Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Urinary Bladder Neoplasms

Carcinoma, Transitional Cell

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Transitional Cell Carcinoma

Patients will undergo urinary cytology, multimodal spectroscopy in urine and urologic surgical intervention

The group of cases will consist of patients who meet the inclusion and exclusion criteria in the operative note for:

* Transurethral Resection of Bladder Neoplasia (TURBT)
* Radical Cystectomy for Bladder Neoplasia
* Diagnostic ureterorenoscopy and / or laser treatment of ureteral and / or renal pelvis neoplasia
* Segmental ureterectomy with or without ureteral reimplantation
* Nephroureterectomy with or without bladder cuff excission

Patients will undergo urinary cytology, multimodal spectroscopy in urine and urologic surgical intervention

The control group will consist of patients who meet the inclusion and exclusion criteria in the operative note for:

* Transurethral Resection of Prostate (TURP)
* Other endoscopic treatments of Benign Prostatic Hyperplasia (BPH)
* Open interventions of prostatic adenomectomy
* Endoscopic lithotripsy interventions of bladder stones or cystotomy with removal of bladder stones
* Rigid and / or flexible ureterorenoscopy for the treatment of kidney and / or ureteral stones
* Placement of ureteral catheter for ureteral and / or renal stones
* Bladder Neck Incision (TUIP)
* Endoscopic urethrotomy

Approach based on a physical principle, mainly spectroscopy, which is rapid non-invasive and does not require the use of additional substances or contrast media in the diagnosis of urothelial neoplasms in urine samples.

It will be administered through a appositely designed device

Urinary Multimodal Fiber Optic Spectroscopy

An expert cytopathologist will analyze urine samples to detect urinary tract cancer cells. It is the current golden standard to detect urothelial cancer in urine

Urine Cytology

It will provide a reliable information on the presence/absence of cancer in the urinary tract (from direct visualization to pathological analysis)

Surgery

Simone Morselli, MD

Silvia Benemei, MD

Simone Morselli

Alekseja Manera, MD

Andrea Liaci, MD

Luca Gemma, MD

Mauro Gacci, MD

Enrico Baria, PhD

Riccardo Cicchi, PhD

Francesco Saverio Pavone, Prof

Sergio Serni, Prof

Gabriella Nesi, Prof

To facilitate the follow-up of urothelial tumors and also make them more tolerable and less invasive for patients, there is a minimally invasive and easy to perform examination which is urinary cytology on 3 samples. This test is extremely specific, over 90% chance of cancer if it is positive and is performed by expert cytopathologists, but it is burdened by a very low sensitivity, which is especially acute in the case of low grade tumors. This makes it an extremely useful test in case of positivity, but of little use if negative or doubtful, not being able to consider it reliable.

To overcome this problem, our study aims to bring an approach based on a physical principle, that is spectroscopy, which is fast non-invasive and does not require the use of additional substances or contrast media in the diagnosis of urothelial neoplasms in samples of urine.

In our experience, multimodal optical fiber spectroscopy has proved extremely valid in discriminating healthy urothelial tissue from tumor ex vivo, as well as providing important information on the degree of urothelial neoplasia, with accuracy rates higher than 80%, for which developed the idea of a technique based on multimodal spectroscopy.

If our method proves valid, it could improve the follow up and management of patients with urothelial cancer, being able to support normal cytology and provide further support to the cytopathologist, as well as simplify the diagnosis.

Multimodal Spectroscopy to Detect Urothelial Cancer in Urine

"The Feasibility of a Multimodal Spectroscopy Analysis to Detect Urothelial Cancer in Urine"

Evaluate whether multimodal spectroscopy can discriminate between healthy controls and patients with urothelial neoplasia on urine, with an accuracy at least comparable to urinary cytology on 3 samples

Evaluate whether multimodal spectroscopy is able to discriminate between high or low grade urothelial lesions on urine

Evaluate whether multimodal spectroscopy is able to discriminate between lower or upper urinary tract lesions on urine

Fondazione C.N.R./Regione Toscana "G. Monasterio", Pisa, Italy

European Laboratory for Non-Linear Spectroscopy

Careggi Hospital

University of Florence

Symptoms and General Pathology

Hematuria

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Urination Disorders

Hemorrhage

Voided urine was collected from consecutive patients presented with hematuria at our institute for urine cytology and DNA hypermethylation assay of the assigned genes using methylation-specific Polymerase Chain Reaction (PCR). Further assessment by office cystoscopy and imaging with subsequent inpatient cystoscopic biopsy for positive findings, was done. The diagnostic characteristics of DNA hypermethylation and urine cytology were assessed based on its capability to predict UBC noninvasively

diagnostic cystoscopy for detection of any bladder lesions

Cystoscopy

Computed tomography for patients to exclude bladder lesions

Computed tomography

DNA hypermethylation assay of six genes (GATA4, P16, P14, APC, CDH1 and CD99)

DNA hypermethylation assay

Urine cytology

Amr A Elsawy

The current study aimed to assess the diagnostic performance of novel urine-based DNA hypermethylation of six genes (GATA4, P16, P14, APC, CDH1 and CD99) for UBC detection in patients with hematuria.

According to GLOBOCAN data, bladder cancer (BC) is considered a major health problem that represents 3% of all cancer diagnoses. Urothelial bladder carcinoma (UBC) accounts for the vast majority (\>90%) of BC cases with predominance of non-muscle invasive disease (Ta, Tis or T1) in 75% of patients while others show muscle invasion (T2-4).

In refereed population, UBC is usually diagnosed as a result of work-up for hematuria at a rate of 2-5% following an evaluation of asymptomatic microscopic hematuria, and, up to 5-15% of patients with macroscopic hematuria. Therefore, a timely prompt evaluation of hematuria can give to earlier diagnosis and better survival of UBC.

Currently, cystoscopy /cross sectional imaging are the gold standard tools for UBC diagnosis in patients with hematuria. Unfortunately, these costly, invasive and painful diagnostics could miss early, small/flat bladder lesions. Urine cytology has been proposed as a non-invasive alternative test with high specificity, however, it lacks sensitivity for diagnosis of low grade (LG) tumors.

Over the last decades, multiple researches have output different markers for UBC diagnosis. Based on their target of assessment, these markers include screening for soluble antigens (BTA-Stat, NMP-22, surviving, etc.), cell surface antigens (Cytokeratins and UroVysion), genomic markers (Cxbladder and Xpert) and urinary metabolomics (CRAT and SLC25A20). However, most of these markers are limited by unsatisfying diagnostic performance, high cost or lack of validation.

Several preliminary studies have shown that DNA methylation, a critical step in transcription regulation, is chemically stable and can be precisely quantified, making it an attractive marker for UBC detection. Both local and global DNA hypermethylation in BC specimens are usually associated with inactivation of tumor suppressor genes. These methylations changes could be effectively identified in urine sediments as well as tumor tissues.

In the current literature, multiple studies investigated the performance of DNA hypermethylation of either individual or panel genes with reported sensitivity (SN) and specificity (SP) values that range from 40-95 % and 10-100 %, respectively. Most of these studies were limited by tumor characteristics heterogeneity (majority were ≥T2 and high grade (HG) disease; which did not reflect the daily practice, inclusion of different BC histological variants), lack of external validation and small sample size.

The aim of our study is to assess the diagnostic performance of novel urine-based DNA methylation six genes (GATA4, P16, P14, APC, CDH1 and CD99) for UBC detection in patients with hematuria. Moreover, we investigated the methylation pattern of these genes in different stages and grades of UBC.

Novel Urine-Based DNA Methylation Biomarkers for Urothelial Bladder Carcinoma Detection in Patients With Hematuria

Rate of hypermethylation of six genes (GATA4, P16, P14, APC, CDH1 and CD99) in patients with urothelial bladder carcinoma

Mansoura University

Lecturer of Urology

Carcinoma in Situ

Non-Muscle Invasive Bladder Neoplasms

Antipyretics

Analgesics

All Drugs and Chemicals

Antineoplastic Agents

Anti-Allergic Agents

Antiemetics

Central Nervous System Depressants

Gastrointestinal Agents

Dermatologic Agents

Acetaminophen

Durvalumab

Histamine Antagonists

Histamine H1 Antagonists

Diphenhydramine

Promethazine

BCG Vaccine

Histamine

Histamine phosphate

Analgesics, Non-Narcotic

Antineoplastic Agents, Immunological

Hypnotics and Sedatives

Anesthetics

Anesthetics, Local

Neurotransmitter Agents

Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 participants.

Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 participants.

Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg

Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)

Durvalumab 1500 mg is administered intravenously (IV) once every 4 weeks for 12 months with an option to continue therapy for an additional 12 months (total of 24 months) provided that, participant is tolerating therapy and remains free of recurrent high grade NMIBC (see Treatment Period below). The dose of durvalumab is 1500 mg. If optional maintenance therapy continued in the second year, durvalumab 1500 mg will be administered intravenously once every 3 months to provide an immune boost.

Vicineum is administered in a 12-week Induction Phase followed by a Maintenance Phase for at least one year with an option for a total of up to 2 years of treatment. During the Induction Phase, Vicineum is administered once weekly for 12 weeks. During the Maintenance Phase, Vicineum is administered every other week. The dose of Vicineum is 30 mg in 50 mL of saline.

Vicineum

Acetaminophen or equivalent medications per institutional standard may be administered at the discretion of the investigator.

Antihistamine (e.g., diphenhydramine) or equivalent medications per institutional standard may be administered at the discretion of the investigator.

Antihistamine

Bladder biopsy at screening and every 3 months before each cystoscopy per schema.

Bladder Biopsy

Transurethral resection of a bladder tumor (TURBT) at screening and every 3 months before each cystoscopy per schema.

TURBT

Urine cytology at screening and every 3 months before each cystoscopy per schema.

Urine cytology at baseline and every 3 months before each cystoscopy per schema.

Electrocardiogram (ECG) at screening, pre-durvalumb infusion and as clinically indicated during the trial.

Electrocardiogram

Computed tomography (CT) at screening and every 12 months while on study.

Magnetic resonance imaging (MRI) at screening and every 12 months while on study.

Vladimir A Valera Romero, M.D.

Background:

Non-muscle-invasive bladder cancer is in the early stages. But it usually comes back after treatment. The drugs Vicineum and Durvalumab may help the immune system find and destroy cancer cells.

Objective:

To test if the drugs Durvalumab and Vicineum together are safe and effective to treat people with bladder cancer that has not spread to the muscle in the bladder.

Eligibility:

People ages 18 and older who have bladder cancer that has not spread to the muscle in the bladder and was treated unsuccessfully with Bacillus Calmette-Guerin

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Tumor sample from previous surgery. If one is not available, they will have a biopsy: A small piece of tumor is removed.

Cystoscopy to examine the inside of the bladder. This may include a biopsy or removing tumors.

Computed tomography (CT) or magnetic resonance imaging (MRI): They lie in a machine that takes pictures of the body.

Electrocardiogram to test heart function

Participants will receive Durvalumab and Vicineum in 2 phases:

First phase: Durvalumab every 4 weeks and Vicineum once a week for 3 months

Second phase: Durvalumab every 4 weeks and Vicineum once every other week

Participants will have tumor samples taken every 3 months. They will have blood and urine tests throughout the study.

Participants will continue treatment for up to 2 years.

Participants will have a visit about 30 days after their last treatment. This includes blood and urine tests. It may include a cytoscopy or additional biopsies.

In 2016, it is estimated that there will be 76,960 new cases of bladder cancer and 16,390 deaths associated with bladder cancer. Bladder cancer is associated with the highest costs among all types of cancer, due to the need for lifelong routine monitoring and treatment. Approximately 70% of cases are non-muscle invasive bladder cancer (NMIBC) at presentation and are treated by transurethral resection of bladder tumor (TURBT) followed by intravesical treatment with BCG (Bacillus Calmette-Guerin) or mitomycin C. However, in the setting of high-grade disease, these therapies can become ineffective over time in up to two-thirds of patients and disease progression to muscle invasive bladder cancer (MIBC) can occur. In patients who present with CIS (carcinoma in situ) rates of progression are greater than 50%. Progression to MIBC portends a poor outcome as only 50% of patients will survive five years despite undergoing radical cystectomy. Clearly, there is a large unmet need in therapeutic options for NMIBC that recurs or progresses.

Vicineum(TM) is a recombinant fusion protein, VB4-845, that contains a humanized single-chain antibody fragment specific for the epithelial cell adhesion molecule (EpCAM) antigen linked to ETA (252-608), a truncated form of Pseudomonas exotoxin A (ETA). EpCAM is overexpressed on the surface of urothelial carcinoma cells and therefore represents a good target for Vicineum(TM) to bind to. In a previous phase II study in BCG refractory or BCG intolerant patients with high grade bladder cancer, 16% of patients treated with induction and maintenance therapy with Vicineum(TM) remained disease-free at 1 year. As a result, Vicineum(TM) is currently being evaluated as a single agent in a phase III trial.

Pre-clinical work with a drug called Proxinium, an earlier version of Vicineum(TM), demonstrated an abscopal effect and synergy with the use of a checkpoint blockade inhibitor. Although it was done in a non-small cell lung cancer (NSCLC) model, the results were impressive in causing tumor shrinkage. Durvalumab is a human monoclonal antibody (MAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 \[B7-H1\], cluster of differentiation \[CD\]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). Durvalumab has been demonstrated to have activity against advanced metastatic urothelial bladder cancer whose tumor has progressed during or after one standard platinum-based regimen in a phase I trial.

Therefore, this trial will take two agents with single agent activity against urothelial cancer and combine them in a Phase I trial for patients with high-grade NMIBC Previously Treated with BCG.

Objectives:

Primary Objectives:

To evaluate the safety and tolerability of durvalumab and Vicineum when administered in combination to subjects with BCG-refractory high-grade NMIBC

Eligibility:

Subjects must have a histologically confirmed high-grade non-muscle invasive urothelial carcinoma (transitional cell carcinoma) of the bladder as follows:

Carcinoma-in-situ (CIS) with or without papillary tumors

High-grade Ta or T1 disease based on a biopsy/TURBT performed within 12 weeks of the initial dose of study treatment. If multiple bladder biopsies/TURBTs are required to confirm eligibility, the timing of the last bladder biopsy to the initial dose of study treatment must be within 12 weeks.

Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology and the Food and Drug Administration (FDA): Subjects must have received at least two courses of intravesical BCG (at least 5 of 6 induction doses of BCG and at least 2 of 3 maintenance doses of BCG under a maintenance regimen or at least 2 doses of a repeat induction course). See exception below for persistent T1 disease below. There is no upper limit on the amount of prior BCG a subject may have received.

Patients with persistent T1 high grade disease on TURBT following a single induction course of BCG (at least 5 of 6 doses) may also be eligible for this trial provided that the patient is surgically unfit for cystectomy as deemed by the investigator or the patient declines cystectomy

Design:

This is a Phase I, open-label study of the combination of durvalumab and Vicineum in subjects with high-grade NMIBC previously treated with BCG.

All subjects will receive Vicineum intravesically and durvalumab systemically at the standard doses for both drugs as determined by Phase II trials for each drug, as no synergy or additive effect is expected for adverse events.

Vicineum is administered in a 12-week Induction Phase followed by a Maintenance Phase for at least one year with an option for a total of up to 2 years of treatment. During the Induction Phase, Vicineum is administered once weekly for 12 weeks. During the Maintenance Phase, Vicineum is administered every other week. The dose of Vicineum is 30 mg in 50 mL of saline.

Durvalumab 1500 mg is administered intravenously (IV) once every 4 weeks for 12 months with an option to continue therapy for an additional 12 months (total of 24 months) provided that patient is tolerating therapy and remains free of recurrent high grade NMIBC (see Treatment Period below). The dose of durvalumab is 1500 mg. If optional maintenance therapy continued in the second year, durvalumab 1500 mg will be administered intravenously once every 3 months to provide an immune boost.

Vicineum will be given as monotherapy for 1 week followed by treatment with the combination of Vicineum and durvalumab starting week 2.

In the initial six patients, three subjects at a time will enroll at these doses and schedules. Dose-liming toxicity (DLT) for each subject will be determined during the initial 6-week period that the subject is on treatment (i.e., the DLT period). When all subjects in the initial cohort have been on treatment through the DLT period, all available safety data will be considered in decisions to enroll additional subjects at this dose level, or to de-escalate the dose(s) of study drug(s), based on a standard "3 + 3" design. There will be no dose-escalations in this study. The dose of durvalumab will remain at 1500 mg every 4 weeks, and the dose of each intravesical Vicineum treatment can be reduced to 20 mg if the initial doses in combination induce DLTs.

After the first six patients, an additional 18 subjects will be enrolled at the initial doses or at the reduced doses (if DLTs resulted in the first 6 patients) in order to obtain additional safety data, biomarker data and preliminary anti-tumor activity.

Each subject's course will consist of the following periods:

Screening/Baseline Period: The subject is consented and undergoes screening assessments to determine eligibility for the study.

Treatment Period: The subject is treated and monitored for safety. Biomarker data will be obtained prior to treatment and at periodic intervals during treatment. Subjects who remain free of high-grade NMIBC after 12 months of study treatment may continue to receive treatment for an additional 12 months until they develop recurrent high-grade disease, disease progression, or intolerable toxicity, or meet another withdrawal criterion (e.g., consent withdrawal, pregnancy).

Post-Treatment. The subject will return to the study site monthly for up to 90 days after the last dose of immunotherapy for end-of-treatment assessments. Subjects with ongoing clinically significant related adverse events (AEs) or serious adverse events (SAEs) will have additional follow-up after the initial post-treatment visit.

Durvalumab and Vicineum in Subjects With High-Grade Non-Muscle-Invasive Bladder Cancer Previously Treated With Bacillus Calmette-Guerin (BCG)

A Phase I Single-Arm Study of the Combination of Durvalumab (MEDI4736) and Vicineum (Oportuzumab Monatox, VB4-845) in Subjects With High-Grade Non-Muscle-Invasive Bladder Cancer Previously Treated With Bacillus Calmette-Guerin (BCG)

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

The MTD will be identified based on being the dose level at which 0 or 1 participants in 6 has a dose-limiting toxicity (DLT). A DLT will be defined as any Grade 3 or higher toxicity that occurs during the initial 6-week period the subject is on treatment (i.e., the DLT evaluation period). Grade 3 is severe, grade 4 is life-threatening and grade 5 is death related to adverse event.

A DLT will be defined as any Grade 3 or higher toxicity that occurs during the initial 6-week period the subject is on treatment (i.e., the DLT evaluation period). Grade 3 is severe, grade 4 is life-threatening and grade 5 is death related to adverse event.

Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild, grade 2 is moderate, grade 3 is severe, grade 4 is life-threatening, and grade 5 is death related to adverse event.

Urinary EpCAM will be measured and will be compared between participants who have a clinical response to therapy vs. those who do not respond. Although it is expected to have low power, a comparison of the EpCAM levels may be compared between the two response categories using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.

The response to treatment will be determined for evaluable participants who receive treatment and was measured as follows: Recurrence is suspected and/or determined by urine cytology and/or cystoscopic exam and then confirmed pathologically after a transurethral resection of bladder tumor (TURBT). Complete response rate for carcinoma in situ (CIS) is defined as the absence of CIS upon follow-up biopsies. Disease progression is defined as upstaging from a lower stage to a higher stage (e.g., Ta to T1-T4 or T1 to T2-4; CIS to T1 or CIS to T2-T4; or any N+ or M+ in these high-grade tumors).

Evaluate the pharmacokinetic parameters of Vicineum obtained by urine samples. Urinary Vicineum (in ng/mL).

PD-L1 levels will be obtained at baseline and after treatment with both agents. The change in levels will be determined between the two measurements, and these changes will be compared between responders and non-responders. Although it is expected to have low power, in each case the comparisons between the two response categories will be made using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.

PD-1 levels will be obtained at baseline and after treatment with both agents. The change in levels will be determined between the two measurements, and these changes will be compared between responders and non-responders. Although it is expected to have low power, in each case the comparisons between the two response categories will be made using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.

PD-L1 levels will be obtained at baseline and after treatment with both agents. The change will be compared between those who respond or have stable disease (SD (clinical benefit=Complete Response (CR)+Partial Response (PR)+SD) and those with progressive disease (PD). Although it is expected to have low power, in each case the comparisons between the two response categories will be made using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.

PD-1 levels will be obtained at baseline and after treatment with both agents. The change will be compared between those who respond or have stable disease (SD (clinical benefit=Complete Response (CR)+Partial Response (PR)+SD) and those with progressive disease (PD). Although it is expected to have low power, in each case the comparisons between the two response categories will be made using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.

All evaluable participants will have determinations of many immune parameters at baseline, 3 months, and 6 months. The changes in the parameters obtained from blood samples will be determined at baseline vs. 3 months, and baseline vs. 6 months. Comparisons of the paired values will be performed using a Wilcoxon signed rank test, and a Hochberg adjustment may be used.

All evaluable participants will have determinations of many immune parameters at baseline, 3 months, and 6 months. The changes in the parameters obtained from biopsies will be obtained from baseline vs. a single second biopsy at 6 months. Comparisons of the paired values will be performed using a Wilcoxon signed rank test, and a Hochberg adjustment may be used.

A DFS curve will be created using the Kaplan-Meier method based on all participants considered to be evaluable based on having received protocol treatment. DFS survival is defined as the time from the start of treatment until disease recurrence or death. Recurrence is suspected and/or determined by urine cytology and/or cystoscopic exam and then confirmed pathologically after a bladder biopsy or transurethral resection of bladder tumor (TURBT).

National Cancer Institute (NCI)

Principal Investigator

Durvalumab 1500 mg is administered intravenously (IV) once every 4 weeks for 12 months with an option to continue therapy for an additional 12 months (total of 24 months) provided that, participant is tolerating therapy and remains free of recurrent high grade non-muscle invasive bladder cancer (NMIBC) (see Treatment Period below). The dose of durvalumab is 1500 mg. If optional maintenance therapy continued in the second year, durvalumab 1500 mg will be administered intravenously once every 3 months to provide an immune boost.

Vicineum is administered in a 12-week Induction Phase followed by a Maintenance Phase for at least one year with an option for a total of up to 2 years of treatment. During the Induction Phase, Vicineum is administered once weekly for 12 weeks. During the Maintenance Phase, Vicineum is administered every other week. The dose of Vicineum is 30 mg in 50 mL of saline.

Run-In Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg

Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Durvalumab: an option to continue therapy for an additional 12 months (total of 24 months) provided that, participant is tolerating therapy and remains free of recurrent high grade NMIBC (see Treatment Period below). The dose of durvalumab is 1500 mg. If optional maintenance therapy continued in the second year, durvalumab 1500 mg will be administered intravenously once every 3 months to provide an immune boost.

Vicineum is administered in a 12-week Induction Phase followed by a Maintenance Phase for at least one year with an option for a total of up to 2 years of treatment. During the Induction Phase, Vicineum is administered once weekly for 12 weeks. During the Maintenance Phase, Vicineum is administered every other week. The dose of Vicineum is 30 mg in 50 mL of saline.

Expansion Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg

Total Cohort - Durvalumab 1500mg Intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 30 mg

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Vladimir Valera Romero

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Number of Grades 1-5 Adverse Events

Urinary Epithelial Cell Adhesion Molecule (EpCAM) Compared Between Participants Who Have a Clinical Response to Therapy vs. Those Who do Not Respond

Complete response

Recurrence

Disease progression

Response Rate

Baseline

Week 1, Day 1

Week 1

Week 6

Week 12

Pharmacokinetic Parameters in Urine Maximum Concentration (Cmax) of Vicineum

Responders PDL1 levels after treatment (vs baseline

Non-responders PDL1 levels after treatment (vs baseline)

Number of responders and non-responders in the rows below = overall number of participants analyzed for each group.

Change in Programmed Death-ligand 1 (PD-L1) Levels Between Responders and Non-Responders

Change in Programmed Cell Death Protein 1 (PD-1) Levels Between Responders and Non-Responders

PDL1 level changes in participants with SD (treatment vs baseline)

PDL1 level changes in participants with PD (treatment vs baseline

Number of participants with SD and participants with PD in the rows below = overall number of participants analyzed for each group.

Change in Programmed Death-ligand 1 (PD-L1) Levels Between Participants Who Respond and Have Stable Disease (SD), and Those With Progressive Disease (PD)

Change in Programmed Cell Death Protein 1(PD-1) Levels Between Participants Who Respond and Have Stable Disease (SD), and Those With Progressive Disease (PD)

Interferon Gamma (IFN-γ) at 3 weeks compared to their respective baseline values.

Interferon Gamma (IFN-γ) at 5 weeks compared to their respective baseline values.

Tumor Necrosis Factor Alpha (TNF-α) at 3 weeks compared to their respective baseline values.

Tumor Necrosis Factor Alpha (TNF-α ) at 5 weeks compared to their respective baseline values.

Interleukin 6 (IL-6) at 3 weeks as compared to their respective baseline values.

Interleukin 6 (IL-6) at 5 weeks as compared to their respective baseline values.

Interleukin 8 (IL-8) at 3 weeks as compared to their respective baseline values.

Interleukin 8 (IL-8) at 5 weeks as compared to their respective baseline values.

Interleukin 10 (IL-10) at 3 weeks as compared to their respective baseline values.

Interleukin 10 (IL-10) at 5 weeks as compared to their respective baseline values.

3 weeks Interferon Gamma (IFN-γ) vs Baseline

5 weeks Interferon Gamma (IFN-γ) vs Baseline

3 weeks Interleukin 6 (IL-6) vs Baseline

5 weeks Interleukin 6 (IL-6) vs Baseline

3 weeks Interleukin 8 (IL-8) vs Baseline

5 weeks Interleukin 8 (IL-8) vs Baseline

3 weeks Interleukin 10 (IL-10) vs Baseline

5 weeks Interleukin 10 (IL-10) vs Baseline

3 weeks Tumor Necrosis Factor Alpha (TNF-α) vs Baseline

5 weeks Tumor Necrosis Factor Alpha (TNF-α) vs Baseline

Changes in the Immune Parameters Obtained From Blood Samples

Changes in the Immune Parameters Obtained From Biopsies

Disease free survival time was evaluated with the product-limit estimator by Kaplan-Meier test.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Multimodal Spectroscopy to Detect Urothelial Cancer in Urine	NCT04718948	Urothelial Carc... Urinary Bladder... Urinary Tract C...	Urinary Multimo... Urine Cytology Surgery	18 Years -	University of Florence
Novel Urine-Based DNA Methylation Biomarkers for Urothelial Bladder Carcinoma Detection in Patients With Hematuria	NCT05362539	Bladder Cancer	Cystoscopy Computed tomogr... DNA hypermethyl... Urine cytology	18 Years -	Mansoura University
Novel Urine-Based DNA Methylation Biomarkers for Urothelial Bladder Carcinoma Detection in Patients With Hematuria	NCT05362539	Bladder Cancer	Cystoscopy Computed tomogr... DNA hypermethyl... Urine cytology	18 Years -	Mansoura University
Durvalumab and Vicineum in Subjects With High-Grade Non-Muscle-Invasive Bladder Cancer Previously Treated With Bacillus Calmette-Guerin (BCG)	NCT03258593	Urinary Bladder...	Durvalumab Vicineum Acetaminophen Antihistamine Bladder Biopsy TURBT Cystoscopy Urine cytology Electrocardiogr... CT MRI	18 Years -	National Institutes of Health Clinical Center (CC)
Durvalumab and Vicineum in Subjects With High-Grade Non-Muscle-Invasive Bladder Cancer Previously Treated With Bacillus Calmette-Guerin (BCG)	NCT03258593	Urinary Bladder...	Durvalumab Vicineum Acetaminophen Antihistamine Bladder Biopsy TURBT Cystoscopy Urine cytology Electrocardiogr... CT MRI	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for urine cytology