, progression, or death (any cause), whichever happens first during the treatment period.
One dataset version further explains that efficacy is summarized as a hazard ratio comparing time to recurrence, progression, or death between treatment and observation, regardless of factors such as treatment discontinuation or dosing interruptions.
High-grade BCG-unresponsive CIS: alone or in combination
A phase 3, randomized, multi-center, open-label trial evaluates intravesical nadofaragene firadenovec alone or combined with chemotherapy or immunotherapy in participants with high-grade BCG-unresponsive NMIBC with CIS (with or without high-grade Ta/T1).
This trial description notes results from a pivotal phase 3 trial (rAd-IFN-CS 003) in which 55 (53.4%) of 103 subjects with CIS ± high-grade Ta/T1 achieved a complete response at 3 months.
The trial arms include nadofaragene firadenovec alone, nadofaragene firadenovec plus intravesical gemcitabine and docetaxel, and nadofaragene firadenovec plus pembrolizumab given by IV infusion.
The primary outcome is complete response at any time from first treatment, defined as absence of high-grade recurrence.
Secondary outcomes include complete response at month 3 and month 6, durability of complete response (time from CR to high-grade recurrence, progression, or death), muscle-invasive progression, cystectomy-free survival, pathological staging at cystectomy, overall survival, and evidence of malignant lesions in the upper tract and/or prostatic urethra.
The trial also collects adverse events for nadofaragene firadenovec when used in combination with gemcitabine/docetaxel or pembrolizumab.
COMPARE IT trial: comparing FDA-approved/NCCN-recommended options
The COMPARE IT trial is designed to compare effectiveness of different FDA-approved and NCCN-recommended drug treatments for NMIBC, including comparing nadofaragene firadenovec to “usual care” options such as gemcitabine with or without docetaxel, mitomycin, re-treatment with BCG, or pembrolizumab.
For patients randomized to nadofaragene firadenovec in this study, the drug is instilled intravesically in normal saline every 3 months for up to 12 months.
For patients randomized to best usual care, one description notes that the combination intravesical regimen “GemDoce” (gemcitabine followed by docetaxel) is the current standard of care at MSK for most patients with BCG failure.
The primary outcome is high-grade recurrence-free survival (time from treatment initiation to detection of recurrence of high-grade bladder cancer, including biopsy-proven intravesical recurrence or distant metastasis).
A secondary outcome is progression-free survival, where progression includes muscle-invasive disease (stage ≥T2), lymph node or distant metastasis, or death without documented progression.
Low-grade UTUC (renal pelvis) trial: safety and response checks
A phase 1/2, single-arm, open-label trial evaluates safety, tolerability, and efficacy of nadofaragene firadenovec instilled into the renal pelvis for adults with low-grade upper tract urothelial carcinoma (LG-UTUC).
This study includes a safety lead-in period for the first 6 subjects to closely evaluate early safety.
One primary outcome is the number of treatment-emergent adverse events reported by each subject during the trial.
The primary efficacy outcome is complete response at 3 or 6 months, defined as absence of any UTUC in the renal pelvis, including negative urine cytology for high-grade urothelial carcinoma (centrally assessed) plus either no suspicious lesions on ureteroscopy or a negative for-cause biopsy (centrally assessed).
Secondary outcomes include duration of response (from first CR to recurrence, progression defined as any high-grade disease, or disease-specific death) and testing for urinary excretion of IFN-α2b protein.
Safety monitoring and immune system testing
Safety is tracked in different ways depending on the trial, including recording adverse events and measuring their frequency and intensity over time.
In the renal pelvis LG-UTUC trial, researchers also measure immune responses such as development of anti-adenoviral antibodies and anti-interferon-α2b antibodies.
That trial also measures shedding of the adenoviral vector with IFN-α2b and systemic exposures to IFN-α2b protein, adenoviral vector with IFN-α2b, and Syn3NODA, including checks before dosing and up to 15 days after dosing.