Bevacizumab With or Without Interferon Alfa in Treating Patients With Metastatic Malignant Melanoma

Study Overview
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Brief Summary
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This randomized phase II trial is studying giving bevacizumab together with interferon alpha to see how well it works compared to giving bevacizumab alone in treating patients with metastatic malignant melanoma. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or deliver cancer-killing substances to them. Interferon alpha may interfere with the growth of the cancer cells and slow the growth of the tumor. Combining bevacizumab with interferon alpha may kill more tumor cells.

Detailed Description
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OBJECTIVES: I. Compare the objective response rate and progression-free survival in patients with metastatic malignant melanoma treated with bevacizumab with or without low- or high-dose interferon alpha. OUTLINE: This is a randomized study. Patients are randomized to 1 of 3 treatment arms. ARM I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1. Patients also receive low-dose interferon alpha (IFN-alpha) subcutaneously (SC) on days 1-14. ARM II: Patients receive bevacizumab as in arm I. ARM III: Patients receive bevacizumab as in arm I. Patients also receive high-dose IFN-alpha SC on days 1, 3, 5, 8, 10, and 12. In all arms, treatment repeats every 14 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients undergo restaging at the completion of course 12. Patients with stable disease or a clinical response may continue treatment according to their assigned treatment arm for up to 1 year. Patients with stable disease after 1 year of treatment with bevacizumab and IFN-alpha (arms I and III) may continue to receive bevacizumab alone every 21 days (as in arm II) in the absence of disease progression. Patients are followed every 3 months for 2 years.

Official Title
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A Phase 2 Study of Bevacizumab and Interferon-Alpha-2b in Metastatic Malignant Melanoma

Conditions
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Recurrent Melanoma, Stage IV Skin Melanoma

Intervention / Treatment
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* Biological: Recombinant Interferon Alfa
* Biological: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed cutaneous malignant melanoma Must meet one of the following criteria: Clinical evidence of metastatic disease Unresectable regional lymphatic disease Extensive in transit recurrent disease Measurable disease At least 20 mm by conventional techniques OR at least 10 mm by spiral computed tomography (CT) scan No known brain metastases No ocular melanoma Performance status - Eastern Cooperative Oncology Group (ECOG) 0-2 Performance status - Karnofsky 60-100% More than 6 months White blood cells (WBC) at least 3,000/mm^3 Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 No clinical evidence of coagulopathy Bilirubin =< 2.0 mg/dL (3.0 mg/dL for patients with Gilbert's disease provided patient is stable and asymptomatic) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) no greater than 2.5 times upper limit of normal (ULN) Prothrombin time (PT)/International normalized ratio (INR) less than 1.5 Creatinine =< 1.5 mg/dL Creatinine clearance at least 60 mL/min Protein < 1,000 mg on 24-hour urine collection for patients with proteinuria >= 1+ No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No history of thrombosis (e.g., deep vein thrombosis), unless the following criteria are met: INR in normal range (usually 2-3) AND on a stable dose of warfarin or low molecular weight heparin No active bleeding or pathologic condition that would confer a high risk of bleeding (e.g., known varices or tumor involving major vessels) No uncontrolled hypertension Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior allergic reactions to compounds of similar chemical or biologic composition to bevacizumab or interferon alfa No ongoing or active infection No other concurrent uncontrolled illness No psychiatric illness or social situation that would preclude study compliance Human immunodeficiency virus (HIV) allowed provided otherwise well At least 4 weeks since prior adjuvant interferon alfa No prior interferon alfa for metastatic disease No prior cytokine therapy for metastatic disease (e.g., high-dose interleukin-2 [IL-2]) Prior IL-2 allowed for patients randomized to arm III only No prior investigational antiangiogenic agents No more than 1 prior chemotherapy regimen for metastatic disease At least 4 weeks since prior chemotherapy and recovered At least 4 weeks since prior radiotherapy and recovered No other concurrent investigational agents

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (monoclonal antibody and biological therapy)<br>Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive low-dose interferon alfa (IFN-alpha) SC on days 1-14. | Biological: Recombinant Interferon Alfa<br>* Given SC<br>* Other names: IFN-A;Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;|
| Experimental: Arm II (monoclonal antibody)<br>Patients receive bevacizumab as in arm I. | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;|
| Experimental: Arm III (monoclonal antibody and biological therapy)<br>Patients receive bevacizumab as in arm I. Patients also receive high-dose IFN-alpha SC on days 1, 3, 5, 8, 10, and 12. | Biological: Recombinant Interferon Alfa<br>* Given SC<br>* Other names: IFN-A;Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. Evaluated using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by 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 (OR) = CR + PR. | Up to 2 years | 
| Progression-free Survival | Defined as the time from treatment start date until documentation of progressive disease. Evaluated using the new international criteria proposed by the RECIST Committee. 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 | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Plasma Levels of VEGF Following Administration of Bevacizumab Alone or in Combination With IFN-alfa | Analyzed by Enzyme-Linked Immunosorbent Assay (ELISA).VEGF only analyzed at baseline. | At baseline | 
| New Vessel Formation in Patient Tumor Samples | Evaluated using immunohistochemistry. | Up to 2 years |