Effects of Apalutamide on EGFR Expression in Patients With Non-muscle Invasive Bladder Cancer

• ClinicalTrials.gov Identifier: NCT05521698
• Recruitment Status: Not yet recruiting
• First Posted: August 30, 2022
• Last Update Posted: January 27, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

This phase I trial tests the molecular effects of apalutamide 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 epidermal growth factor receptor (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.

Condition or disease	Intervention/treatment	Phase
Non-Muscle Invasive Bladder Urothelial Carcinoma; Recurrent Non-Muscle Invasive Bladder Urothelial Carcinoma	Drug: Apalutamide; Procedure: Biospecimen Collection; Other: Questionnaire Administration; Procedure: Transurethral Resection of Bladder Tumor	Phase 1

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.) untreated participants.

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 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 treated and untreated participants.

III. Comparison of toxicity of treatment group to untreated control.

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 apalutamide treated participants and untreated controls.

III. Ki-67 expression (by IHC) in normal appearing urothelium adjacent to tumor in treated vs. untreated participants.

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 treated vs untreated participants.

VI. Comparison of demographics of two groups. VII. Change in EGFR expression by rt-PCR in tumor from treated vs. untreated participants.

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 treated vs. untreated participants.

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

XII. Analyze tumor (biopsy specimen) infiltrating CD8+ T-cells by single RNA Sequencing (scRNA-seq) and high dimensional spectral flow cytometry to evaluate TCF1/Tcf7 transcript levels, and perform IHC of CD44+, CD62L, and SLAMF6.

XIII. Other exploratory markers.

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 transurethral resection of bladder tumor (TURBT) on day 21. Up to 28 days of treatment is permitted in the absence of unacceptable toxicity. Patients undergo blood specimen collection at baseline and at time of TURBT.

ARM 2: Patients undergo TURBT on day 21. Patients undergo blood specimen collection at baseline and at time of TURBT.

After completion of study treatment, patients are followed up 20-30 days after TURBT.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: A Randomized Trial of Apalutamide in Non-Muscle Invasive Bladder Cancer
• Estimated Study Start Date: July 24, 2023
• Estimated Primary Completion Date: December 1, 2025
• Estimated Study Completion Date: December 1, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: ARM 1 (apalutamide,TURBT); Patients receive apalutamide PO QD on days 1-21. Patients undergo TURBT on day 21. Up to 28 days of treatment is permitted in the absence of unacceptable toxicity. Patients undergo blood specimen collection at baseline and at time of TURBT.	Drug: Apalutamide; Given PO; Other Names: ARN 509; ARN-509; ARN509; Erleada; JNJ 56021927; JNJ-56021927; Procedure: Biospecimen Collection; Correlative studies; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Other: Questionnaire Administration; Ancillary studies; Procedure: Transurethral Resection of Bladder Tumor; Undergo TURBT; Other Names: Transurethral resection (TURBT); TURBT
Active Comparator: ARM 2 (TURBT); Patients undergo TURBT on day 21. Patients undergo blood specimen collection at baseline and at time of TURBT.	Procedure: Biospecimen Collection; Correlative studies; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Other: Questionnaire Administration; Ancillary studies; Procedure: Transurethral Resection of Bladder Tumor; Undergo TURBT; Other Names: Transurethral resection (TURBT); TURBT

Outcome Measures

Primary Outcome Measures :

1. The relative Epidermal Growth Factor Receptor (EGFR) expression level [ Time Frame: Up to 28 days ]
   Will be analyzed as a continuous variable. A two-sample Wilcoxon rank-sum test will be conducted to test whether there is significant differences of the log-transformed EGFR expression level 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.) untreated participants.

Secondary Outcome Measures :

1. Effect of apalutamide on EGFR expression [ Time Frame: Up to 28 days ]
   A two-sample Wilcoxon rank-sum test will be conducted to compare the difference of EGFR expression in androgen receptor (AR) positive participants treated with and without apalutamide
2. AR expression in adjacent urothelium with EGFR expression in treated and untreated participants. [ Time Frame: Up to 28 days ]
   Pearson correlation and Spearman's rank correlation will be calculated between the AR expression and EGFR expression.
3. Toxicity of treated to untreated control [ Time Frame: Up to 28 days ]
   Descriptive statistics will be provided for these outcomes.

Other Outcome Measures:

1. AR and EGFR (and possibly phosphorylated EGFR [pEGFR]) staining levels [ Time Frame: Up to 28 days ]
   Will be summarized by descriptive statistics such as rates and proportions and compared between untreated and apalutamide using nonparametric tests such as the Kurskal-Wallis test.
2. Expression of direct androgen response gene (ADAR)-2 [ Time Frame: Up to 28 days ]
   Will be summarized by descriptive statistics such as rates and proportions and compared between untreated and apalutamide using nonparametric tests such as the Kurskal-Wallis test.
3. Ki-67 expression [ Time Frame: Up to 28 days ]
   Will be summarized by descriptive statistics such as rates and proportions and compared between untreated and apalutamide using nonparametric tests such as the Kurskal-Wallis test.
4. Ki-67 expression in the AR+ subgroup [ Time Frame: Up to 28 days ]
   Will be summarized by descriptive statistics such as rates and proportions and compared between untreated and apalutamide using nonparametric tests such as the Kurskal-Wallis test.
5. Differences in expression of AR, EGFR, pEGFR, and Ki-67 [ Time Frame: Up to 28 days ]
   Will be summarized by descriptive statistics such as rates and proportions and compared between untreated and apalutamide using nonparametric tests such as the Kurskal-Wallis test.
6. Demographics of two groups [ Time Frame: Up to 28 days ]
   Will be summarized by descriptive statistics such as rates and proportions and compared between untreated and apalutamide using nonparametric tests such as the Kurskal-Wallis test.
7. Change in EGFR expression in tumor from treated vs. untreated participants [ Time Frame: Up to 28 days ]
   Will be summarized by descriptive statistics such as rates and proportions and compared between untreated and apalutamide using nonparametric tests such as the Kurskal-Wallis test.
8. Morbidities of treatment [ Time Frame: Up to 28 days ]
   Breast tenderness, sexual or urinary side effects, seizure(s), depression, abnormal liver function tests (LFTs). Will be summarized by descriptive statistics such as rates and proportions and compared between untreated and apalutamide using nonparametric tests such as the Kurskal-Wallis test.
9. Pre vs. post intervention urinary biomarkers [ Time Frame: 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.
10. Analysis of fibroblast growth factor receptor 3 (FGFR3) in deoxyribonucleic acid (DNA) [ Time Frame: Up to 28 days ]
    Extracted from fixed paraffin embedded (FFPE) blocks from neighboring normal urothelium and tumor tissue in treated vs. untreated participants. Will be summarized by descriptive statistics such as rates and proportions and compared between untreated and apalutamide using nonparametric tests such as the Kurskal-Wallis test.
11. Changes in the tumor immune microenvironment pre- and post-apalutamide [ Time Frame: Up to 28 days ]
    Will be summarized by descriptive statistics such as rates and proportions and compared between untreated and apalutamide using nonparametric tests such as the Kurskal-Wallis test.
12. Analysis of tumor (biopsy specimen) infiltrating CD8+ T-cells [ Time Frame: Up to 28 days ]
    Measured by single RNA Sequencing (scRNA-seq) and high dimensional spectral flow cytometry to evaluate TCF1/Tcf7 transcript levels, and perform IHC of CD44+, CD62L, and SLAMF6. Will be summarized by descriptive statistics such as rates and proportions and compared between untreated and apalutamide using nonparametric tests such as the Kurskal-Wallis test.
13. Exploratory markers [ Time Frame: Up to 28 days ]
    Will be summarized by descriptive statistics such as rates and proportions and compared between untreated and apalutamide using nonparametric tests such as the Kurskal-Wallis test.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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 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 that can lead to pregnancy must use an acceptable form of contraception (vasectomy with the absence of sperm, sexual abstinence, condoms) throughout the course of the study
• 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
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Contacts and Locations

Locations

United States, Arizona

University of Arizona Cancer Center - Prevention Research Clinic

Tucson, Arizona, United States, 85719

Contact: Juan Chipollini 520-694-4032 jchipollini@surgery.arizona.edu

Principal Investigator: Juan Chipollini

United States, California

Cedars Sinai Medical Center

Los Angeles, California, United States, 90048

Contact: Michael A. Ahdoot 310-423-2659 Michael.Ahdoot@cshs.org

Principal Investigator: Michael A. Ahdoot

United States, Maryland

National Cancer Institute Urologic Oncology Branch

Bethesda, Maryland, United States, 20892

Contact: Sandeep Gurram 240-858-3700 Sandeep.Gurram@nih.gov

Principal Investigator: Sandeep Gurram

United States, New York

University of Rochester

Rochester, New York, United States, 14642

Contact: Edward M. Messing 585-275-3345 edward_messing@urmc.rochester.edu

Principal Investigator: Edward M. Messing

United States, Ohio

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States, 43210

Contact: Debasish Sundi 219-713-9783 D.Sundi@osumc.edu

Principal Investigator: Debasish Sundi

United States, Wisconsin

University of Wisconsin Carbone Cancer Center

Madison, Wisconsin, United States, 53792

Contact: Kyle A. Richards 608-262-0759 richardsk@urology.wisc.edu

Principal Investigator: Kyle A. Richards

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Edward M Messing; University of Wisconsin, Madison

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT05521698
• Other Study ID Numbers: NCI-2022-06871; NCI-2022-06871 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); Pending12 ( Other Identifier: University of Wisconsin Carbone Cancer Center ); INT22-09-01 ( Other Identifier: DCP ); P30CA014520 ( U.S. NIH Grant/Contract ); UG1CA242635 ( U.S. NIH Grant/Contract )
• First Posted: August 30, 2022
• Last Update Posted: January 27, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
• URL: https://grants.nih.gov/policy/sharing.htm

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Transitional Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms