First-Line Gemcitabine, Cisplatin + Ipilimumab for Metastatic Urothelial Carcinoma

Study Overview
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Brief Summary
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Gemcitabine plus cisplatin is standard treatment for advanced urothelial cancer. Ipilimumab has shown intriguing activity as neoadjuvant therapy in patients with clinically localized bladder cancer undergoing radical cystectomy. The combination of gemcitabine, cisplatin, plus ipilimumab may build on the chemosensitivity of urothelial carcinoma to produce more durable responses and improved outcomes.

Detailed Description
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OUTLINE: This is a multi-center study Gemcitabine 1000 mg/m2 Days 1 & 8 Cisplatin 70 mg/m2 Day 1 Ipilimumab 10 mg/kg Day 1 (start cycle 3) Treatment during the induction phase will be administered in six 21-day cycles. During cycles 1 and 2, gemcitabine plus cisplatin will be administered WITHOUT ipilimumab. During cycles 3-6, combination therapy with gemcitabine, cisplatin, plus ipilimumab will be administered. Patients without evidence of disease progression (by irRC) after completion cycle 6 will continue single-agent ipilimumab maintenance every 3 months. Karnofsky performance status (KPS) ≥ 80% within 14 days prior to registration for protocol therapy. Life Expectancy: Not Specified Hematopoietic: White blood cell count (WBC) ≥ 3.5K/mm3 Hemoglobin (Hgb) ≥ 9 g/dL Platelets ≥ 100K/mm3 Absolute neutrophil count (ANC) ≥ 1.5k/mm3 Hepatic: Bilirubin ≤ 1.5 times x Upper Limit of Normal (ULN) (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL) Aspartate aminotransferase (AST, SGOT) ≤ 2.5 x ULN. NOTE: If the patient has liver metastases present, then ≤ 5 x ULN Renal: Calculated creatinine clearance of ≥ 55 cc/min using the Cockcroft-Gault formula Cardiovascular: Not Specified

Official Title
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Phase II Trial of Gemcitabine, Cisplatin, Plus Ipilimumab as First-line Treatment for Patients With Metastatic Urothelial Carcinoma: Hoosier Cancer Research Network GU10-148

Conditions
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Urothelial Carcinoma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological proof of urothelial carcinoma of the urethra, bladder, ureters, or renal pelvis. Advanced (clinical stage T4b, unresectable) or metastatic disease. Prior radiation therapy is allowed to < 25% of the bone marrow. Age > 18 years at the time of consent. Written informed consent and HIPAA authorization for release of personal health information. Females must not be pregnant or breastfeeding. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of ipilimumab. Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study [and for up to 26 weeks after the last dose of investigational product] in such a manner that the risk of pregnancy is minimized. Prior Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis). Patients with other immune disorders should not be enrolled without discussion with the principal investigator. Exclusion Criteria: No active CNS metastases. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. No prior malignancy is allowed except for cancers that have been definitively treated with a risk of recurrence of < 30% based on the treating oncologists assessment. Patients may not have received prior systemic chemotherapy for metastatic/advanced urothelial carcinoma. Prior neoadjuvant/adjuvant therapy is permitted if completed ≥ 12 months prior to registration for protocol therapy. Prior intravesical therapy is permitted. No treatment with any investigational agent within 30 days prior to registration for protocol therapy. No underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea. No non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab). No history of prior treatment with ipilimumab or prior CD137 agonist or CTLA 4 inhibitor or agonist. No known active or chronic infection with HIV, Hepatitis B, or Hepatitis C. No clinically significant infections as judged by the treating investigator. No chronic systemic corticosteroids (defined as the equivalent of prednisone ≥ 20 mg PO daily for > 6 months during the past year)

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Gemcitabine 1000 mg/m2 Days 1 & 8 Cisplatin 70 mg/m2 Day 1 Ipilimumab 10 mg/kg Day 1 (start cycle 3) | Drug: Gemcitabine<br>* Gemcitabine 1000 mg/m2 Days 1 & 8 (all cycles)<br>Drug: Cisplatin<br>* Cisplatin 70 mg/m2 Day 1 (all cycles)<br>Drug: Ipilimumab<br>* Ipilimumab 10 mg/kg Day 1 (start cycle 3)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival | To determine the median overall survival of patients with advanced/metastatic urothelial cancer treated with gemcitabine, cisplatin, plus ipilimumab, calculated from the date of registration until the date of final analysis, projected to be 48 months from the start of the study. | 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival | To determine the progression-free survival (using irRC and RECIST v1.0) of patients with advanced/metastatic urothelial carcinoma treated with gemcitabine, cisplatin, and ipilimumab. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Progression is definied by IrRC as at least 25% increase in tumor burden compared with nadir (at any single time point) in two consecutive observations at least 4 wk apart. | 12 months | 
| Best Overall Response Rate | To determine the best overall response rate to treatment with gemcitabine, cisplatin, plus ipilimumab, per RECIST 1.1 criteria. | 12 months | 
| Number of Adverse Events Experienced by Patients | To determine the safety of treatment with gemcitabine, cisplatin, plus ipilimumab. The highest grade adverse event for each subject is presented. | 12 months |