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

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.

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)