Targeting androgen signaling in bladder cancer treatment

Targeting Androgen Signaling in Urothelial Cell Carcinoma - Neoadjuvant (TASUC-Neo): A Pilot Study of Degarelix in Combination With Neoadjuvant Gemcitabine and Cisplatin in Muscle-Invasive Urothelial Cell Carcinoma of the Bladder

This study is testing if adding a medication that lowers testosterone to standard chemotherapy can help improve treatment results for patients with a specific type of bladder cancer.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 32 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Brown University (other)
• Drugs / interventions: chemotherapy
• Locations: 1 site (Providence, Rhode Island)
• Trial ID: NCT05839119 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the effects of adding Degarelix, a medication that lowers testosterone levels, to the standard chemotherapy regimen of gemcitabine and cisplatin for patients with muscle-invasive urothelial cell carcinoma (UCC) that expresses androgen receptors. The study aims to determine if this combination can improve treatment outcomes, such as pathologic complete response (pCR) rates and overall survival. Participants will be screened for androgen receptor positivity and must meet specific eligibility criteria related to their cancer stage and treatment history. The trial is designed to enhance the effectiveness of existing therapies for bladder cancer.

Who should consider this trial

Good fit: Ideal candidates are patients with muscle-invasive urothelial cell carcinoma of the bladder who are eligible for standard chemotherapy and have androgen receptor positive tumors.

Not a fit: Patients with non-muscle invasive bladder cancer or those without androgen receptor positivity may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could lead to improved survival rates and better treatment outcomes for patients with androgen receptor positive bladder cancer.

How similar studies have performed: While the combination of androgen signaling modulation with chemotherapy is a novel approach in this context, similar strategies have shown promise in other cancer types.

Eligibility criteria

Inclusion Criteria:

3.1.1 Patients must have the following:

* Histologically confirmed muscle invasive urothelial cell carcinoma of the bladder (pT2 - pT4)
* Eligible for standard cisplatin/gemcitabine chemotherapy as determined by the treating Medical Oncologist

3.1.2 Patients must have muscle-invasive urothelial cell carcinoma of the bladder (pT2 - pT4, N0-N1, M0,) as determined by bladder biopsy or trans-urethral resection of bladder tumor (TURBT) and staging imaging studies. Patients with \<10% non-urothelial histology will remain eligible for enrollment.

3.1.3 Androgen receptor positivity by IHC within the nucleus of tumor cells (as determined by study Pathologist) is required to receive study treatment.

3.1.4 Patients previously treated with intravesical therapy for non-muscle invasive urothelial carcinoma of the bladder are eligible for enrollment if the agent used was not gemcitabine or a platinum-containing agent (i.e, cisplatin, carboplatin, or oxaliplatin).

3.1.5 Age ≥18 years.

Because the safety and efficacy of Degarelix in pediatric patients have not been established, children (patients \<18 years of age) are excluded from this study.

3.1.6 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).

3.1.7 Patients must have adequate organ and marrow function as defined below:

* absolute neutrophil count ≥1,000/mcL
* platelets ≥100,000/mcL
* total bilirubin ≤ institutional upper limit of normal (ULN)
* AST(SGOT)/ALT(SGPT) ≤3 1.5 × institutional ULN
* creatinine ≤ institutional ULN OR glomerular filtration rate (GFR) ≥40 mL/min/1.73 m2

3.1.8 Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

3.1.9 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

3.1.10 Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

3.1.11 Patients with metastases, including treated brain metastases, are not eligible for enrollment.

3.1.12 Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen, and prior therapy did not include gemcitabine or a platinum-containing agent, are eligible for this trial.

3.1.13 Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.

3.1.14 For women of childbearing potential, a negative serum pregnancy test within 7 days prior to registration

3.1.15 Women of childbearing potential and male participants must practice highly effective form of non-hormonal contraception throughout the study, which is defined as from study screening (ICF) through at least six months post last treatment. It must be documented this was discussed with the patient.

The effects of Degarelix on the developing human fetus are unknown. However, based on animal studies and the mechanism of action, Degarelix may cause fetal loss. For this reason and that other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception.

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

Exclusion Criteria:

3.2.1 Patients who have previously received systemic or intravesical gemcitabine or platinum-containing chemotherapy

3.2.2 Patients taking testosterone, estrogen, or other sex hormone modifying agents are excluded from this study as these medications may interfere with the activity of the study drug, Degarelix.

3.2.3 Patients with uncontrolled intercurrent illness, as determined by the treating physician

3.2.4 Patients who are pregnant or breastfeeding. (The effects of Degarelix on the developing human fetus are unknown. However, "based on findings in animal studies, \[Degarelix\] can cause fetal harm and loss of pregnancy when administered to a pregnant woman. In animal developmental and reproductive toxicity studies in rats and rabbits, oral administration of Degarelix during organogenesis caused embryo-fetal lethality and abortion as well as increased post-implantation loss and decreased the number of live fetuses in animals at doses less than the clinical loading dose based on body surface area." (Degarelix package insert). For this reason and the fact that other therapeutic agents used in this trial are known to be teratogenic, pregnant women are excluded from this study.

Where this trial is running

Providence, Rhode Island

• Lifespan Cancer Institute — Providence, Rhode Island, United States (RECRUITING)

Study contacts

• Principal investigator: Sheldon L Holder, MD, PhD — Brown University
• Study coordinator: Brown University Oncology Research Group

Conditions: Urothelial Carcinoma Bladder, Androgen Receptor Positive, UCC, Bladder Cancer, AR+