Title
A Randomized Trial of Bicalutamide in Non-Muscle Invasive Bladder Cancer

Description
This phase I trial evaluates the effects of apalutamide, compared to placebo, on epidermal growth factor receptor (EGFR) protein expression in patients with non-muscle invasive bladder cancer. Apalutamide 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 apalutamide has any effect on EGFR expression in patients with non-muscle invasive bladder cancer.

Objective
PRIMARY OBJECTIVE:

I. 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 placebo.

SECONDARY OBJECTIVES:

I. To determine effect of apalutamide 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).

II. To correlate AR expression in adjacent urothelium (by IHC score) with EGFR expression by rtPCR in participants randomized to apalutamide versus placebo.

III. Comparison of toxicity in participants randomized to apalutamide versus placebo.

EXPLORATORY OBJECTIVES:

I. 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 cytology.

II. 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 apalutamide versus placebo.

III. Ki-67 expression (by IHC) in normal appearing urothelium adjacent to tumor in participants randomized to apalutamide versus placebo.

IV. Subgroup analysis of Ki-67 expression in the AR+ subgroup. V. Differences in expression of AR, EGFR, pEGFR, and Ki-67 (by semi-quantitative IHC) in tumor in participants randomized to apalutamide versus placebo.

VI. Comparison of demographics of two groups. VII. Change in EGFR expression by rt-PCR in tumor in participants randomized to apalutamide versus placebo.

VIII. Morbidities of treatment (breast tenderness, sexual or urinary side effects, seizure[s], depression, abnormal liver function tests [LFTs]).

IX. Comparison of pre vs. post intervention urinary biomarkers (CxBladderTM) in both groups, examining the 5 RNAs (by rtPCR) that make up the test, both as a group and each RNA separately.

X. 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 apalutamide versus placebo.

XI. Define changes in the tumor immune microenvironment pre- and post-apalutamide through liquid biopsies of blood and urine using high-dimensional flow cytometry.

XII. Analyze tumor (biopsy specimen) immune microenvironment via multiplex immunofluorescence and spatial transcriptomics.

XIII. Compare AR, EGFR, and pEGFR in biopsies of tumors done at index cystoscopy vs. TURBT in participants randomized to apalutamide versus placebo. (Optional) XIV. Other exploratory markers such as changes in the urinary microbiome in bladder cancer participants randomized to apalutamide versus placebo.

Treatment OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive apalutamide orally (PO) once daily (QD) on days 1-21. Patients undergo TURBT on day 21. Up to 28 days of apalutamide 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 placebo PO QD on days 1-21. Patients undergo TURBT on day 21. Up to 28 days of placebo 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.

Key Eligibility Inclusion Criteria:

Biologic male adults (>= 18 years old)



Note: Because no dosing or adverse event (AE) data are currently available on the use of apalutamide in participants < 18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable



Have suspected non-muscle invasive bladder carcinoma (NMIBC) on clinic-based cystoscopy or imaging as viewed by an American Urological Association (AUA) board-certified urologist

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



Newly suspected, diagnosed, or occasionally recurrent bladder cancer (BC)



Note: Occasional recurrence is defined as =< 2 prior NMIBC episodes in the 18 months preceding cystoscopy where the index tumor was identified



Participants with single and multiple tumor lesions

Eastern Cooperative Oncology Group (ECOG) performance status =< 1

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)

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2 × institutional upper limit of normal

Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2 × institutional upper limit of normal

Urine Culture < 50,000 colonies/cc of 1 or more organisms (if found and treated and a confirmed negative culture obtained off antibiotics before study drug is started, they will be eligible)

Serum Testosterone >= 300 ng/dL

Thyroid stimulating hormone (TSH) within institutional normal

White blood cell count (WBC) >= 0.5 × institutional lower limit of normal

The effects of apalutamide 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 90 days 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 90 days after receiving the last dose of study intervention

Ability to understand and the willingness to sign a written informed consent document

Applicable Disease Sites
Bladder

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital