Neoadjuvant Intravesical Nadofaragene Firadenovec With Gemcitabine, Cisplatin and Durvalumab for the Treatment of Muscle Invasive Bladder Cancer, TRIFECTA Trial

NCT07332351 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: RG1126027NCI-2025-09407
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial tests the effect of intravesical nadofaragene firadenovec in combination with gemcitabine, cisplatin and durvalumab before (neoadjuvant) radical cystectomy (RC) in treating patients with muscle invasive bladder cancer. The combination of gemcitabine, cisplatin and durvalumab are already considered standard of care in the treatment of muscle invasive bladder cancer. This trial attempts to determine whether the addition of nadofaragene firadenovec to the current standard regiment is safe and can improve oncological outcomes for those with muscle invasive bladder cancer. Nadofaragene firadenovec, a type of intravesical gene therapy, is a weakened adenovirus that carries a copy of the gene for interferon alfa-2b. This medication gets absorbed by the bladder and stimulates the bladder to naturally create interferon alfa-2b, which is thought to kill bladder cancer. Nadofaragene firadenovec is given in a solution that is placed directly into the bladder (intravesical) using a thin tube called a catheter. It is a medication that is already FDA approved for the treatment of non-muscle invasive bladder cancer. Gemcitabine is a chemotherapy drug that blocks the cells from making deoxyribonucleic acid and may kill tumor cells. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread.

Conditions

Stage II Bladder Cancer AJCC v8; Stage IIIA Bladder Cancer AJCC v8; Muscle Invasive Bladder Urothelial Carcinoma

Keywords

Urinary Bladder

Outcome Measures

Primary Outcomes (2)

• Pathological complete response (pCR) on radical cystectomy (RC) specimen

  Will be defined as the proportion of participants achieving ypT0N0. Will employ Simon's optimal two-stage design (Simon, 1989) to test the null hypothesis that the true pCR rate is 33.8% versus the alternative hypothesis of 56%. The observed pCR rate will be reported with an exact 95% confidence interval using the Clopper-Pearson method.

  At time of radical cystectomy (RC), approximately 4-8 weeks following completion of neoadjuvant systemic therapies

• Downstaging (≤ ypT1N0) on RC specimen

  At time of radical cystectomy (RC), approximately 4-8 weeks following completion of neoadjuvant systemic therapies

Secondary Outcomes (3)

• Proportion of patients who undergo RC

  Within 10 weeks from last neoadjuvant therapy dose

• Incidence of grade 3 or higher treatment-related adverse events (AE)

  From initiation of neoadjuvant systemic therapies (day 1 of cycle 1; 4 cycles total; each cycle is 21 days), through 30 days post-RC (RC occurs approximately 4-8 weeks after completion of neoadjuvant systemic therapies)

• Incidence of AEs

  From initiation of neoadjuvant systemic therapies (day 1 of cycle 1; 4 cycles total; each cycle is 21 days), through 30 days post-RC (RC occurs approximately 4-8 weeks after completion of neoadjuvant systemic therapies)

Study Arms (1)

Treatment (durvalumab, chemotherapy, nadofaragene firadenovec)

EXPERIMENTAL

Patients receive durvalumab IV over 60 minutes on day 1, gemcitabine IV over 30 minutes on days 1 and 8, and cisplatin IV on day 1 or days 1 and 8 of each cycle. Patients also receive nadofaragene firadenovec intravesically on day 1 of cycles 1 and 4. Cycles repeat every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Starting 4-8 weeks after treatment, patients undergo RC per standard clinical care. Following RC, patients may receive durvalumab at the discretion of the clinician. Additionally, patients undergo urine and blood sample collection and CT, MRI or PET/CT throughout the study.

Biological: Nadofaragene Firadenovec; Biological: Durvalumab; Drug: Gemcitabine; Drug: Cisplatin; Procedure: Radical Cystectomy; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Positron Emission Tomography; Procedure: Magnetic Resonance Imaging

Interventions

Durvalumab BIOLOGICAL

Given IV

Also known as: Imfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, MEDI 4736

Treatment (durvalumab, chemotherapy, nadofaragene firadenovec)

Gemcitabine DRUG

Given IV

Treatment (durvalumab, chemotherapy, nadofaragene firadenovec)

Cisplatin DRUG

Given IV

Also known as: Cisplatinum, Platinol

Treatment (durvalumab, chemotherapy, nadofaragene firadenovec)

Radical Cystectomy PROCEDURE

Undergo RC

Also known as: RC

Treatment (durvalumab, chemotherapy, nadofaragene firadenovec)

Biospecimen Collection PROCEDURE

Undergo urine and blood sample collection

Also known as: Biological Sample Collection

Treatment (durvalumab, chemotherapy, nadofaragene firadenovec)

Computed Tomography PROCEDURE

Undergo CT or PET/CT

Also known as: CT, CT Scan, CAT Scan

Treatment (durvalumab, chemotherapy, nadofaragene firadenovec)

Positron Emission Tomography PROCEDURE

Undergo PET/CT

Also known as: PET, PET Scan

Treatment (durvalumab, chemotherapy, nadofaragene firadenovec)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: MRI

Treatment (durvalumab, chemotherapy, nadofaragene firadenovec)

Nadofaragene Firadenovec BIOLOGICAL

Given intravesically

Also known as: Adstiladrin, Instiladrin, Recombinant Adenovirus-Interferon SCH 721015, Recombinant Adenovirus-Interferon With Syn3, Recombinant Adenovirus-Interferon/Syn3, SCH 721015

Treatment (durvalumab, chemotherapy, nadofaragene firadenovec)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years at the time of screening
• Ability to understand and willingness to sign the written informed consent document
• Patients with confirmed muscle-invasive urothelial carcinoma of the bladder (cT2-4a, N0-1, M0 or cT1, N1, M0), who are planning to undergo RC
• Pure urothelial or mixed histologic subtypes are allowed if urothelial is the primary histology (regardless of the % of conventional urothelial histology)
• Eligible to receive neoadjuvant cisplatin/gemcitabine and durvalumab per the patient's medical oncologist's discretion
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Hemoglobin count ≥ 9 gm/dL
• Absolute neutrophil count of ≥ 1500 cells/uL
• Platelet count of ≥ 100,000/uL
• Alanine and aspartate aminotransferase levels ≤ 2.5 x upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 x ULN (≤ 2.5 x ULN for Gilbert syndrome)
• Creatinine clearance or estimated glomerular filtration rate (GFR) ≥ 40ml/min (using Chronic Kidney Disease Epidemiology Collaboration Formula \[CKD-EPI\] 2021 equation)
• For patients with evidence of, or history of HIV, chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, the viral load must be undetectable, or the infection must have been treated and cured. Patients are not allowed to be on immunosuppressive agents for HIV, HBV or HCV. Routine testing for HIV, HBV and HCV is not required for patients without such history unless clinically indicated
• Individuals with a prior malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are allowed to enroll

You may not qualify if:

• cT4b, N2-3, or M1 stage at time of screening
• Any known concurrent clinically relevant malignancies
• Prior systemic therapy for muscle-invasive bladder carcinoma (MIBC) (prior intravenous pembrolizumab for non-muscle invasive bladder carcinoma \[NMIBC\] is allowed)
• Current or prior use of systemic immunosuppressive medication within 14 days before first dose of investigational product. The following are allowed (not systemic route): intranasal, inhaled, intra-articular, topical steroids, local steroid injections
• Pure non-urothelial histology subtype/variant or any neuroendocrine (small or large cell) component
• Prior treatment with adenovirus-based drugs
• Known hypersensitivity or allergy to any components of rAd-interferon (IFN)a/Syn3
• Currently receiving other investigational agent
• Pregnant or lactating women

Sponsors & Collaborators

• University of Washington: lead
• Ferring Pharmaceuticals: collaborator

Study Sites (1)

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Interventions

Synapsins; durvalumab; Immunoglobulin G; Disulfides; Gemcitabine; Cisplatin; Cystectomy; Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Nerve Tissue Proteins; Proteins; Amino Acids, Peptides, and Proteins; Phosphoproteins; Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Sulfides; Anions; Ions; Electrolytes; Inorganic Chemicals; Hydrogen Sulfide; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Chlorine Compounds; Nitrogen Compounds; Platinum Compounds; Urologic Surgical Procedures; Urogenital Surgical Procedures; Surgical Procedures, Operative; Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques

Study Officials

• Jonathan Wright, MD

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jonathan Wright, MD

CONTACT

206-598-4294; jlwright@uw.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 6, 2026
• First Posted: January 12, 2026
• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): February 1, 2027
• Last Updated: March 13, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)