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

Phase 2

Completed

Conditions: Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter
Recurrent Bladder 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
Adenocarcinoma of the Bladder
Distal Urethral Cancer

Interventions: Biological: ziv-aflibercept
Other: pharmacological study

Registration Number: NCT00407485

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (ziv-aflibercept)	pharmacological study	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.
Treatment (ziv-aflibercept)	ziv-aflibercept	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.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	From start of treatment to time of progression, assessed up to 4 months	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.
Tumor Response Rate	From the start of the treatment until disease progression or recurrence, assessed up to 4 years	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.

Secondary Outcome Measures