A Randomized Phase II Trial of Carboplatin, Paclitaxel, Bevacizumab, With or Without Everolimus for Therapy of Metastatic Malignant Melanoma

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically* confirmed malignant melanoma

- Stage IV disease

- Not amenable to surgery

- NOTE: *Biopsy may be of locoregional disease in the setting of clinically evident
stage IV disease, but primary tumor alone will not qualify

- Measurable disease, defined as ≥ 1 lesion whose longest diameter can be accurately
measured as ≥ 2.0 cm by chest x-ray OR as ≥ 1.0 cm by CT scan, CT component of a
PET/CT scan, or MRI scan

- No disease measurable by physical examination only

- No radiographically documented tumor invading major blood vessels

- No primary brain tumor or brain metastases by MRI or CT scan

- Patients who have had primary therapy for brain metastases (e.g., surgical
resection, whole brain radiotherapy, or stereotactic radiotherapy) are not
eligible, even if the metastases are stable

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Life expectancy ≥ 4 months

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 9 g/dL (transfusion allowed)

- Total cholesterol ≤ 300 mg/dL AND triglycerides ≤ 2.5 times upper limit of normal
(ULN)

- Anti-lipid therapy to lower elevated serum levels of cholesterol or
triglycerides allowed

- Total bilirubin ≤ 1.5 mg/dL (elevated bilirubin levels allowed in patients with
documented Gilbert's syndrome)

- SGOT ≤ 2.5 times ULN

- Alkaline phosphatase ≤ 2.5 times ULN

- Creatinine ≤ 1.5 times ULN

- Urine protein:creatinine ratio < 1.0 OR proteinuria < 2+ by urine dipstick OR ≤ 1g of
protein by 24-hour urine collection

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 8 weeks after
completion of study therapy

- Hormonal contraceptives are not acceptable as a sole method of contraception

- Willing to provide mandatory blood samples for research purposes

- Willing to follow a diet low in fat and cholesterol while taking everolimus

- No other medical condition including, but not limited to, the following:

- History of liver disease (e.g., cirrhosis, chronic active hepatitis, chronic
persistent hepatitis, or hepatitis B or C [positive hepatitis B antigen or
hepatitis C serology])

- Active infection requiring parenteral antibiotics

- Poorly controlled high BP (i.e., systolic BP ≥ 150 mm Hg and/or diastolic BP ≥
100 mm Hg) despite treatment

- NYHA class II-IV congestive heart failure

- Serious cardiac arrhythmia requiring medication

- Myocardial infarction or unstable angina within the past 6 months

- Clinically significant peripheral vascular disease

- Deep venous thrombosis or pulmonary embolus within the past year

- Active bleeding or pathological condition that carries a high risk of bleeding
(e.g., known esophageal varices)

- Serious, non-healing wound (including wounds healing by secondary intention),
ulcer, or bone fracture

- Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within the past 6 months

- History of CNS disease (e.g., vascular abnormalities), clinically significant
stroke or TIA within the past 6 months, or seizures not controlled with standard
medical therapy

- History of hypertensive crisis or hypertensive encephalopathy

- Uncontrolled diabetes, defined as fasting serum glucose > 1.5 times ULN

- Severely impaired lung function, defined as DLCO that is 50% of the normal
predicted value and/or 0_2 saturation ≤ 88% at rest on room air

- Known history of HIV seropositivity

- No peripheral sensory neuropathy ≥ grade 2

- No other malignancy within the past 5 years except basal cell or squamous cell
carcinoma of the skin treated with local resection or curatively treated carcinoma in
situ (e.g., of the cervix, breast, prostate, etc.)

- No active hemoptysis (≥ ½ teaspoon of bright red blood per episode) within the past
30 days

- No significant traumatic injury within the past 4 weeks

- No known hypersensitivity to any of the components of everolimus, bevacizumab,
carboplatin, or paclitaxel

PRIOR CONCURRENT THERAPY:

- No more than one prior chemotherapy-based regimen for metastatic melanoma

- No prior taxane-based regimens

- Prior adjuvant non-taxane-based chemotherapy and/or adjuvant immunotherapy
allowed

- Any number of prior biologic, immunologic, or targeted therapies allowed

- More than 2 weeks since any prior biologic, immunologic, or targeted
therapies

- More than 3 weeks since prior chemotherapy

- At least 7 days since prior and no concurrent drugs that are known to be strong
inhibitors or inducers of CYP3A4

- More than 4 weeks since prior investigational agents

- More than 4 weeks since prior major surgical procedure or open biopsy

- More than 7 days since prior fine needle aspiration or core biopsy

- More than 4 weeks since prior adjuvant radiotherapy

- More than 2 weeks since prior palliative radiotherapy

- No prior radiotherapy to > 25% of the functioning bone marrow

- No prior treatment with agents disrupting VEGF activity (e.g., bevacizumab,
aflibercept, or anti-VEGFR monoclonal antibody) or targeting VEGFR (e.g., sunitinib
malate or sorafenib tosylate)

- No prior mTOR inhibitors (e.g., sirolimus, temsirolimus, or everolimus) for melanoma

- No concurrent major surgical procedure

- No concurrent anti-platelet therapy other than low-dose aspirin (i.e., 81 mg of
aspirin 81 daily)

- No concurrent full-dose oral or parenteral anticoagulation or prophylactic
anticoagulation

- No concurrent grapefruit or grapefruit juice

- No concurrent radiotherapy

- No other concurrent chemotherapy

- No concurrent enrollment in another clinical trial involving investigational
procedures or agents to treat the primary malignancy

- No planned immunization with attenuated live vaccines ≤ 7 days