A Randomized Phase II Trial of Carboplatin, Paclitaxel, Bevacizumab, With or Without Everolimus for Therapy of Metastatic Malignant Melanoma
A Randomized Phase II Trial of Carboplatin, Paclitaxel, Bevacizumab, With or Without Everolimus for Therapy of Metastatic Malignant Melanoma
This randomized phase II trial is studying how well carboplatin, paclitaxel, and bevacizumab work when given with or without everolimus in treating patients with malignant melanoma that has spread from where it started to other places in the body. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, may block the ability of tumor cells to grow and spread. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It is not yet known whether combination chemotherapy given together with bevacizumab is more effective with or without everolimus in treating patients with metastatic melanoma.
OBJECTIVES:
Primary
Secondary
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.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive bevacizumab intravenously (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 everolimus orally (PO) once daily (QD) 3 times weekly. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3-6 months for up to 5 years.
Inclusion Criteria:
Exclusion Criteria
Prior treatment with agents disrupting vascular endothelial growth factor (VEGF) activity (i.e., bevacizumab, VEGF-trap, anti-VEGF receptor [R] monoclonal antibody [Mab]) or targeting VEGFR (e.g. sunitinib, sorafenib)
Prior treatment with an mTOR inhibitor for melanoma (sirolimus, temsirolimus, everolimus)
Brain metastases per MRI or CT at any time prior to registration; note: patients that have had primary therapy for brain metastasis (i.e. surgical resection, whole brain radiation, or stereotactic radiation therapy [SRT] even if stable) are not eligible
Other investigational agents =< 4 weeks prior to registration/randomization
Chemotherapy treatment =< 3 weeks prior to registration/randomization
Any biologic, immunologic or targeted therapy =< 2 weeks prior to registration/randomization
Major surgical procedure, open biopsy, or significant traumatic injury =< 4 weeks prior to registration/randomization
Fine needle aspirations or core biopsies =< 7 days prior to registration/randomization
Planned/or anticipated major surgical procedure during the course of the study
Other medical conditions including but not limited to:
Any of the following as this regimen may be harmful to a developing fetus or nursing child:
Existence of peripheral sensory neuropathy >= grade 2
History of other malignancy =< 5 years with the exception of basal cell or squamous cell carcinoma of the skin, treated with local resection only, or carcinoma in situ (e.g. of the cervix, breast, prostate, etc.)
=< 4 weeks since last day of adjuvant radiation therapy prior to registration or =< 2 weeks since last day of palliative radiation therapy; NOTE: patients who have had > 25% of their functional bone marrow irradiated are not eligible for this trial
Active or recent history of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) =< 30 days prior to registration
Known hypersensitivity to any of the components of the everolimus, bevacizumab, carboplatin, or paclitaxel
Current use of drugs that are known to be strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4); note: if these agents are discontinued, everolimus therapy can begin >= 7 days after discontinuation of such agent
Positive hepatitis B antigen (HBsAg) or hepatitis C serology (HCV) tests
Planned immunization with attenuated live vaccines =< 7 days prior to registration or during study period; note: close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus; examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guérin (BCG), yellow fever, varicella and TY21a typhoid vaccines
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