Enzalutamide in Combination With Gemcitabine and Cisplatin in Bladder Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I/1b Study of Enzalutamide in Combination With Gemcitabine and Cisplatin in Bladder Cancer

Conditions
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Bladder Cancer, Carcinoma, Transitional Cell, Renal Pelvis Cancer, Ureter Cancer, Urethra Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Cisplatin
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Dose Escalation: Begin with Level 1 dose of enzalutamide (orally), with standard doses of cisplatin and gemcitabine via intravenous (IV). | Drug: Enzalutamide<br>* Enzalutamide orally once a day. Dose Escalation Level 1: 80 mg; Level 2: 160 mg. Dose Expansion at recommended dose level, after dose escalation.<br>* Other names: XTANDI®;Drug: Cisplatin<br>* Cisplatin at 70 mg/m^2 IV on day 1, repeated every 21 days for total of 6 cycles.<br>* Other names: Platinol®-AQ;Drug: Gemcitabine<br>* Gemcitabine at 1000 mg/m^2 IV on days 1, 8, repeated every 21 days for total of 6 cycles.<br>* Other names: Gemzar ®;|
| Experimental: Dose Expansion<br>Dose Expansion: Enzalutamide at recommended dose level with standard doses of cisplatin and gemcitabine. | Drug: Enzalutamide<br>* Enzalutamide orally once a day. Dose Escalation Level 1: 80 mg; Level 2: 160 mg. Dose Expansion at recommended dose level, after dose escalation.<br>* Other names: XTANDI®;Drug: Cisplatin<br>* Cisplatin at 70 mg/m^2 IV on day 1, repeated every 21 days for total of 6 cycles.<br>* Other names: Platinol®-AQ;Drug: Gemcitabine<br>* Gemcitabine at 1000 mg/m^2 IV on days 1, 8, repeated every 21 days for total of 6 cycles.<br>* Other names: Gemzar ®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Dose of Enzalutamide | Dose Escalation. Maximum Tolerated Dose (MTD) of Enzalutamide when given with Cisplatin and Gemcitabine at standard doses. Dose Level 1: 80 mg Enzalutamide; Dose Level 2: 160 mg Enzalutamide. Dose-Limiting Toxicity (DLT) is defined as any of the following occurring in the first 21 days (cycle 1) of study participation that are considered at least possibly related to enzalutamide administration. Toxicities that are in the opinion of the investigator(s) attributable exclusively to gemcitabine or cisplatin will not be considered DLT. 7 consecutive missed doses (out of 21 doses) of enzalutamide in 21 days due to study drug related toxicity. Missed day 8 dose of gemcitabine in cycle 1 will not be considered DLT. Delay of greater than 3 weeks from scheduled date in initiating cycle 2 due to study drug related toxicity. Discontinuation of a patient due to study drug related toxicity before completing cycle 1. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR): Complete Response (CR) + Partial Response (PR) | Dose Expansion. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | Up to 6 months | 
| Progression Free Survival (PFS) | Dose Expansion. PFS is defined as the time from randomization until objective tumor progression or death. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). | 14 months | 
| Overall Survival (OS) | Dose Expansion. Overall survival is defined as the time from randomization until death from any cause, and is measured in the intent-to-treat population. | Up to 24 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ureteral Diseases, Urinary Bladder Diseases, Transitional Cell Carcinoma, Bladder, Carcinoma, Renal, Pelvis, Ureter, Urethra