Trial Title:
Targeting Androgen Signaling in Urothelial Cell Carcinoma - Neoadjuvant
NCT ID:
NCT05839119
Condition:
Urothelial Carcinoma Bladder
Androgen Receptor Positive
Conditions: Official terms:
Carcinoma
Urinary Bladder Neoplasms
Gemcitabine
Conditions: Keywords:
UCC
Bladder Cancer
AR+
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Degarelix
Description:
initial dose is 240 mg administered as two 120 mg (3 mL) injections (SC), followed by
subsequent doses at 80 mg (4 mL) administered as one injection (SC)
Arm group label:
Treatment
Other name:
Firmagon Kit
Intervention type:
Combination Product
Intervention name:
Gemcitabine/Cisplatin
Description:
SOC Neoadjuvant Chemotherapy: Gemcitabine/Cisplatin 21-day cycles (4 cycles total)
- Gemcitabine: 1000 mg/m2 (IV) Days 1 and 8 of each cycle
- Cisplatin: 70 mg/m2 (if borderline renal function: 35 mg/m2) (IV) Day 1 of each
cycle (if borderline renal function, days 1 and 8 of each cycle).
Arm group label:
Treatment
Summary:
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.
Detailed 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.
Criteria for 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Lifespan Cancer Institute
Address:
City:
Providence
Zip:
02912
Country:
United States
Status:
Recruiting
Contact:
Last name:
Sheldon L Holder, MD, PhD
Email:
Sheldon_holder@brown.edu
Investigator:
Last name:
Ali Amin, MD
Email:
Sub-Investigator
Start date:
October 2, 2023
Completion date:
January 2030
Lead sponsor:
Agency:
Brown University
Agency class:
Other
Collaborator:
Agency:
Legorreta Cancer Center at Brown University
Agency class:
Other
Collaborator:
Agency:
Lifespan
Agency class:
Other
Collaborator:
Agency:
Cures Within Reach
Agency class:
Other
Source:
Brown University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05839119
