Ethacrynic Acid Elimination in Non-Muscle Invasive Bladder Cancer Patients Undergoing Transurethral Resection

Bladder cancer continues to be a significant healthcare and financial liability in the
United States. Patients with Non-Muscle Invasive Bladder Cancer (NMIBC) are in desperate
need for both effective and easily tolerated treatment options. Current standard of care
includes immediate post-operative Mitomycin C (MMC), which decreases the rate of recurrence
but does not alter progression. Furthermore, in patients with high-grade NMIBC, standard of
care dictates that patients undergo intravesical Bacillus Calmette-Guerin (BCG) therapy.
This treatment has a high degree of morbidity with both local and systemic side effects
along with significant discomfort from treatment (intra-urethral catheterization and bladder
instillation). Our goal is to develop a bladder cancer treatment strategy designed to
decrease recurrence/progression rates in addition to decreasing the morbidity of treatment.

Twelve evaluable NMIBC patients will participate in this Phase 1 trial.

Treatment - patients will receive a single, 50 mg oral dose of ethacrynic acid administered
as two 25 mg strength EDECRIN® tablets immediately prior to transurethral resection of
bladder tumor.

Concentrations and excretion rates of ethacrynic acid in the urine, as well as of cysteine,
glutathione, and mercapturate metabolites, will be measured for each of 4 urine specimens
collected on the day of surgery (before, during, and at 2 timepoints after surgery).

Adverse events, serious adverse events, laboratory values, and vital sign measurements will
be collected.

Efficacy of ethacrynic acid treatment will be estimated by recording
recurrence/non-recurrence of disease at 3 months post-treatment

INCLUSION CRITERIA:

NOTE: Both patients who will and will not receive standard of care concomitant mitomycin C
are eligible to enroll in this study.

- Ability to understand and the willingness to sign a written informed consent

- Diagnosis of presumed non-muscle invasive bladder cancer based on office based
cystoscopy (primary or recurrent), and planned transurethral resection of bladder
tumor (TURBT)

- Participants must have tumors with anticipated transurethral resection time ≤ 1 hour

- Previous history of intravesical therapy allowed

- Age ≥ 18 years

- Performance Status 0-1 (Appendix A.)

- Adequate organ and marrow function as defined below:

- leukocytes ≥ 3,000/mcL

- absolute neutrophil count ≥ 1,500/mcL

- platelets ≥ 100,000/mcl

- total bilirubin within normal institutional limits

- Aspartate Aminotransferase (AST) ≤ 2.5 X institutional upper limit of normal

- Alanine Aminotransferase (ALT) ≤ 2.5 X institutional upper limit of normal

- creatinine within normal institutional limits

- Women of child-bearing potential (WOCP) and men with partners of child-bearing
potential must agree to use adequate contraception (hormonal or barrier method of
birth control; abstinence) prior to study entry, for the duration of study
participation, and for 90 days following completion of therapy. Should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately

A woman of child-bearing potential is any female (regardless of sexual orientation, having
undergone a tubal ligation, or remaining celibate by choice) who meets the following
criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy; or

- Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has
had menses at any time in the preceding 12 consecutive months)

EXCLUSION CRITERIA:

Participants meeting any of the exclusion criteria at baseline will be excluded from study
participation.

- Current or anticipated use of other investigational agents.

- Patient has known nodal or distant metastatic disease. Patients with nodal or
metastatic disease require systemic chemotherapy. Furthermore, they should be
excluded from this clinical trial because of their poor overall prognosis.

- Patients with locally advanced bladder cancer based on cross-sectional imaging
(suspicion of extravesical disease or hydronephrosis)

- Patients with tumors with anticipated transurethral resection time greater than 1
hour

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Ethacrynic acid or other agents used in study.

- Systolic blood pressure < 90 mmHg and/or diastolic blood pressure < 50 mmHg

- 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.

- Pregnant or nursing. There is a potential for congenital abnormalities and for this
regimen to harm nursing infants.