Enzalutamide in Combination With Gemcitabine and Cisplatin in Bladder Cancer

For the phase 1 dose escalation phase, the starting dose of enzalutamide will be 80 mg orally
once a day (Level 1). The dosing regimen of cisplatin and gemcitabine will be at standard
doses of Gemcitabine at 1000 mg/m^2 IV on days 1, 8 and cisplatin at 70 mg/m2 IV on day 1,
repeated every 21 days for total of 6 cycles.

Three patients will be treated dose level 1 (enzalutamide 80 mg daily). If 0 patients
experience dose limiting toxicity (DLT), dose escalation will be done to level 2 of
enzalutamide 160 mg daily. If 1 patient experiences DLT, 3 more patients will be treated at
the same dose level; if 1 of 6 experiences DLT, escalate the dose to next level, and if 2 or
more of 6 experiences DLT, the dose level 1 (80 mg enzalutamide) will be the recommended dose
for dose expansion cohort.

The cohort expansion will then be done by enrolling 12 patients with stage IV bladder cancer,
who express androgen receptor (AR) staining of 1+ and above by immunohistochemistry (IHC), to
determine the safety and tolerability of cisplatin and gemcitabine with the recommended dose
level of enzalutamide (80 mg or 160 mg, depending upon the safety results from dose
escalation part) in this expanded cohort of patients with AR + bladder cancer.

Enzalutamide would be continued after completion of 6 cycles of gemcitabine-cisplatin for
patients exhibiting a response or stable disease, until they experience disease progression.

Inclusion Criteria:

- Cytologically or histologically confirmed evidence of transitional cell carcinoma of
bladder, renal pelvis, ureter or urethra.

- Patients with Stage IV (locally advanced or metastatic) disease. Must have measurable
disease, as per Response Evaluation Criteria in Solid Tumors (RECIST).

- Minimum of 4 weeks since any major surgery, completion of radiation.

- Prior treatment with cytotoxic chemotherapy is not a requirement, but allowed only if
used in neoadjuvant, adjuvant or for bladder preserving protocols, as long as was
administered > 6 months prior to starting study.

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

- Life expectancy 12 weeks or more.

- Must have normal organ and marrow function.

- Women of childbearing potential must have a negative serum or urine pregnancy test
within 14 days of the administration of the first study treatment. Women must not be
lactating.

- Sexually active women of childbearing age and men should be willing to follow birth
control guidelines.

- Should be able to swallow enzalutamide and comply with study requirements.

Exclusion Criteria:

- Prior treatment with any cytotoxic chemotherapy in metastatic setting. Prior treatment
with cytotoxic chemotherapy is allowed only if used in neoadjuvant, adjuvant or for
bladder preserving protocols, as long as was administered > 6 months prior to starting
study.

- Have undergone major surgery within 4 weeks prior to study enrollment.

- Chronic treatment with steroids or any other immunosuppressant drugs.

- Should not receive immunization with attenuated live vaccines during study period or
within 1 week of study entry.

- History of seizures, predisposing factors for seizures, including underlying brain
injury with loss of consciousness within previous 12 months, transient ischemic attack
within previous 12 months, cerebral vascular accident or brain arteriovenous
malformation.

- Untreated brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases.

- Congestive heart failure (NYHA Class III or IV), unstable angina, sustained
ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia,
advanced heart block or a history of acute myocardial infarction within the 6 months
preceding enrollment.

- Known history of HIV.

- Have any severe and/or uncontrolled medical conditions or other conditions that could
affect their participation in the study.

- Women who are pregnant or breast feeding, or women/men able to conceive and unwilling
to practice birth control guidelines.

- Concurrent medications which strongly inhibit or induce CYP enzymes (gemfibrozil,
Rifampin, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine,
bosentan, efavirenz, etravirine, modafinil, nafcillin, St. John's Wort).

- History of stage III or greater cancer, except basal or squamous cell skin cancers
adequately treated or any other stage I or II cancer adequately treated and
disease-free for ≥ 2 years. Incidental findings of stage I or II prostate cancer that
is considered to be cured with radical cystoprostatectomy is allowed.

- Prior use of enzalutamide.

- Radiation therapy via external beam or brachytherapy within 28 days of registration.

- Patients who are ineligible to receive cisplatin: Creatinine clearance of less than 60
mL/minute, hearing loss of 25 decibel (dB) at 2 contiguous frequencies, grade 2 or
higher peripheral neuropathy, or New York Heart Association Class III or higher heart
failure.

- Allergy/sensitivity to any study drug (gemcitabine, cisplatin, enzalutamide), or drugs
chemically related to study drug, or excipients.

- Brain metastases (including treated or stable brain metastases)