VEGF Trap in Treating Patients With Recurrent, Locally Advanced, or Metastatic Cancer of the Urothelium

Study Overview
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Brief Summary
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This phase II trial is studying the side effects and how well VEGF Trap works in treating patients with recurrent, locally advanced, or metastatic cancer of the urothelium. VEGF Trap may stop the growth of tumor cells by blocking blood flow to the tumor.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the response rate in patients with recurrent, locoregionally advanced, or metastatic transitional cell carcinoma of the urothelium treated with VEGF Trap. II. Determine the time to progression in patients treated with this drug. III. Determine overall survival of patients treated with this drug. IV. Determine the tolerability and safety of this drug in these patients. OUTLINE: This is a multicenter study. Patients receive VEGF Trap IV over 1 hour on day 1. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood collection periodically during study for pharmacokinetic/pharmacodynamic correlative studies. After completion of study treatment, patients are followed periodically.

Official Title
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A Phase II Study of VEGF Trap (NSC 724770) in Patients With Recurrent or Metastatic Transitional Carcinoma of the Urothelium

Conditions
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Adenocarcinoma of the Bladder, Distal Urethral Cancer, Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter, Proximal Urethral Cancer, Recurrent Bladder Cancer, Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter, Recurrent Urethral Cancer, Squamous Cell Carcinoma of the Bladder, Stage III Bladder Cancer, Stage III Urethral Cancer, Stage IV Bladder Cancer, Transitional Cell Carcinoma of the Bladder, Urethral Cancer Associated With Invasive Bladder Cancer

Intervention / Treatment
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* Biological: ziv-aflibercept
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed transitional cell carcinoma (TCC) of the urothelium Must have predominance of transitional histology, but foci of squamous and/or adenocarcinoma histology allowed Poorly differentiated transitional cell carcinoma allowed TCC of any of the following sites allowed: Bladder Renal pelvis Ureter Urethra Measurable disease, defined as >= 1 unidimensionally measurable lesion >= 20 mm by conventional techniques OR >= 10 mm by spiral CT scan Locoregionally advanced or metastatic disease that is not amenable to curative surgery and/or radiotherapy Must have received 1 prior systemic chemotherapy regimen containing a platinum compound (e.g., cisplatin, carboplatin, or oxaliplatin) in the neoadjuvant, adjuvant, or metastatic setting No evidence of CNS disease, including primary brain tumor or brain metastases ECOG performance status 0-2 Absolute neutrophil count >= 1,000/mm^3 Platelet count >= 75,000/mm^3 Bilirubin =< 1.5 times upper limit of normal (ULN) AST or ALT =< 2.5 times ULN Creatinine =< 2.5 times ULN OR creatinine clearance => 40 mL/min Urine protein: creatinine ratio =< 1 OR 24-hour urine protein < 500 mg INR =< 1.5 (unless on full-dose warfarin) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for >= 6 months after completion of study treatment No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies No history of allergic reactions attributed to compounds of similar chemical or biological composition to other agents used in the study No serious or nonhealing wound, ulcer, or bone fracture No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days No significant traumatic injury within the past 28 days No clinically significant cardiovascular disease, including any of the following: Myocardial infarction, coronary artery bypass graft, or unstable angina pectoris within the past 6 months New York Heart Association class III or IV congestive heart failure Serious cardiac arrhythmia requiring medication Clinically significant peripheral vascular disease within the past 6 months Cerebrovascular accident within the past 6 months Pulmonary embolism, deep vein thrombosis, or other thromboembolic event within the past 6 months Uncontrolled hypertension, defined as blood pressure (BP) > 150/100 mm Hg or systolic BP > 180 mm Hg (if diastolic BP < 90 mm Hg) within the past 3 months No evidence of bleeding diathesis or coagulopathy No uncontrolled intercurrent illness, including, but not limited to, any of the following: Ongoing or active infection Psychiatric illness or social situation that would preclude study compliance Recovered from prior therapy Prior biologic or targeted therapies allowed No more than 1 prior systemic chemotherapy regimen for metastatic disease No prior antiangiogenic therapy primarily targeting the vascular endothelial growth factor pathway At least 4 weeks since prior radiotherapy or systemic therapy (6 weeks for mitomycin C or nitrosoureas) More than 28 days since prior major surgery or open biopsy More than 7 days since prior core biopsy No concurrent major surgery Concurrent full-dose anticoagulants (e.g., warfarin) allowed provided all of the following criteria are met: In-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or low molecular weight heparin No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices) No other concurrent investigational agents No concurrent combination antiretroviral therapy for HIV-positive patients

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 (ziv-aflibercept)<br>Patients receive 4 mg/kg VEGF Trap IV over 1 hour on day 1. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. | Biological: ziv-aflibercept<br>* Given IV<br>Other: pharmacological study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response Rate | Response rate (RR) and progression free survival (PFS) were assessed in a 2-stage accrual design (22+18). A maximum of 40 patients were to be accrued to rule out a null hypothesized RR of 4% and PFS of 3 months versus alternative of 15% RR and 5.4 months PFS (corresponding to 4 month PFS of 40% vs 60%) with α=0.12 and β=0.19. If no more than 1 objective response (no more than 4.5%), and no more than 10 instances of 4-month PFS (no more than 45%), were observed among the initial 22 patients, the study would be terminated early and declared negative. Tumor response was evaluated by CT or MRI using RECIST v1.0 criteria. Responders were confirmed partial or complete responses to treatment. | From the start of the treatment until disease progression or recurrence, assessed up to 4 years | 
| Progression-free Survival (PFS) | 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 PFS using the product-limit method of Kaplan and Meier. | From start of treatment to time of progression, assessed up to 4 months |