Phase 3 Randomized Trial of Nadofaragene Firadenovec with Gemcitabine, Docetaxel, or Pembrolizumab in BCG-Unresponsive High-Grade NMIBC
- Trial ID
- 2024-512177-27-01
- Protocol
- 000434
- Sponsor
- Ferring Pharmaceuticals A/S
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase 3, randomized, multi-center, open-label trial is to evaluate the **efficacy** of intravesical instillation, including reinduction, of **nadofaragene firadenovec** alone or in combination with chemotherapy (gemcitabine and docetaxel) or immunotherapy (pembrolizumab) in subjects with high-grade Bacillus Calmette-Guerin (BCG) unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without concomitant high-grade Ta or T1 papillary disease. This objective is clinically relevant as it addresses the therapeutic challenge in patients with high-risk NMIBC who do not respond to BCG therapy, a common first-line treatment. The study aims to provide alternative treatment options that could potentially improve patient outcomes in this difficult-to-treat population.
Participants
The clinical trial involves a total of **100 participants** diagnosed with **high-risk Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC)** with carcinoma in situ (CIS), with or without papillary tumors. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their unresponsiveness to at least two courses of BCG therapy within the last 12 months, among other criteria. The trial does not include a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) status of 2 or less and a life expectancy of more than two years. Lifestyle considerations such as diet and physical activity are not specified. The selection criteria ensure that participants have adequate laboratory values and are free from concomitant upper tract urothelial carcinoma or urothelial carcinoma within the prostatic urethra. The trial does not provide specific information on the general health status beyond the inclusion criteria.
Plans and Procedures
The clinical trial is a **randomized**, multi-center, open-label study designed to evaluate the safety and efficacy of **intravesical** nadofaragene firadenovec, either alone or in combination with chemotherapy agents **gemcitabine** and **docetaxel**, or the immunotherapy agent **pembrolizumab**. The trial targets subjects with high-grade Bacillus Calmette-Guerin (BCG) unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papillary tumors. The primary objective is to assess the complete response rate, defined as the absence of high-grade recurrence at any time from the first treatment. The trial is expected to run until December 31, 2028, with recruitment starting on October 1, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, ECOG status, and laboratory values. The inclusion visit will also involve obtaining informed consent and conducting necessary baseline assessments. Following the inclusion visit, participants will receive treatment according to their assigned group, with regular follow-up visits scheduled to monitor safety, efficacy, and any adverse events. The end-of-study visit will occur after the completion of the treatment period, which is set at a maximum of 24 months. During this visit, final assessments will be conducted to evaluate the overall response to the treatment.
The expected length of participant involvement is up to 24 months, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any medical condition that, in the opinion of the investigator, would make continued participation detrimental to the participant's health. The trial is structured to ensure rigorous monitoring and data collection throughout the study duration, adhering to ethical standards and regulatory requirements.
Treatment
The clinical trial involves the use of several experimental medications, each with specific administration protocols. **Gemcitabine hydrochloride** is administered as a **cytotoxic, antitumoral** agent in the form of a pharmaceutical preparation coded as PHF00230MIG. It is delivered via **intravesical use** with a maximum daily dose of 0.02 g/mL and a total dose not exceeding 0.56 g/mL over a treatment period of up to 24 weeks. This chemical substance is utilized for its antineoplastic properties in the treatment of high-grade Bacillus Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC).
**Pembrolizumab**, marketed as KEYTRUDA, is provided as a 25 mg/mL concentrate for solution for infusion. This **immunotherapy** is administered through **intravenous infusion** with a maximum daily dose of 400 mg and a total dose limit of 6400 mg over a 24-week period. Pembrolizumab is a protein-based therapeutic agent, specifically a monoclonal antibody, used to enhance the immune response against cancer cells in NMIBC patients.
**Nadofaragene firadenovec**, branded as ADSTILADRIN, is delivered as an **intravesical suspension**. This advanced therapy involves a replication-deficient recombinant type 5 adenovirus vector, designed for **intravesical use**. The dosing schedule is determined by the study protocol, with a treatment duration of up to 24 weeks. This structurally diverse substance is employed for its gene transfer capabilities in the management of NMIBC.
**Docetaxel** is another **antineoplastic agent** used in the trial, also prepared in the form of PHF00230MIG for **intravesical use**. The maximum daily dose is set at 0.75 mg/mL, with a total dose not exceeding 21 mg/mL over the course of 24 weeks. As a chemical substance, docetaxel is utilized for its efficacy in disrupting cancer cell division, contributing to the therapeutic regimen for NMIBC.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the **complete response (CR)** at any time from the first treatment, defined as the absence of high-grade (HG) recurrence. This primary endpoint will be used to determine the effectiveness of intravesical nadofaragene firadenovec, either alone or in combination with chemotherapy agents such as gemcitabine and docetaxel, or with the immunotherapy agent pembrolizumab, in subjects with high-grade Bacillus Calmette-Guerin (BCG) unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without concomitant high-grade Ta or T1 papillary disease.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed informed consent obtained before beginning any trial-related procedures
- Diagnosed, as documented, with carcinoma in situ (CIS) ±Ta/T1 high-grade disease • For T1 disease biopsies should contain muscle fibres
- Unresponsive to ≥2 courses of Bacillus Calmette-Guerin (BCG) therapy within the last 12 months. BCG-unresponsive refers to subjects with high-grade non-muscle-invasive bladder cancer (NMIBC) who are unlikely to benefit from and who will not be receiving further intravesical BCG. The term “BCG-unresponsive” includes subjects who did not respond to BCG treatment and have a persistent high-grade recurrence within 12 months after BCG was initiated, and those who despite an initial complete response (CR) to BCG, relapse with CIS within 12 months of their last intravesical treatment with BCG or relapse with high grade Ta/T1 NMIBC within 6 months of their last intravesical treatment with BCG. The following criteria define the subjects who may be included in the trial: • Have received at least 2 courses of BCG within a 12-month period – defined as at least 5 of 6 induction BCG instillations and at least 2 of 3 instillations of maintenance BCG, or at least 2 of 6 instillations of a second induction course, where maintenance BCG is not given. o Exception: those who have T1 high-grade disease at 1st evaluation after induction BCG alone (at least 5 of 6 doses) may qualify in the absence of disease progression • At the time of tumour recurrence, subjects with CIS alone or high-grade Ta/T1 with CIS should be within 12 months of last exposure to BCG • No maximum limit to the amount of BCG administered • All visible papillary tumours must be resected and those with persistent T1 disease on transurethral resection of bladder tumour (TURBT) should undergo an additional re TURBT within 14 to 70 days prior to beginning trial treatment. Obvious areas of CIS should also be fulgurated
- Eastern Cooperative Oncology Group (ECOG) status ≤2
- Aged ≥18 years at the time of consent
- Available for the whole duration of the trial
- Life expectancy >2 years, in the opinion of the investigator
- Absence of concomitant upper tract urothelial carcinoma or urothelial carcinoma within the prostatic urethra. Freedom from upper tract disease (if clinically indicated) as indicated by no evidence of upper tract tumour by either intravenous pyelogram, retrograde pyelogram, computed tomography (CT) scan with or without urogram, or magnetic resonance imaging (MRI) with or without urogram performed within 6 months of enrolment. Absence of locally advanced disease as assessed by CT scan or MRI
- Subjects who elect not to undergo cystectomy
- Subjects with prostate cancer on active surveillance at low risk for progression are permitted to be included into the trial at the discretion of the investigator (see exclusion criterion 16)
- 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, as 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 11.
- Adequate laboratory values: • Haemoglobin ≥10 g/dL • White blood cells (WBC) ≥3800/µL • Absolute neutrophil count (ANC) ≥2000/µL • Platelet count ≥100,000/µL • International normalised ratio (INR)a below institutional upper limit of normal (ULN) • Activated partial thromboplastin time (aPTT)a below institutional ULN • Aspartate aminotransferase (AST) ≤1.5 x ULN • Alanine aminotransferase (ALT) ≤1.5 x ULN • Total bilirubin ≤1.5 x ULN • Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 a 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 in regard to their current concomitant anticoagulant therapy.
Exclusion Criteria
- Current or previous evidence of muscle-invasive (muscularis propria) or metastatic disease presented at the screening visit. Examples of increased risk of muscle-invasive disease include but are not limited to: • Presence of lymphovascular invasion and / or micropapillary, sarcomatoid, plasmacytoid and / or neuroendocrine disease as shown in the histology of the biopsy sample • Subjects with CIS+T1 disease accompanied by the presence of hydronephrosis secondary to the primary tumour
- Current systemic therapy for bladder cancer other than IMP used in randomisation arm
- Current or prior investigational treatment for BCG-unresponsive NMIBC or any other investigational drug (drug used in a clinical trial, i.e. drug used in a Ferring sponsored non-interventional study does not apply) within 1 month prior to screening
- Current or prior pelvic external beam radiotherapy within 2 years of screening
- Prior treatment with nadofaragene firadenovec at any time
- Prior systemic therapy for bladder cancer at any time
- Prior intravesical chemotherapy for the treatment of BCG-unresponsive NMIBC (see exclusion criterion 19)
- Use of other adenovirus vector-based drugs, e.g. COVID-19 vaccines, within 14 days before and after nadofaragene firadenovec instillation
- Suspected hypersensitivity or immune-mediated reactions to any of the IMPs
- Current or prior autoimmune disease
- Immunocompromised, or immunodeficient, or undergoing any form of treatment known to cause immunosuppression
- Symptomatic urinary tract infection or bacterial cystitis (once satisfactorily treated, subjects can enter the trial)
- Clinically significant and unexplained elevated liver or renal function tests
- Female subjects who are pregnant or lactating or refuse to commit to use contraception during the trial
- Any other significant disease or other clinical findings which in the opinion of the investigator would prevent trial entry
- History of malignancy of other organ system within past 5 years, except treated basal cell carcinoma or squamous cell carcinoma of the skin and ≤pT2 upper tract urothelial carcinoma at least 24 months after nephroureterectomy. Also subjects with genitourinary cancers other than urothelial cancer or prostate cancer, and subjects with renal mass ≤3 cm that are under active surveillance are excluded (see inclusion criterion 10)
- Subjects who cannot hold instillation for 1 hour
- Subjects who cannot tolerate intravesical dosing or intravesical surgical manipulation
- Intravesical therapy within 8 weeks prior to beginning IMP with the exception of: • Cytotoxic agents (e.g., Mitomycin C, doxorubicin, epirubicin and gemcitabine) when administered as a single instillation immediately following a TURBT procedure, which is permitted within 70 days prior to beginning trial treatment • Previous intravesical BCG therapy, which can be given ≥5 weeks prior to the biopsy that is required for trial entry
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Recruiting | 01 Oct 2025 | 18 |
 Denmark | Not Yet Recruiting | 01 Oct 2025 | 8 |
 France | Recruiting | 01 Oct 2025 | 23 |
 Poland | Recruiting | 01 Oct 2025 | 25 |
 Spain | Recruiting | 01 Oct 2025 | 67 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
GEMCITABINE | Test | PHF00230MIG | INTRAVESICAL USE | 0.02 | 24 | SCP1128788 |
ADSTILADRIN | Test | INTRAVESICAL SUSPENSION | INTRAVESICAL USE | 0.0 | 24 | PRD11646730 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 400 | 24 | PRD4323105 |
DOCETAXEL | Test | PHF00230MIG | INTRAVESICAL USE | 0.75 | 24 | SCP126226 |