Overview
This study is for patients who have bladder cancer that invades into the muscle wall of the bladder. The standard treatment for patients with muscle invasive bladder cancer is to give 4 cycles of chemotherapy with the drugs cisplatin and gemcitabine, then to do an operation to remove the bladder (cystectomy).
In this study, the investigators will test participants' bladder cancer to see if their bladder cancer has a receptor for testosterone inside the bladder cancer cells. If it has the testosterone receptor participants will receive a medication called Degarelix that lowers testosterone levels in the blood. Degarelix will be given during the period that participants are receiving the standard of care chemotherapy drugs gemcitabine and cisplatin.
The purpose of this study is to evaluate the effects, good and bad, of adding Degarelix to standard chemotherapy for patients with bladder cancer that have the testosterone receptor.
Description
Annually, over 80,000 people will be diagnosed with urothelial cell carcinoma (UCC) of the bladder in the USA, with over 17,000 deaths. For patients with muscle-invasive disease (stage II and IIIA), standard of care therapy is neoadjuvant chemotherapy followed by radical cystectomy. Neoadjuvant chemotherapy has been shown by multiple clinical trials and meta-analyses to improve pCR rates, disease free survival, and overall survival when compared to cystectomy alone. Specifically, neoadjuvant gemcitabine/cisplatin has been shown to be tolerable and effective and is a level 1 recommendation for treatment of muscle invasive bladder cancer by the National Comprehensive Cancer Network Guidelines.
The presence of a pCR in response to neoadjuvant chemotherapy is prognostic, but only about 35% of patients achieve a pCR. Thus improved neoadjuvant chemotherapy regimens are necessary to improve recurrence free survival and overall survival rates in patients with bladder cancer.
UCC is more common in men than women, with incidence rates of 3:1 to 4:1. This disparity persists even after controlling for smoking and occupational hazards/exposures and is likely influenced by androgen signaling. Androgen receptor (AR) positive UCC cells display increased proliferation, migration, and invasion in the presence of androgen and these effects are nullified in the presence of an AR antagonist. Preclinical studies show decreased rates of UCC incidence in response to a chemical carcinogen in castrated mice versus sham castrated mice and AR knockout mice versus AR intact mice. In retrospective human studies patients with UCC receiving androgen targeted therapy for concurrent prostate cancer had approximately 50% lower recurrence rates of UCC. Similarly, men receiving androgen targeted therapy for prostate cancer or benign prostatic hyperplasia have lower incidence rates of UCC than men not receiving androgen directed therapy.
Two prospective human clinical trials related to this concept have been performed. The first evaluated enzalutamide (an AR antagonist) as chemoprevention in non-muscle invasive UCC. This study was closed due to poor accrual after accruing only one patient. The second study added enzalutamide to standard chemotherapy in patients with metastatic UCC. Seven patients accrued at the therapeutic dose of enzalutamide. Overall, there was no signal for increased efficacy. However, one patient achieved a complete response lasting 2 years at last report. This patient was noted to have >90% positivity for AR in their tumor and, notably, was the only woman to participate in the study (and presumably had low testosterone levels). These data support further evaluation of androgen targeted therapy in AR+ UCC.
TASUC-neo is a pilot study conducted in patients with androgen receptor positive (AR+), pT2 - pT4, N0 - N1, M0 urothelial cell carcinoma (UCC) of the bladder. The study medication, Degarelix, will be administered concurrently with neoadjuvant gemcitabine/cisplatin.
Eligibility
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.