Cisplatin, Gemcitabine and Bevacizumab in Combination for Metastatic Transitional Cell Cancer

Study Overview
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Brief Summary
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Cisplatin is a very important agent for the treatment of TCC as it has a single agent response rate of approximately 15%. However, it has been most important as a part of combination chemotherapy, MVAC initially and now in combination with gemcitabine. Single agent gemcitabine has demonstrated an overall response rate (ORR) of approximately 25%, including some complete responses (CR), with minimal toxicity in patients with advanced bladder cancer. Bevacizumab, a murine anti-human VEGF monoclonal antibody, has been advanced for use in combination with cytotoxic chemotherapy to delay time to disease progression in patients with metastatic solid tumors. This trial is designed to further assess the efficacy, safety and tolerability of this regimen in this patient population.

Detailed Description
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OUTLINE: This is a multi-center study. Cisplatin 70 mg/m2 Day 1 Gemcitabine 1250 mg/m2 Day 1 and 8 Bevacizumab 15 mg/kg Day 1 Review toxicity every cycle (every 3 weeks) Review for radiographic response every 2 cycles (every six weeks) Progressive disease = off protocol therapy Patients will be treated for up to a maximum of 8 cycles of cisplatin and gemcitabine (24 weeks of therapy). If a patient has not progressed by the end of 24 weeks (completion of cisplatin and gemcitabine), then patient will be treated with bevacizumab at 15 mg/kg every three weeks for a maximum of 12 months of bevacizumab therapy (since study entry). If at any time patient has undue toxicity or progressive disease, patient will be removed from the study and followed until progression and for survival. If the patient has Grade 3 or 4 neurotoxicity and/or the creatinine rises above 2.0, then the cisplatin will be discontinued and the patient continued on study and treated with gemcitabine and bevacizumab at the same dose and schedule. ECOG Performance Status 0 or 1 Hematopoietic: White blood cell count > 3000/mm3 Absolute neutrophil count (ANC) > 1500 mm/3 Platelet count > 100,000/mm3 Hemoglobin > 8 g/dL (may be transfused or receive erythropoietin support to maintain or exceed this level). INR < 1.5 No full dose/therapeutic anticoagulation with either low molecular weight heparin or unfractionated heparin or coumadin Hepatic: Total bilirubin of <1.5 mg/dL ALT <5 times upper limit of normal for subjects with documented liver metastases; <2.5 times the upper limit of normal for subjects without evidence of liver metastases. Renal: Serum creatinine of < 1.5 mg/dL. Urine protein:creatinine ratio < 1.0 at screening Cardiovascular: No history of myocardial infarction or stroke within the last 6 months No uncontrolled hypertension (blood pressure of >160 systolic and/or 110 diastolic mmHg on medication) No unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure No unstable symptomatic arrhythmia requiring medication (subjects with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia are eligible), or clinically significant peripheral vascular disease. Pulmonary: Not specified

Official Title
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A Phase II Trial of Cisplatin, Gemcitabine and Bevacizumab in Combination for Metastatic Transitional Cell Cancer: Hoosier Oncology Group GU04-75

Conditions
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Bladder Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously untreated or relapsed locally advanced or metastatic transitional cell carcinoma of the bladder. (Patients with pathology showing ANY component of non-transitional cell histology are not eligible). Relapsed patients may have received prior chemotherapy ≥ one year prior to study registration as part of a neoadjuvant or adjuvant regimen and must not have had intervening therapy from the end of that treatment until study entry. Measurable disease as per RECIST. Prior radiation therapy, immunotherapy, cytokine, biologic or vaccine therapy must be greater than 28 days prior to being registered for protocol therapy, Exclusion Criteria: No known central nervous system metastasis. (imaging of brain only required if clinically indicated) No prior organ allograft. No history of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications. No evidence of bleeding diathesis or coagulopathy. No history of serious, non-healing wound, ulcer or bone fracture No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to being registered for protocol therapy. No prior history of malignancy in the past 5 years with the exception of basal cell and squamous cell carcinoma of the skin. Other cancers with low potential for metastasis, such as in situ cancers (e.g., Grade 1, TA TCC (low grade superficial bladder cancer), colonic polyp with focus of adenocarcinoma) can also be enrolled after approval from the study chair. No major surgical procedure, open biopsy, or significant traumatic injury less than 28 days prior to being registered for protocol therapy. Patients are not eligible if the need for any major surgical procedure is anticipated during the course of the study. Any minor surgical procedures, fine needle aspirations or core biopsies must be greater than 7 days prior to being registered for protocol therapy except procedures to secure a vascular access device which must be greater than 7 days prior to the start of protocol therapy.

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: Single Group Assignment<br>Cisplatin + Gemcitabine + Bevacizumab | Drug: Cisplatin<br>* Cisplatin 70 mg/m2, day 1<br>Drug: Gemcitabine<br>* Gemcitabine 1250 mg/m2, day 1 and 8<br>Drug: Bevacizumab<br>* Bevacizumab 15mg/kg, day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | - To determine the progression free survival of patients with metastatic transitional cell cancer treated with cisplatin, gemcitabine and bevacizumab. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Time | To estimate overall survival time in months. | 36 months | 
| Estimate Response Rates | To estimate rate of partial response (PR), complete response (CR) and overall response (PR plus CR). | 36 months | 
| Duration of Response for Responding Patients | To estimate duration of response for responding patients. | 36 months |