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

Phase 2

Completed

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

Interventions: Biological: ziv-aflibercept
Other: pharmacological study

Registration Number: NCT00450255

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 41

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)

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	pharmacological study	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.
Arm I	ziv-aflibercept	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.

Primary Outcome Measures

Name	Time	Method
4 Month Progression-free Survival	4 months	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.
Objective Response Rate (CR + PR)	Start of treatment to disease progression/recurrence, up to 5 years	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.",

Secondary Outcome Measures

Name	Time	Method
Overall Survival	From the initial date of treatment to the recorded date of death, assessed up to 5 years	Will be estimated by the Kaplan-Meier method.
Number of Participants With Toxicities	Up to 5 years	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.
Impact of the VEGF Trap Therapy on Laboratory Correlates	Up to 5 years