Clinical trial NCT05521698: Study to Determine Possible Effects of Apalutamide, Compared to Placebo, on EGFR Expression in Patients With Non-muscle Invasive Bladder Cancer
Official title: A Randomized Trial of Apalutamide in Non-Muscle Invasive Bladder Cancer
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Non-Muscle Invasive Bladder Urothelial Carcinoma
Recurrent Non-Muscle Invasive Bladder Urothelial Carcinoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2022-08-30
Enrollment: 80
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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.

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.

Eligibility criteria: 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

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 who are taking the following medications that increase seizure risks: (e.g., clozapine, olanzapine, risperidone, ziprasidone), phenothiazine, antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine), bupropion, lithium, meperidine, pethidine, phenothiazine and tricyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, imipramine, maprotiline), mirtazapine, selective serotonin reuptake inhibitors (e.g., escitalopram, citalopram, fluoxetine), serotonin norepinephrine reuptake inhibitors (e.g., venlafaxine, desvenlafaxine, levomilnacipran), stimulants (e.g., amphetamines, methylphenidate), monoamine oxidase inhibitors (e.g., phenelzine, selegiline)
* Participants taking any form of anticoagulation (e.g., heparin, warfarin, lovenox, apixaban, rivaroxaban, dabigatran, edoxaban, betrixaban)
* Concurrent use of drugs in category X drug interactions with apalutamide
* Participants receiving any other investigational agents
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to apalutamide
* 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 (eg compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
* History of seizures or central nervous system (CNS) metastasis or any condition that in the opinion of the investigator may predispose to seizure or treatment with drugs known to lower the seizure threshold within 4 weeks prior to enrollment in the study
* Participants with severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, uncontrolled hypertension, long QT, arterial or venous thromboembolic events (eg pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias
* In the opinion of the investigator, participant has uncontrolled hypertension, high cholesterol, or diabetes
* Allergy or hypersensitivity to apalutamide, or excipients, unable or unwilling to take antiandrogen therapy (ADT)
* Plans to father a child while enrolled in this study or within 12 weeks after the last dose of study intervention

Primary outcomes:
measure: Average Epidermal Growth Factor Receptor (EGFR) expression level
timeFrame: Up to 28 days
Secondary outcomes:
measure: Effect of apalutamide on EGFR expression
timeFrame: Up to 28 days
measure: AR expression in adjacent urothelium
timeFrame: Up to 28 days
measure: Toxicity of treatment
timeFrame: Up to 28 days
Other outcomes:
measure: AR and EGFR (and possibly phosphorylated EGFR [pEGFR]) staining levels
timeFrame: Up to 28 days
measure: Expression of direct androgen response gene (ADAR)-2
timeFrame: Up to 28 days
measure: Ki-67 expression
timeFrame: Up to 28 days
measure: Ki-67 expression in the AR+ subgroup
timeFrame: Up to 28 days
measure: Differences in expression of AR, EGFR, pEGFR, and Ki-67
timeFrame: Up to 28 days
measure: Demographics of two groups
timeFrame: Up to 28 days
measure: Change in EGFR expression in tumor from participants randomized to apalutamide versus placebo
timeFrame: Up to 28 days
measure: Morbidities of treatment
timeFrame: Up to 28 days
measure: Pre vs. post intervention urinary biomarkers
timeFrame: Up to 28 days
measure: Analysis of fibroblast growth factor receptor 3 (FGFR3) in deoxyribonucleic acid (DNA)
timeFrame: Up to 28 days
measure: Changes in the tumor immune microenvironment pre- and post-apalutamide
timeFrame: Up to 28 days
measure: Analysis of tumor (biopsy specimen) infiltrating CD8+ T-cells
timeFrame: Up to 28 days
measure: AR, EGFR, and pEGFR in biopsies of tumors
timeFrame: At index cystoscopy and TURBT
measure: Exploratory markers
timeFrame: Up to 28 days
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center - Prevention Research Clinic
state: Arizona
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Bethesda
country: United States
facility: National Cancer Institute Urologic Oncology Branch
state: Maryland
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center - University Hospital
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: Edward M Messing
role: PRINCIPAL_INVESTIGATOR
References: