A Phase 4, Multi-center, Open Label Trial to Evaluate Efficacy of Retreatment With Nadofaragene Firadenovec in Subjects With CIS ± High-grade Ta/T1 and no Complete Response to First Nadofaragene Firadenovec Dose — ABLE-42  

Bladder Cancer Clinical Trial

Official title: A Phase 4, Multi-center, Open Label Trial to Evaluate Efficacy of Retreatment With Nadofaragene Firadenovec in Subjects With CIS ± High-grade Ta/T1 and no Complete Response to First Nadofaragene Firadenovec Dose

Status Not yet recruiting

Clinical Trial Summary

In this phase 4 trial (000439), subjects with NMIBC CIS (± high-grade Ta/T1) who have not responded to their first dose of nadofaragene firadenovec (commercial ADSTILADRIN received before trial entry) will be offered retreatment when entering the trial. Retreatment is justified at 3 months after first dose of nadofaragene firadenovec, since 3-months' follow-up scheme is the standard of care in high-risk NMIBC. Retreatment at month 3 is used in a trial investigating intravesical instillation of a IL 15 superagonist (nogapendekin alfa inbakicept [NAI], also known as N 803), and lead to a CR in 46% (11 of 24) of the subjects at month 6. Moreover, retreatment is a widely accepted concept in immuno-oncology and has been used in IFN α treatment of kidney cancer in the past. It is currently also used in an ongoing phase 3 trial investigating the efficacy of oncolytic virus (CG0070) in BCG-unresponsive NMIBC. In this trial, around one third of the subjects who did not respond to the first treatment of CG0070 achieved CR after retreatment at 3 months. Therefore, it is also expected that a retreatment with nadofaragene firadenovec would show a comparable response rate.

Clinical Trial Description

Intravesical nadofaragene firadenovec was approved by the US Food and Drug Administration (FDA) in December 2022 for the treatment of high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors under the tradename ADSTILADRIN (hereafter nadofaragene firadenovec). It has only been approved in the US. Nadofaragene firadenovec is being developed as a vector-based gene therapy for NMIBC treatment to potentiate durable therapeutic responses by interferon alfa-2b (IFN-α2b) amplification. It is a non-replicating recombinant adenovirus serotype 5 vector containing a transgene encoding the human IFN-α2b gene. In addition, a single use vial of ADSTILADRIN contains the excipient [N-(3-cholamidopropyl)-N-(3-lactobionamidopropyl)]-cholamide (referred to as Syn3NODA) that enhances gene transfer across the urothelium.

Nadofaragene firadenovec is an efficacious and well tolerated intravesical bladder-sparing therapy, which has been investigated in clinical trials from phase 1 to 3 as part of the clinical development program. These trials established the safety and clinical efficacy of nadofaragene firadenovec in the treatment of CIS and high-grade Ta/T1 disease in subjects who are unresponsive to BCG treatment, as measured by complete response (CR) for CIS and high-grade recurrence-free survival for high-grade Ta/T1.

In this phase 4 trial (000439), subjects with NMIBC CIS (± high-grade Ta/T1) who have not responded to their first dose of nadofaragene firadenovec (commercial ADSTILADRIN received before trial entry) will be offered retreatment when entering the trial. Retreatment is justified at 3 months after first dose of nadofaragene firadenovec, since 3-months' follow-up scheme is the standard of care in high-risk NMIBC. Retreatment at month 3 is used in a trial investigating intravesical instillation of a IL 15 superagonist (nogapendekin alfa inbakicept [NAI], also known as N 803), and lead to a CR in 46% (11 of 24) of the subjects at month 6. Moreover, retreatment is a widely accepted concept in immuno-oncology and has been used in IFN α treatment of kidney cancer in the past. It is currently also used in an ongoing phase 3 trial investigating the efficacy of oncolytic virus (CG0070) in BCG-unresponsive NMIBC. In this trial, around one third of the subjects who did not respond to the first treatment of CG0070 achieved CR after retreatment at 3 months. Therefore, it is also expected that a retreatment with nadofaragene firadenovec would show a comparable response rate.

In BCG treatment of NMIBC, studies show that 40-60% of those who did not respond to initial treatment at 3 months, responded at month 6 to a second cycle at month 3. Retreatment has been shown to reduce the frequency of tumor recurrences over standard 6 weeks BCG treatment alone. Tumors recurred in 11% of subjects receiving 2 BCG courses vs. 29% of subjects treated with initial 6 weeks BCG treatment (p=0.03). Further, those subjects that received retreatment of BCG had higher CR rates after 6 months and longer disease-free intervals. The hypothesis is that first exposure to BCG primes the immune system to enhance anti-tumor effects of subsequent therapy. The same principle may apply for nadofaragene firadenovec retreatment. The first nadofaragene firadenovec instillation is likely to activate an initial immune response that enhances the antiinflammatory and anti-tumor effects of the second administration. As a result, subjects with no CR after 3 months may benefit from retreatment, with the first dose acting as the stimulator which enhances the anti-tumor effects of the second dose ;

Related Conditions & MeSH terms

• Bladder Cancer
• CIS
• Urinary Bladder Neoplasms

• NCT number: NCT06390111
• Study type: Interventional
• Source: Ferring Pharmaceuticals
• Contact: Global Clinical Compliance
• Phone: 1-888-FERRING (1-888-337-7464)
• Email: DK0-Disclosure@ferring.com
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: April 30, 2024
• Completion date: July 31, 2026