VEGF Trap in Treating Patients With Recurrent Stage III or Stage IV Melanoma That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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This phase II trial is studying how well VEGF Trap works in treating patients with recurrent stage III or stage IV melanoma that cannot be removed by surgery. Combinations of biological substances in VEGF Trap may be able to carry tumor-killing substances directly to melanoma cells. It may also stop the growth of melanoma by blocking blood flow to the tumor.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the antitumor response rate (complete and partial response) in patients with recurrent inoperable stage III or IV melanoma treated with VEGF Trap. II. Compare the progression-free survival of patients treated with this regimen vs historical controls. SECONDARY OBJECTIVES: I. Determine the overall survival of patients treated with this regimen. II. Determine the toxicity and tolerability of this regimen in these patients. III. Determine the impact of this regimen on laboratory correlates including anti-VEGF Trap antibody testing and pharmacokinetics 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 for at least 6 courses in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline, prior to course 2, and 60 days after completion of study treatment for pharmacokinetic and pharmacodynamic studies. Samples are analyzed by enzyme-linked immunosorbent assay. After completion of study treatment, patients are followed periodically for 5 years.

Official Title
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A Phase 2 Study Evaluating the Efficacy of VEGF Trap in Patients With Recurrent Inoperable Stage III or Stage IV Melanoma

Conditions
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Ciliary Body and Choroid Melanoma, Medium/Large Size, Extraocular Extension Melanoma, Iris Melanoma, Metastatic Intraocular Melanoma, Recurrent Intraocular Melanoma, Recurrent Melanoma, Stage III Melanoma, Stage IV Melanoma

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 stage III or IV melanoma Cutaneous, ocular, or mucosal melanoma allowed Recurrent, inoperable disease Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan No evidence of CNS disease, including primary brain tumor or brain metastases No brain metastases by MRI or CT scan within the past 4 weeks ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100% Life expectancy > 3 months WBC ≥ 3,000/mm³ Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 75,000/mm³ Bilirubin < 1.5 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min Urine protein:creatinine ratio < 1 OR urine protein < 500 mg by 24-hour urine collection PT 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 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: Cerebrovascular accident 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 Myocardial infarction, coronary artery bypass graft, or unstable angina within the past 6 months New York Heart Association class III-IV congestive heart failure Serious cardiac arrhythmia requiring medication Unstable angina pectoris within the past 6 months Clinically significant peripheral vascular disease within the past 6 months Pulmonary embolism, deep vein thrombosis, or other thromboembolic event within the past 6 months No evidence of bleeding diathesis or coagulopathy No concurrent uncontrolled 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 all prior therapy and major surgery No prior chemotherapy or hormonal therapy More than 7 days since prior core visceral organ biopsy More than 4 weeks since prior biologic therapy or radiotherapy More than 28 days since prior major surgery or open biopsy No concurrent major surgery No other concurrent investigational agents No concurrent combination antiretroviral therapy for HIV-positive patients Concurrent full-dose warfarin with PT INR > 1.5 allowed provided the following criteria are met: INR in range (2-3) 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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Arm I<br>Patients receive Aflibercept IV at 4 mg/kg over 1 hour on day 1. Treatment repeats every 14 days for at least 6 courses in the absence of disease progression or unacceptable toxicity. | Biological: ziv-aflibercept<br>* Given IV<br>* Other names: Zaltrap;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (CR + PR) | Using the RECIST v1.0 criteria for target lesions assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Objective Response = CR + PR., | Start of treatment to disease progression/recurrence, up to 5 years | 
| 4 Month Progression-free Survival | Estimated using the product-limit method of Kaplan and Meier. 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. | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Will be estimated by the Kaplan-Meier method. | From the initial date of treatment to the recorded date of death, assessed up to 5 years | 
| Number of Participants With Toxicities | The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 were utilized for AE grading and reporting. Grade 3 and higher adverse events considered possibly, probably or definitely related to aflibercept are summarized. | Up to 5 years | 
| Impact of the VEGF Trap Therapy on Laboratory Correlates |  | Up to 5 years |