A Randomized Phase II Study of Sequential Biotherapy With Aflibercept and High Dose IL-2 Versus High Dose IL-2 Alone in Patients With Inoperable Stage III or Stage IV Melanoma: Efficacy and Biomarker Study

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed metastatic melanoma,
including:

- AJCC stage IV or advanced/inoperable stage III

- Patients with a history of lower-stage melanoma and subsequent recurrent
metastatic disease that is either locally/regionally advanced/inoperable disease
or distant metastases allowed

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >
10 mm with CT scan or clinically (must be measurable with calipers) according to
RECIST version 1.1

- Patients must be free of brain metastasis by contrast-enhanced CT/MRI scans within 4
weeks prior to enrollment

- If known to have prior brain metastases, must not have evidence of active brain
disease after definitive therapy (surgery, radiation therapy, or stereotactic
radiosurgery) on two successive MRI evaluations at least 3 months apart(one of
which is ≤ 4 weeks prior to starting the study drugs)

- ECOG performance status 0 or 1 (Karnofsky > 70%)

- Life expectancy of greater than 3 months, in the opinion of the investigator

- Leukocytes ≥ 3,000/mcL

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Total bilirubin within 1.5 x institutional upper limit of normal

- AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal

- Creatinine within 1.5 x institutional upper limit of normal OR creatinine clearance ≥
60 mL/min

- Urine protein creatinine ratio (UPCR) ≤ 1 (for UPCR > 1, a 24-hour urine protein
should be obtained and the level should be < 500 mg)

- No PT INR > 1.5 unless the patient is on full-dose warfarin

- Patients on full-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 are
eligible provided that both of the following criteria are met:

- The patient has an in-range INR (usually between 2 and 3) on a stable dose
of oral anticoagulant or on a stable dose of low molecular weight heparin

- The patient has no active bleeding or pathological condition that carries a
high risk of bleeding (e.g., tumor involving major vessels or known
varices)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry, for the duration of study participation,
and for at least 6 months after completion of study therapy

- FEV 1 > 2.0 liters or > 75% of predicted for height and age

- PFTs are required for patients over 50 years old or with significant pulmonary
or smoking history

- No evidence of congestive heart failure, symptoms of coronary artery disease,
myocardial infarction less than 6 months prior to entry, or serious cardiac
arrhythmias

- Patients who are over 40 years old or have had previous myocardial infarction
greater than 6 months prior to study entry or have significant cardiac family
history(CAD or serious arrhythmias) will be required to have a negative or low
probability cardiac stress test (for example, thallium stress test, stress MUGA,
stress echo, or exercise stress test) for cardiac ischemia within 8 weeks prior
to registration

- An echocardiogram should be performed at baseline in all patients and ejection
fraction (EF) from baseline echocardiogram must be within the institutional
limits of normal as determined by the reading cardiologist

- If the baseline cardiac stress test incorporates an echocardiogram, then this
will not need to be done again at baseline

- No patients with clinically significant cardiovascular or cerebrovascular disease:

- History of cerebrovascular accident or transient ischemic attacks within the
past 6 months

- Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg or systolic
BP > 180 mm Hg if diastolic blood pressure < 90 mm Hg, on at least 2 repeated
determinations on separate days within past 3 months

- CABG within the past 6 months

- New York Heart Association grade III or greater congestive heart failure,
serious cardiac arrhythmia requiring medication, or unstable angina pectoris
within past 6 months

- Clinically significant peripheral vascular disease within past 6 months

- Pulmonary embolism, DVT, or other thromboembolic event within past 6 months

- No history of tumor-related or other serious hemorrhage, bleeding diathesis, or
underlying coagulopathy

- Patient who have received prior anti-CTLA4 monoclonal antibody therapy (ipilimumab or
tremelimumab) AND who have a history of colitis or diarrhea during anti-CTLA4
monoclonal antibody therapy should have a formal evaluation by a gastroenterologist
and a colonoscopy should be considered to demonstrate the absence of active bowel
inflammation

- No serious or non-healing wound, ulcer, or bone fracture

- No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 28 days of treatment

- No significant traumatic injury within 28 days prior to day 1 of treatment

- Patients who have other current malignancies are not eligible

- Patients with other malignancies are eligible if they have been continuously
disease free for > 5 years prior to the time of randomization

- Patients with history at any time of any in situ cancer, lobular carcinoma of
the breast in situ, cervical cancer in situ, atypical melanocytic hyperplasia,
or melanoma in situ are eligible

- Patients with a history of basal cell or squamous cell skin cancer are eligible

- Patients who have had multiple primary melanomas are eligible

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements

- HIV-positive patients on combination antiretroviral therapy are ineligible

- Patients must not have autoimmune disorders or conditions of immunosuppression that
require current ongoing treatment with systemic corticosteroids (or other systemic
immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or
continuous use of topical steroid creams or ointments or ophthalmologic steroids or
steroid inhalers

- No patients with known hypersensitivity to Chinese hamster ovary cell products or
other recombinant human antibodies or with a history of allergic reactions attributed
to compounds of similar chemical or biologic composition to other agents used in the
study

- No anticipation of need for major surgical procedures during the course of the study

- No prior therapy with bevacizumab, aflibercept, or aldesleukin

- A patient may be treatment naive

- Up to two prior regimens for metastatic melanoma are allowed

- Prior adjuvant IFN-α is allowed

- Patients must not have received systemic therapy, radiotherapy, or chemotherapy
within the preceding 4 weeks (6 weeks for nitrosoureas or mitomycin C) and patients
must have recovered from adverse events due to agents administered more than 4 weeks
earlier

- Patients must be at least 4 weeks from major surgery or open biopsy and have fully
recovered from any effects of surgery and be free of significant detectable infection

- At least 2 weeks must have passed since the last dose of steroids

- No minor surgical procedures, fine-needle aspirations, or core biopsies within 7 days
prior to day 1 of therapy

- Central venous catheter placements are permitted to be completed 7 or more days
prior to day 1 of therapy

- Peripherally inserted central catheter (PICC or PIC line) may be placed at any
time prior to or during therapy

- Patients may not be receiving any other investigational agents