A Study to Investigate the Efficacy and Safety of Alpha1H as a Neoadjuvant Therapy in Participants With Low- to Intermediate-Risk/Low-Grade Papillary Non-Muscle Invasive Bladder Cancer

Phase 3RecruitingNCT07804056

Hamlet Pharma AB194 enrolled

Overview

The goal of this clinical trial is to learn if the drug Alpha1H works to treat low-to-intermediate risk non-muscle-invasive bladder cancer in adults. It will also learn about the safety of drug Alpha1H. The main questions it aims to answer are: * Does giving drug Alpha1H before surgery lower the risk of cancer returning or worsening compared to standard care alone? * Is drug Alpha1H safe and well-tolerated by participants? Researchers will compare participants receiving drug Alpha1H before standard surgery to participants receiving standard care alone to see if drug Alpha1H lowers the risk of cancer returning or progressing. Participants will: * Be randomly assigned to receive either drug Alpha1H before surgery or standard care alone. * Receive drug Alpha1H directly into the bladder 6 times over about 1 month if assigned to the Alpha1H group. * Hold the liquid in the bladder for up to 2 hours during each visit. * Undergo standard surgery through the urethra (TURBT) to remove remaining tumor tissue. * Visit the clinic regularly for follow-up checkups (including bladder examinations and urine tests) to check if the cancer returns. * Fill out questionnaires about their quality of life.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

194

Conditions

Urinary Bladder Neoplasms Non-muscle Invasive Bladder Cancer (NMIBC)

Interventions

Alpha1HDRUG

Administered via intravesical instillation directly into the urinary bladder. Participants in the experimental group receive a total of 6 instillations on Days 1, 3, 5, 8, 15, and 22 over approximately 1 month prior to TURBT. During each treatment, participants are asked to retain the solution in the bladder for up to 2 hours.

Transurethral Resection of Bladder Tumor (TURBT)PROCEDURE

Standard endoscopic surgical procedure performed through the urethra to resect and remove papillary bladder tumor tissue. Performed approximately 30 days after study entry (on Visit 8). Resected tumor tissue is collected for histopathology and central analysis.

Intravesical ChemotherapyDRUG

A single early intravesical instillation of standard-of-care chemotherapy (epirubicin, mitomycin, or gemcitabine) administered into the urinary bladder shortly following TURBT surgery in accordance with local institutional guidelines.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Signed and dated informed consent. * Low- or intermediate-risk non-muscle-invasive bladder cancer (NMIBC) meeting one of the following definitions: * Low-risk NMIBC: Primary, solitary, Ta, low-grade, 0.5 cm to 3 cm. * Intermediate-risk NMIBC (low-to-intermediate risk subgroup per IBCG classification): * Primary multifocal (\<10 lesions), Ta, low-grade, 0.5 cm to 3 cm; * Recurrent solitary, Ta, low-grade, 0.5 cm to 3 cm; or * Recurrent multifocal (\<10 lesions), Ta, low-grade, \>1 year after previous recurrence. * Men and women aged 18 years or older. * Negative pregnancy test at screening for women of childbearing potential. * Women of childbearing potential must agree to use highly effective contraception methods throughout study participation; men of childbearing potential must refrain from donating sperm during the study. * Ability to retain bladder contents for 2 hours. Exclusion Criteria: * Patient with non-papillary tumor appearance at the time of initial cystoscopy. * Previous history of T1 or high-grade disease in recurrent tumors. * Patients with T1 or high-grade non-muscle invasive papillary bladder cancer (NMIBC). * Previous intravesical BCG immunotherapy. * Patients with any other cancer diagnosis within the last 5 years (except for skin basalioma). * Acute urinary tract infection requiring antibiotic treatment. * Prior radiotherapy or systemic chemotherapy. * WHO performance status of 3 or 4. * Any other investigational agent or non-marketed product within one month prior to Visit 1 and during the trial. * Known active HIV infection, defined as detectable HIV viral load at screening. * Active hepatitis B virus (HBV) infection, defined as hepatitis B surface antigen (HBsAg) positivity with detectable HBV DNA at screening. * Active hepatitis C virus (HCV) infection, defined as anti-HCV antibody positivity with detectable HCV RNA at screening in a patient not on stable antiviral treatment. * Any concurrent illness that may render a participant ineligible or limit compliance with study requirements. * Previously enrolled in this trial.

Outcomes

Primary Outcomes

Event-Free Survival (EFS)

Time frame: From randomization until the occurrence of an EFS event or study completion, assessed at 3, 6, 9 (optional), and 12 months post-randomization, and every 6 months thereafter for up to 3 years.

Secondary Outcomes

Complete Response (CR) Rate

Time frame: Day 30 (±5 days), prior to TURBT

Overall Survival (OS)

Time frame: From randomization through study completion (assessed at 3, 6, 9 [optional], and 12 months, and every 6 months thereafter for up to 3 years).

Tumor Response (Morphological and Cellular)

Assessed as: (1) change in papillary tumor size (% reduction from baseline); (2) tumor cell shedding in urine (cells/mL); (3) apoptosis in shed cells (% TUNEL-positive cells); (4) Alpha1H uptake in shed cells (% Alpha1H-positive cells). Each parameter reported separately.

Time frame: Baseline (Day 1) to Day 30 (±5 days)

Tumor Gene Expression

Assessed by RNA sequencing (whole transcriptome) in tumor tissue and urine RNA. Reported as number of differentially expressed cancer-related genes and pathways between the Alpha1H and SOC arms.

Time frame: Baseline (Day 1) to Day 30 (±5 days)

Urinary Biomarkers and Immune Response

Assessed by proteomic profiling of urine samples. Reported as change in concentration (pg/mL) of cytokines, chemokines, and interferons between pre- and post-instillation samples, compared between the Alpha1H and SOC arms.

Time frame: Day 1, 3, 5, 8, 15, and 22 (pre- and post-instillation), and Day 30 (±5 days)

Incidence and Severity of Adverse Events (AEs)

Time frame: From Visit 1 (Screening) through Visit 9 (Day 40/50) and follow-up period (up to 3 years)

Change in Quality of Life (QoL) as Assessed by the QLQ-NMIBC24 Questionnaire

Quality of life will be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Non-Muscle-Invasive Bladder Cancer Module (EORTC QLQ-NMIBC24), a 24-item, disease-specific patient-reported outcome instrument. Each domain score is linearly transformed to range from 0 to 100. On functional scales (e.g., sexual function), higher scores indicate better functioning; on symptom-related scales (e.g., urinary symptoms, future perspective), higher scores indicate greater symptom burden. Scores are calculated per the EORTC scoring manual.

Time frame: From Visit 1 (Screening) through follow-up visits (up to 3 years)