#1 Clinical Trials Search in Europe

NADOFARAGENE FIRADENOVEC

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.

Table of Contents

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[1][2][3][5].

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[2][5].

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[5].

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[1][5].

It is also being studied for intermediate risk non-muscle invasive bladder cancer in a randomized controlled trial comparing treatment versus observation (surveillance)[2][6].

A separate phase 1/2 study evaluates nadofaragene firadenovec for low-grade upper tract urothelial carcinoma (LG-UTUC) when administered into the renal pelvis[3][8].

How the treatment is given (bladder and renal pelvis)

Several trials use intravesical instillation, meaning the medicine is placed directly into the bladder[1][2][4][5].

In one phase 4 study of reinduction, treatment is instilled quarterly (every 3 months) and followed by quarterly disease assessments[1].

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[2].

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[4].

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)[3].

Types of clinical trials and what they compare

The provided data includes different study designs, which affects what questions the trial can answer[1][2][3][4][5].

  • 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[1][3][5].

  • 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[2].

  • 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)[4].

Main outcomes researchers measure

Trials measure whether the cancer disappears, how long it stays away, and whether it progresses to more serious disease[1][2][3][4][5].

  • 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[1][5].

  • Durability of CR: how long CR lasts, such as evaluations at months 6, 9, and 12 after retreatment in one reinduction trial[1].

  • 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[2][6].

  • 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[4].

  • 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[4].

  • 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[1][5].

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[1].

In this study, eligible subjects receive quarterly instillations into the bladder, followed by quarterly disease assessments[1].

The primary outcome is complete response achieved at month 3 after retreatment[1].

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[1].

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[1].

Intermediate-risk NMIBC: treatment vs observation

A phase 3b randomized controlled trial compares nadofaragene firadenovec versus observation in participants with intermediate-risk NMIBC[2][6].

In the treatment arm, participants receive quarterly instillations for 24 months, with evaluations scheduled near dosing visits[2].

In the observation arm, subjects are followed using a quarterly surveillance schedule based on AUA/SUO guideline surveillance during the 24-month period[2].

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[2][6].

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[6].

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)[5][7].

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[5].

The trial arms include nadofaragene firadenovec alone, nadofaragene firadenovec plus intravesical gemcitabine and docetaxel, and nadofaragene firadenovec plus pembrolizumab given by IV infusion[5].

The primary outcome is complete response at any time from first treatment, defined as absence of high-grade recurrence[5][7].

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[5].

The trial also collects adverse events for nadofaragene firadenovec when used in combination with gemcitabine/docetaxel or pembrolizumab[5].

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[4].

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[4].

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[4].

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)[4].

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[4].

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)[3][8].

This study includes a safety lead-in period for the first 6 subjects to closely evaluate early safety[3].

One primary outcome is the number of treatment-emergent adverse events reported by each subject during the trial[3][8].

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)[3][8].

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[3].

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[2][3][5].

In the renal pelvis LG-UTUC trial, researchers also measure immune responses such as development of anti-adenoviral antibodies and anti-interferon-α2b antibodies[3].

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[3].

Main drug studied Nadofaragene firadenovec (Adstiladrin)
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)

FAQ

  • What is nadofaragene firadenovec (Adstiladrin) in these trials? In these trials, nadofaragene firadenovec (Adstiladrin) is described as a vector-based gene therapy. It uses a modified adenovirus (a type of virus used as a delivery tool) to deliver the gene for interferon alfa-2b, with the goal of boosting anti-tumor effects in the urinary tract.
  • Which cancers are being studied with nadofaragene firadenovec? Trials in the provided data study it mainly for non-muscle invasive bladder cancer (including carcinoma in situ, with or without high-grade Ta/T1 disease) and also for low-grade upper tract urothelial carcinoma in the renal pelvis.
  • How is the treatment given in these studies? Several trials use intravesical instillation, meaning the medicine is put directly into the bladder. Some studies give it every 3 months (quarterly). Another study evaluates giving it into the renal pelvis (part of the kidney’s drainage system) for low-grade upper tract urothelial carcinoma.
  • What does “complete response” mean in these trials? A complete response generally means there is no evidence of the targeted cancer after treatment. For carcinoma in situ and other high-grade NMIBC, it is defined as absence of high-grade recurrence. In the renal pelvis upper-tract study, complete response includes no visible tumor and testing such as urine cytology being negative for high-grade cancer.
  • What are researchers measuring besides complete response? Depending on the trial, researchers also measure how long patients stay free of recurrence (recurrence-free survival), whether cancer progresses to muscle-invasive disease, cystectomy outcomes (bladder removal surgery), overall survival in one study, and safety outcomes like adverse events and antibody development against the virus or interferon.

Ongoing Clinical Trials on NADOFARAGENE FIRADENOVEC

  • Study of nadofaragene firadenovec alone or with gemcitabine, docetaxel or pembrolizumab in adults with non-muscle invasive bladder cancer who did not respond to BCG therapy

    Recruiting

    1 1 1 1
    Investigated diseases:
    Investigated drugs:
    Czechia Denmark France Poland Spain

  • Study of Nadofaragene Firadenovec for Adults with Intermediate Risk Non-Muscle Invasive Bladder Cancer

    Recruiting

    1 1 1
    Investigated diseases:
    Investigated drugs:
    Czechia Denmark France Italy Poland Spain

  • Safety and efficacy study of nadofaragene firadenovec administered to the renal pelvis in adults with low-grade upper tract urothelial carcinoma

    Not yet recruiting

    1 1
    Investigated diseases:
    Investigated drugs:
    France The Netherlands Spain

Glossary

  • Nadofaragene firadenovec: A medicine studied as a gene therapy for urothelial cancers. In the trials, it is placed into the bladder (intravesical) or into the renal pelvis. It uses a modified adenovirus to deliver the gene for interferon alfa-2b to help create an anti-cancer effect.
  • Adstiladrin / ADSTILADRIN: Another name used for nadofaragene firadenovec in the trial information.
  • Gene therapy: A treatment approach that delivers genetic instructions into cells. In these trials, the goal is to increase production of a helpful immune-signaling protein (interferon alfa-2b) in the urinary tract to fight cancer.
  • Vector-based gene therapy: Gene therapy that uses a “vector,” which is a delivery vehicle. Here, a modified adenovirus is used as the vector to carry the interferon alfa-2b gene.
  • Adenovirus vector (non-replicating / replication-deficient): A modified virus used to deliver a gene. “Non-replicating” or “replication-deficient” means it is designed not to multiply in the body like a normal virus would.
  • Interferon alfa-2b (IFN-α2b): A protein that can help the immune system respond to cancer cells. In these trials, the treatment aims to amplify (increase) interferon alfa-2b effects by delivering the gene that produces it.
  • Intravesical instillation: Placing a medicine directly into the bladder, usually through a catheter. This targets the bladder lining where non-muscle invasive bladder cancers occur.
  • Renal pelvis: The part of the kidney that collects urine before it moves to the ureter. One trial studies delivering nadofaragene firadenovec into the renal pelvis for upper tract disease.
  • Urothelial carcinoma: Cancer that starts in the urothelium, the lining of the urinary system (bladder, ureters, and parts of the kidneys such as the renal pelvis).
  • Non-muscle invasive bladder cancer (NMIBC): Bladder cancer that has not grown into the bladder muscle. It often affects the inner layers of the bladder and is commonly treated with medicines placed directly into the bladder.
  • Carcinoma in situ (CIS): A flat, high-grade cancer on the surface lining of the bladder (or urinary tract) that has not invaded deeper layers. It can be aggressive even though it is “surface-level.”
  • Ta / T1 stage (papillary tumors): Staging terms for NMIBC. Ta tumors are on the surface lining. T1 tumors have grown into the layer just under the lining (lamina propria) but not into the bladder muscle.
  • High-grade vs low-grade: Describes how abnormal the cancer cells look under a microscope. High-grade cancers usually grow and spread more aggressively than low-grade cancers.
  • Intermediate-risk NMIBC: A risk group for NMIBC (between low-risk and high-risk). One trial compares nadofaragene firadenovec to observation in this group over a 24-month period.
  • BCG (Bacillus Calmette-Guérin): A common intravesical treatment for NMIBC that uses a weakened bacterium to stimulate the immune system in the bladder.
  • BCG-unresponsive: A term used when high-grade NMIBC did not respond well enough to BCG or came back soon after BCG. In one trial, participants have CIS with or without high-grade Ta/T1 disease and are considered unlikely to benefit from more BCG.
  • Reinduction / retreatment: Giving the treatment again after an earlier course did not lead to a complete response or when the study plan includes repeating doses. One phase 4 trial offers reinduction for people who did not have a complete response to their first dose.
  • Complete response (CR): No evidence of the target cancer after treatment. In NMIBC CIS trials, CR is defined as absence of high-grade recurrence. In the renal pelvis study, CR includes negative urine cytology for high-grade cancer and no suspicious lesions on ureteroscopy or a negative biopsy when needed.
  • Durability of response: How long a complete response lasts before cancer comes back or progresses. Trials measure durability at specific time points such as 6, 9, and 12 months.
  • Recurrence-free survival (RFS): The time from a starting point (often randomization) until the cancer returns, progresses, or the person dies from any cause (depending on the trial definition).
  • Progression-free survival (PFS): The time during and after treatment when the cancer does not get worse. In one trial, progression includes developing muscle-invasive disease (≥T2), lymph node or distant spread, or death without documented progression.
  • Muscle-invasive disease (≥T2): Cancer that has grown into the bladder muscle layer. This is a more serious stage and is tracked as an outcome in several trials.
  • Cystectomy: Surgery to remove the bladder. Trials may measure how often cystectomy happens, time to cystectomy, and pathology results at cystectomy.
  • Pathological staging: The cancer stage based on examination of tissue under a microscope, often after surgery such as cystectomy. It can include tumor (T), nodes (N), and metastasis (M).
  • Adverse event: An unwanted medical problem that happens during a trial. Trials track how often side effects occur and how severe they are.
  • Treatment-emergent adverse event: A side effect that starts or worsens after the treatment begins.
  • Antibodies (anti-adenoviral, anti-interferon): Proteins made by the immune system that can react to the adenovirus vector or interferon. One upper-tract trial measures whether these antibodies appear.
  • Shedding of adenoviral vector: Testing whether the viral vector is detectable in body fluids after treatment. One upper-tract trial checks shedding for up to 15 days after dosing.
  • Systemic exposure: How much of a treatment (or related proteins) is found in the bloodstream or body outside the treated area. One upper-tract trial measures systemic exposure to interferon protein and the adenoviral vector after dosing.
  • Ureteroscopy: A procedure using a thin scope to look inside the ureter and renal pelvis. In one trial, it is used to check for suspicious lesions when assessing response.
  • Urine cytology: A lab test that looks for cancer cells in urine. In the renal pelvis trial, negative urine cytology for high-grade cancer is part of the complete response definition.
  • TURBT (transurethral resection of bladder tumor): A procedure to remove bladder tumors through the urethra. In an intermediate-risk NMIBC trial, participants must have had a complete TURBT within a set time window before randomization.
  • Observation (surveillance): A trial group where participants do not receive the study drug and are followed with scheduled check-ups to watch for recurrence or progression.
  • Pembrolizumab: An immune checkpoint inhibitor (immunotherapy) that blocks PD-1, which can help restore anti-tumor immune responses. One trial studies it in combination with intravesical nadofaragene firadenovec.
  • Gemcitabine and docetaxel (intravesical chemotherapy): Chemotherapy medicines that can be placed directly into the bladder. Some trials compare nadofaragene firadenovec to usual care that may include gemcitabine with or without docetaxel, and another trial tests a combination of nadofaragene firadenovec with intravesical gemcitabine and docetaxel.

References