Efectos de apalutamida sobre la expresión de EGFR en pacientes con cáncer de vejiga sin invasión muscular
Un ensayo aleatorizado de apalutamida en el cáncer de vejiga sin invasión muscular
This phase I trial evaluates the effects of bicalutamide, compared to no study drug (NSD), on epidermal growth factor receptor (EGFR) protein expression in patients with non-muscle invasive bladder cancer. Bicalutamide is in a class of medications called androgen receptor inhibitors. It works by blocking the effects of androgen (a male reproductive hormone) to stop the growth and spread of tumor cells. Previous studies have suggested that expression of a protein called EGFR on tumor cells is related to bladder cancer disease progression. This trial may help doctors evaluate if bicalutamide has any effect on EGFR expression in patients with non-muscle invasive bladder cancer.
Descripción general del estudio
Estado
Condiciones
Descripción detallada
PRIMARY OBJECTIVE:
1. To compare epidermal growth factor receptor (EGFR) messenger ribonucleic acid (mRNA) expression measured by reverse transcriptase polymerase chain reaction (rt-PCR) in normal appearing urothelium adjacent to tumor (measured as a ratio relative to urothelium and lamina-propria specific markers) in participants treated with anti-androgen therapy versus (vs.) participants given NSD.
SECONDARY OBJECTIVES:
- To determine effect of bicalutamide on EGFR expression (by rtPCR) in the subgroup of patients whose normal appearing urothelium adjacent to tumor expresses the androgen receptor (AR) (at least "1" by immunohistochemistry [IHC] score).
- To correlate AR expression in adjacent urothelium (by IHC score) with EGFR expression by rtPCR in participants randomized to bicalutamide versus NSD.
- Comparison of pre vs. post intervention urinary biomarkers (CxBladderTM) in both groups, examining the 5 RNAs (by RT-PCR) that make up the test, both as a group and each RNA separately.
EXPLORATORY OBJECTIVES:
- Comparison of AR and EGFR (and possibly phosphorylated EGFR [pEGFR]) staining levels (low, moderate, high; by immunocytology) in pre-treatment vs. post-treatment bladder wash immunocytology.
- To compare expression of direct androgen response gene (ADAR)-2 measured by rtPCR in normal appearing adjacent (to tumor) urothelium that does and does not express AR (by IHC), in participants randomized to bicalutamide versus NSD.
- Ki-67 expression (by IHC) in normal appearing urothelium adjacent to tumor in participants randomized to bicalutamide versus NSD.
- Subgroup analysis of Ki-67 expression in the AR+ subgroup.
- Differences in expression of AR, EGFR, pEGFR, and Ki-67 (by semi-quantitative IHC) in tumor in participants randomized to bicalutamide versus NSD.
- Change in EGFR expression by rt-PCR in tumor in participants randomized to bicalutamide versus NSD.
- Fibroblast growth factor receptor 3 (FGFR3) mutation analysis in deoxyribonucleic acid (DNA) extracted from formalin fixed paraffin embedded (FFPE) blocks from neighboring normal urothelium and tumor tissue in participants randomized to bicalutamide versus NSD.
- Define changes in the tumor immune microenvironment pre- and post-bicalutamide through liquid biopsies of blood and urine using high-dimensional flow cytometry.
- Analyze tumor (biopsy specimen) immune microenvironment via multiplex immunofluorescence and spatial transcriptomics.
- Other exploratory markers such as changes in the urinary microbiome in bladder cancer participants randomized to bicalutamide versus NSD.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM 1: Patients receive bicalutamide orally (PO) once daily (QD) on days 1-21. Patients undergo TURBT on day 21. Up to 28 days of bicalutamide prior to TURBT is permitted in the absence of unacceptable toxicity. Patients undergo blood and urine sample collection throughout the study. Patients may optionally undergo tumor biopsy at baseline.
ARM 2: Patients receive NSD PO QD on days 1-21. Patients undergo TURBT on day 21. Up to 28 days of NSD prior to TURBT is permitted in the absence of unacceptable toxicity. Patients undergo blood and urine sample collection throughout the study. Patients may optionally undergo tumor biopsy at baseline.
After completion of study treatment, patients are followed up 20-30 days after TURBT.
Tipo de estudio
Inscripción (Estimado)
Fase
- Fase 1
Contactos y Ubicaciones
Ubicaciones de estudio
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Arizona
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Tucson, Arizona, Estados Unidos, 85719
- Reclutamiento
- University of Arizona Cancer Center - Prevention Research Clinic
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Contacto:
- Juan Chipollini
- Número de teléfono: 520-694-4032
- Correo electrónico: jchipollini@surgery.arizona.edu
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Investigador principal:
- Juan Chipollini
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California
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Los Angeles, California, Estados Unidos, 90048
- Aún no reclutando
- Cedars Sinai Medical Center
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Contacto:
- Michael A. Ahdoot
- Número de teléfono: 310-423-2659
- Correo electrónico: Michael.Ahdoot@cshs.org
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Investigador principal:
- Michael A. Ahdoot
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Maryland
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Bethesda, Maryland, Estados Unidos, 20892
- Aún no reclutando
- National Cancer Institute Urologic Oncology Branch
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Contacto:
- Sandeep Gurram
- Número de teléfono: 240-858-3700
- Correo electrónico: Sandeep.Gurram@nih.gov
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Investigador principal:
- Sandeep Gurram
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New York
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Rochester, New York, Estados Unidos, 14642
- Aún no reclutando
- University of Rochester
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Contacto:
- Edward M. Messing
- Número de teléfono: 585-275-3345
- Correo electrónico: edward_messing@urmc.rochester.edu
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Investigador principal:
- Edward M. Messing
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Ohio
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Columbus, Ohio, Estados Unidos, 43210
- Reclutamiento
- Ohio State University Comprehensive Cancer Center
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Contacto:
- Debasish Sundi
- Número de teléfono: 219-713-9783
- Correo electrónico: D.Sundi@osumc.edu
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Investigador principal:
- Debasish Sundi
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Wisconsin
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Madison, Wisconsin, Estados Unidos, 53792
- Reclutamiento
- University of Wisconsin Carbone Cancer Center - University Hospital
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Contacto:
- Kyle A. Richards
- Número de teléfono: 608-262-0759
- Correo electrónico: richardsk@urology.wisc.edu
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Investigador principal:
- Kyle A. Richards
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion Criteria:
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Biologic male adults (>= 18 years old)
- Note: Because no dosing or adverse event (AE) data are currently available on the use of bicalutamide in participants < 18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable
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Have suspected new or occasionally recurrent NMIBC (i.e., </= 2 prior NMIBC episodes in the 18 months preceding the cystoscopy where the index tumor was identified) on clinic-based cystoscopy or imaging as viewed by an American Urological Association (AUA) board-certified urologist
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Have had cross sectional imaging of the abdomen and pelvis (computed tomography [CT] or magnetic resonance imaging [MRI] with or without contrast) within 6 months prior to enrollment with no signs of upper tract urothelial cancer (UC), invasive, nor metastatic disease
- Note: If adenopathy or upper tract abnormalities are identified, a negative biopsy and or ureteroscopy is required prior to enrollment
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Participants with single and multiple tumor lesions
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In the opinion of the treating urologist, the participant is suitable to undergo surgery.
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Participants may have received intravesical chemotherapy at any time.
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Total bilirubin =< 1.5 x institutional upper limit of normal (note: in participants with Gilbert's syndrome, if total bilirubin is > 1.5 x upper limit of normal, measure direct and indirect bilirubin and if direct bilirubin is =< 1.5 x upper limit of normal, participants may be eligible)
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Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2 × institutional upper limit of normal
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Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2 × institutional upper limit of normal
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Serum Testosterone >= 250 ng/dL
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Thyroid stimulating hormone (TSH) within institutional normal
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The effects of bicalutamide on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, men who are having sex must wear a condom when engaging in any activity that allows for passage of ejaculate to another person throughout the course of the study and 4 months after receiving last dose of study intervention. Male participants should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak. Additionally, men must agree to not donate sperm for the purpose of reproduction during the study and for a minimum of 4 months after receiving the last dose of study intervention
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Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Participants who have had a previous exposure to sex hormone (e.g., exogenous androgens) or anti-androgenic therapies (e.g., luteinizing hormone-releasing hormone [LHRH] agonists, LHRH antagonists, 5 alpha reductase-inhibitors, abiraterone or other anti-androgens) within 6 months of accrual
- Participants taking Coumarin derivative anticoagulation (e.g., warfarin). Other anticoagulation medications are allowed.
- Participants receiving any other investigational agents.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to bicalutamide.
- History of prior or concurrent muscle invading UC, or concurrent prostatic urethral, urethral, or upper tract UC or non-urothelial bladder cancer
- History of radiation therapy to the pelvis, prostate or prostatic bed, or rectum
- Any condition (uncontrolled intercurrent illness, psychiatric illness, or social situation) for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
- Allergy or hypersensitivity to bicalutamide, or excipients, unable or unwilling to take ADT.
- Plans to father a child while enrolled in this study or within 4 months after the last dose of study intervention.
- Participants with suspected Carcinoma in Situ (CIS) without suspected Ta or T1 disease are not eligible.
- Participants with a history of documented CIS within 2 years are not eligible.
- Participants who have received Gacillus Calmette-Guerin (BCG) within 2 years are not eligible.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Prevención
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Cuadruplicar
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
|---|---|
|
Experimental: Arm 1 (bicalutamide,TURBT)
Patients receive bicalutamide PO QD on days 1-21. Patients undergo TURBT on day 21. Up to 28 days of bicalutamide prior to TURBT is permitted in the absence of unacceptable toxicity. Patients undergo blood and urine sample collection throughout the study. Patients may optionally undergo tumor biopsy at baseline. |
Ancillary studies Undergo tumor biopsy
Otros nombres:
Undergo blood and urine sample collection
Otros nombres:
Given PO
Otros nombres:
Undergo TURBT
Otros nombres:
|
|
Experimental: Arm 2 (TURBT)
Patients undergo TURBT on day 21. Patients undergo blood and urine sample collection throughout the study. Patients may optionally undergo tumor biopsy at baseline. |
Ancillary studies Undergo tumor biopsy
Otros nombres:
Undergo blood and urine sample collection
Otros nombres:
Undergo TURBT
Otros nombres:
|
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Average Epidermal Growth Factor Receptor (EGFR) expression level
Periodo de tiempo: Up to 28 days
|
Will be analyzed as a continuous variable. A two-sample t-test will be conducted to test whether there are significant differences of the log-transformed EGFR expression level (measured by reverse transcriptase polymerase chain reaction [rtPCR]) in normal appearing urothelium adjacent to tumor in participants treated with anti-androgen therapy versus (vs.) NSD participants. In case the normality assumption of the two-sample t-test does not hold, Wilcoxon rank-sum test will be performed as a sensitivity analysis. Considering androgen receptor (AR) status can be a treatment effect modifier, a regression analysis will also be performed with the log-transformed EGFR expression level as the outcome and treatment status (bicalutamide or NSD), AR status, and treatment-AR interaction as the predictors. |
Up to 28 days
|
Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Effect of bicalutamide on EGFR expression
Periodo de tiempo: Up to 28 days
|
A two-sample Wilcoxon rank-sum test will be conducted to compare the difference of EGFR expression in AR positive participants treated with and without bicalutamide. |
Up to 28 days
|
|
AR expression in adjacent urothelium
Periodo de tiempo: Up to 28 days
|
Will evaluate the correlation between AR expression in adjacent urothelium with EGFR expression. Pearson correlation and Spearman's rank correlation will be calculated between the AR expression and EGFR expression. |
Up to 28 days
|
|
Pre vs. post intervention urinary biomarkers
Periodo de tiempo: Up to 28 days
|
Comparison of pre vs. post intervention urinary biomarkers (CxBladderTM) in both groups, examining the 5 ribonucleic acids (RNAs) (by rtPCR) that make up the test, both as a group and each RNA separately. Will be summarized by descriptive statistics such as rates and proportions and compared between NSD and bicalutamide using nonparametric tests such as the Kruskal-Wallis test. |
Up to 28 days
|
Otras medidas de resultado
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
AR and EGFR (and possibly phosphorylated EGFR [pEGFR]) staining levels
Periodo de tiempo: Up to 28 days
|
Will be summarized by descriptive statistics such as rates and proportions and compared between NSD and bicalutamide using nonparametric tests such as the Kruskal-Wallis test. |
Up to 28 days
|
|
Expression of direct androgen response gene (ADAR)-2
Periodo de tiempo: Up to 28 days
|
Will be summarized by descriptive statistics such as rates and proportions and compared between NSD and bicalutamide using nonparametric tests such as the Kruskal-Wallis test. |
Up to 28 days
|
|
Ki-67 expression
Periodo de tiempo: Up to 28 days
|
Will be summarized by descriptive statistics such as rates and proportions and compared between NSD and bicalutamide using nonparametric tests such as the Kruskal-Wallis test. |
Up to 28 days
|
|
Ki-67 expression in the AR+ subgroup
Periodo de tiempo: Up to 28 days
|
Will be summarized by descriptive statistics such as rates and proportions and compared between NSD and bicalutamide using nonparametric tests such as the Kruskal-Wallis test. |
Up to 28 days
|
|
Differences in expression of AR, EGFR, pEGFR, and Ki-67
Periodo de tiempo: Up to 28 days
|
Will be summarized by descriptive statistics such as rates and proportions and compared between NSD and bicalutamide using nonparametric tests such as the Kruskal-Wallis test. |
Up to 28 days
|
|
Change in EGFR expression in tumor from participants randomized to bicalutamide versus NSD
Periodo de tiempo: Up to 28 days
|
Will be summarized by descriptive statistics such as rates and proportions and compared between NSD and bicalutamide using nonparametric tests such as the Kruskal-Wallis test. |
Up to 28 days
|
|
Analysis of fibroblast growth factor receptor 3 (FGFR3) in deoxyribonucleic acid (DNA)
Periodo de tiempo: Up to 28 days
|
Extracted from fixed paraffin embedded (FFPE) blocks from neighboring normal urothelium and tumor tissue in participants treated with or without bicalutamide. Will be summarized by descriptive statistics such as rates and proportions and compared between NSD and bicalutamide using nonparametric tests such as the Kruskal-Wallis test. |
Up to 28 days
|
|
Changes in the tumor immune microenvironment pre- and post-bicalutamide
Periodo de tiempo: Up to 28 days
|
Will be summarized by descriptive statistics such as rates and proportions. |
Up to 28 days
|
|
Analysis of tumor (biopsy specimen) infiltrating CD8+ T-cells
Periodo de tiempo: Up to 28 days
|
The tumor immune microenvironment will be analyzed via multiplex immunofluorescence and spatial transcriptomics. Assessments will include CD8+ T-cell functional markers: TCF1/Tcf7 of CD44+, CD62L, PD-1, TIM3 and SLAMF6. Will be summarized by descriptive statistics such as rates and proportions and compared between NSD and bicalutamide using nonparametric tests such as the Kruskal-Wallis test. |
Up to 28 days
|
|
AR, EGFR, and pEGFR in biopsies of tumors
Periodo de tiempo: At index cystoscopy and TURBT
|
Optional biopsy tissue will be used to compare AR, EGFR, and pEGFR in biopsies of tumors done at index cystoscopy vs. transurethral resection of bladder tumor in participants randomized to bicalutamide versus NSD. |
At index cystoscopy and TURBT
|
|
Exploratory markers
Periodo de tiempo: Up to 28 days
|
Will be summarized by descriptive statistics such as rates and proportions and compared between NSD and bicalutamide using nonparametric tests such as the Kruskal-Wallis test. |
Up to 28 days
|
Colaboradores e Investigadores
Patrocinador
Colaboradores
Investigadores
- Investigador principal: Edward M Messing, University of Wisconsin, Madison
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Actual)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Términos MeSH relevantes adicionales
- Técnicas de investigación
- Técnicas de laboratorio clínico
- Técnicas y procedimientos de diagnóstico
- Diagnóstico
- Procedimientos quirúrgicos, operativo
- Técnicas citológicas
- Citodiagnóstico
- Técnicas de diagnóstico, quirúrgico
- Procedimientos quirúrgicos urológicos
- Procedimientos quirúrgicos urogenitales
- Biopsia
- Manejo de muestras
- Resección transuretral de la vejiga
- bicalutamida
Otros números de identificación del estudio
- 2026-0131
- P30CA014520 (Subvención/contrato del NIH de EE. UU.)
- UG1CA242635 (Subvención/contrato del NIH de EE. UU.)
- NCI-2022-06871 (Identificador de registro: CTRP (Clinical Trial Reporting Program))
- INT22-09-01 (Otro identificador: DCP)
- 2026-0131 (Otro identificador: UWCCC)
- Protocol Version 8/26/26 (Otro identificador: DCP)
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Descripción del plan IPD
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Información sobre medicamentos y dispositivos, documentos del estudio
Estudia un producto farmacéutico regulado por la FDA de EE. UU.
Estudia un producto de dispositivo regulado por la FDA de EE. UU.
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