A Trial to Evaluate Efficacy of Reinduction With Nadofaragene Firadenovec in Subjects With CIS ± High-grade Ta/T1 and no Complete Response to First Nadofaragene Firadenovec Dose. (ABLE-42)

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

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 reinduction when entering the trial.

Study Overview

• Status: Withdrawn
• Conditions: Bladder Cancer; CIS; Ta/T1
• Intervention / Treatment: Drug: nadofaragene firadenovec

Detailed 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

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72211
      • Ferring Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30328
      • Ferring Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosed, as documented, with CIS ± high-grade disease Ta/T1 and absence of progression after first dose of nadofaragene firadenovec within the last 5 months from instillation.

• Diagnosed, as documented, with:

  • Low risk of disease progression as assessed at the discretion of the investigator
  • Previous Bacillus Calmette Guerin (BCG) therapy (BCG exposed) with no maximum limit to the amount of BCG administered

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 include but are not limited to:

  • Presence of lymphovascular invasion and / or micropapillary disease as shown in the histology of the biopsy sample
  • Subjects with T1 disease accompanied by the presence of hydronephrosis secondary to the primary tumor
• Current and prior systemic or local therapy for bladder cancer since first dose of nadofaragene firadenovec
• 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) since first dose of nadofaragene firadenovec
• Clinically significant and unexplained elevated liver or renal function tests
• 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 that are under active surveillance are excluded

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nadofaragene Firadenovec; Eligible subjects will receive nadofaragene firadenovec. This will be instilled quarterly in the bladder followed by quarterly disease assessments.	Drug: nadofaragene firadenovec; The investigational medicinal product dose, concentration, and assessments are aligned with nadofaragene firadenovec US prescribing information.; Other Names: Adstiladrin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Complete response (CR) achieved at month 3 after nadofaragene firadenovec retreatment	at month 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maintenance of CR at months 6 after nadofaragene firadenovec retreatment		at 6 months after nadofaragene firadenovec retreatment
Maintenance of CR at months 9 after nadofaragene firadenovec retreatment		at 9 months after nadofaragene firadenovec retreatment
Maintenance of CR at months 12 after nadofaragene firadenovec retreatment		at 12 months after nadofaragene firadenovec retreatment
Durability of CR at months 6 after nadofaragene firadenovec retreatment	No evidence of CIS and/or high-grade Ta/T1	at 6 months after nadofaragene firadenovec retreatment
Durability of CR at months 9 after nadofaragene firadenovec retreatment	No evidence of CIS and/or high-grade Ta/T1	at 9 months after nadofaragene firadenovec retreatment
Durability of CR at months 12 after nadofaragene firadenovec retreatment	No evidence of CIS and/or high-grade Ta/T1	at 12 months after nadofaragene firadenovec retreatment
Muscle-invasive progression of disease up to month 12 after nadofaragene firadenovec retreatment		Up to12 months after nadofaragene firadenovec retreatment
Incidence of cystectomy		Up to 12 months after nadofaragene firadenovec retreatment
Time to cystectomy		Up to 12 months after nadofaragene firadenovec retreatment
Pathological staging at cystectomy		Up to 12 months after nadofaragene firadenovec retreatment

Collaborators and Investigators

• Sponsor: Ferring Pharmaceuticals
• Investigators: Study Director: Global Clinical Compliance, Ferring Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2024
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): July 31, 2026

Study Registration Dates

• First Submitted: April 19, 2024
• First Submitted That Met QC Criteria: April 25, 2024
• First Posted (Actual): April 30, 2024

Study Record Updates

• Last Update Posted (Estimated): November 22, 2024
• Last Update Submitted That Met QC Criteria: November 20, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urologic Neoplasms; Urinary Bladder Diseases; Urinary Bladder Neoplasms
• Other Study ID Numbers: 000439

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No