Enzalutamide in Combination With Gemcitabine and Cisplatin in Bladder Cancer
Condition: Bladder Cancer; Carcinoma, Transitional Cell; Renal Pelvis Cancer; Ureter Cancer; Urethra Cancer
MeSH terms: Carcinoma; Urinary Bladder Neoplasms; Ureteral Neoplasms; Pelvic Neoplasms; Carcinoma, Transitional Cell; Urethral Neoplasms
Intervention: Enzalutamide; Cisplatin; Gemcitabine
Intervention description: Enzalutamide orally once a day. Dose Escalation Level 1: 80 mg; Level 2: 160 mg. Dose Expansion at recommended dose level, after dose escalation.; Cisplatin at 70 mg/m^2 IV on day 1, repeated every 21 days for total of 6 cycles.; Gemcitabine at 1000 mg/m^2 IV on days 1, 8, repeated every 21 days for total of 6 cycles.
Intervention MeSH terms: Cisplatin; Gemcitabine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Ureteral Diseases; Urinary Bladder Diseases; Transitional Cell Carcinoma; Bladder; Carcinoma; Renal; Pelvis; Ureter; Urethra

Summary:

      The main purpose of this study is to find out the dose of enzalutamide that can be safely
      given with gemcitabine and cisplatin in patients with advanced bladder cancer. Researchers
      also want to find out the side effects of these drugs when given together. This study will
      also help in finding out the effect on tumor of the combination of enzalutamide, gemcitabine
      and cisplatin.
    

Eligibility criteria:

        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)