- To assess whether there is sufficient promise of an impact of the addition of everolimus to the combination of carboplatin, paclitaxel, and bevacizumab on progression-free survival that it would be recommended for further testing in patients with metastatic malignant melanoma.
- Estimate the confirmed tumor response rate in patients treated with carboplatin, paclitaxel, and bevacizumab with or without everolimus.
- Estimate the distribution of overall survival time in patients treated with these regimens.
- Assess the safety profile of these regimens in these patients.
- Examine the impact of therapy on angiogenesis and immune homeostasis.
- Assess common genetic variants in mTOR and associated genes that may impact response to therapy.
- Collect circulating tumor cells in a valid and reproducible way and assess target marker expression using immunofluorescence and reverse transcriptase-PCR.
OUTLINE: This is a multicenter study. Patients are stratified according to elevated LDH (above upper limit of normal) at baseline (yes vs no), location of metastatic disease (M1a [skin, subcutaneous tissue, or lymph node only] vs M1b [lung] vs M1c [other visceral sites]) and prior chemotherapy for metastatic disease (yes vs no). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, paclitaxel IV over 60 minutes on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
- Arm II: Patients receive bevacizumab, paclitaxel, and carboplatin as in arm I. Patients also receive oral everolimus on 3 days a week. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Blood samples are collected at baseline and periodically during study for analysis of plasma VEGF levels by ELISA; changes in immune homeostasis by immunophenotyping, tetramer assay, and ELISPOT assay; and analysis of genetic variants in mTOR and associated genes by polymorphism studies.
After completion of study therapy, patients are followed up every 3-6 months for up to 5 years.
- 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
- 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
Last updated: 02/21/2013