Carboplatin, Paclitaxel, and Bevacizumab With or Without Everolimus in Treating Patients With Metastatic Malignant Melanoma
Condition: Melanoma (Skin)
MeSH terms: Melanoma
Intervention: bevacizumab; carboplatin; everolimus; paclitaxel
Intervention description: Given IV; Given IV; Given orally; Given IV
Intervention MeSH terms: Paclitaxel; Bevacizumab; Carboplatin; Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 149.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Stage IV Skin Melanoma; recurrent melanoma

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologic proof of stage IV malignant melanoma not amenable to surgery; (biopsy can
             be of locoregional disease in setting of clinically evident stage IV disease, but
             primary tumor alone will not qualify)

          -  At most one prior chemotherapy based regimen for metastatic melanoma (no prior
             taxane-based regimens allowed); note: prior adjuvant non-taxane based chemotherapy
             and/or adjuvant immunotherapy are allowed; no limit on the number of prior biologic,
             immunologic or targeted therapies

          -  Measurable disease defined as at least one lesion whose longest diameter can be
             accurately measured as >= 2.0 cm with chest x-ray, or as >= 1.0 cm with computed
             tomography (CT) scan, CT component of a positron emission tomography (PET)/CT, or
             magnetic resonance imaging (MRI) scan; note: disease that is measurable by physical
             examination only is not eligible

          -  Life expectancy >= 4 months

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

          -  Absolute neutrophil count (ANC) >= 1500/mL

          -  Platelets (PLT) >= 100,000 x 10^9/L

          -  Hemoglobin (Hgb) >= 9 g/dL (patients may be transfused to meet this requirement)

          -  Total cholesterol =< 300 mg/dL and; (note: serum levels of cholesterol or
             triglycerides found to be elevated may be lowered with anti-lipid therapy, but must be
             documented to be below these levels prior to enrollment)

          -  Triglycerides =< 2.5 X upper limit of normal (ULN); (note: serum levels of cholesterol
             or triglycerides found to be elevated may be lowered with anti-lipid therapy, but must
             be documented to be below these levels prior to enrollment)

          -  Creatinine =< 1.5 x ULN

          -  Total bilirubin =< 1.5 mg/dL (exception: patients with documented Gilbert's syndrome
             are allowed to participate despite elevated bilirubin)

          -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =<
             2.5 x ULN

          -  Alkaline phosphatase =< 2.5 x ULN

          -  Urine protein:creatinine (UPC) ratio < 1.0 at screening OR

          -  Urine dipstick for proteinuria < 2+ (patients discovered to have >= 2+ proteinuria on
             dipstick urinalysis at baseline should undergo a 24 hour urine collection and must
             demonstrate =< 1 g of protein in 24 hours to be eligible)

          -  Negative pregnancy test done =< 7 days prior to registration/randomization, for women
             of childbearing potential only

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Willing to return to a North Central Cancer Treatment Group (NCCTG) institution for
             follow-up

          -  Willing to provide mandatory blood samples for research purposes

          -  Willing to follow a diet low in fat and cholesterol while taking everolimus

          -  Willing to abstain from eating grapefruit or drinking grapefruit juice for the
             duration of the study

        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:

               -  History of liver disease such as cirrhosis, chronic active hepatitis, chronic
                  persistent hepatitis or hepatitis B or C

               -  Active infection requiring parenteral antibiotics

               -  Poorly controlled high blood pressure (>=150 mm Hg systolic and/or 100 mmHg
                  diastolic) despite treatment

               -  New York Heart Association class II-IV congestive heart failure

               -  Serious cardiac arrhythmia requiring medication

               -  Myocardial infarction or unstable angina =< 6 months prior to
                  registration/randomization

               -  Clinically significant peripheral vascular disease

               -  Deep venous thrombosis or pulmonary embolus =< 1 year of
                  registration/randomization and/or ongoing need for full-dose oral or parenteral
                  anticoagulation

               -  Ongoing anti-platelet treatment other than low-dose aspirin (i.e., aspirin 81 mg
                  orally [p.o.] daily)

               -  Active bleeding or pathological conditions that carry high risk of bleeding
                  (e.g., known esophageal varices, etc.)

               -  Serious, non-healing wound (including wounds healing by secondary intention),
                  ulcer or bone fracture

               -  History of abdominal fistula, gastrointestinal perforation or intra-abdominal
                  abscess =< 6 months prior to registration/randomization

               -  History of central nervous system (CNS) disease (e.g., primary brain tumor,
                  vascular abnormalities, etc.), clinically significant stroke or transient
                  ischemic attack (TIA) =< 6 months prior to registration/randomization, seizures
                  not controlled with standard medical therapy

               -  Radiographically documented tumor invading major blood vessels

               -  History of hypertensive crisis or hypertensive encephalopathy

               -  Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN

               -  Severely impaired lung function as defined as spirometry and diffusing capacity
                  of the lung for carbon monoxide (DLCO) that is 50% of the normal predicted value
                  and/or 02 saturation that is 88% or less at rest on room air

               -  A known history of human immunodeficiency virus (HIV) seropositivity

          -  Any of the following as this regimen may be harmful to a developing fetus or nursing
             child:

               -  Pregnant women

               -  Nursing women

               -  Men and women of reproductive potential who are not using effective birth control
                  methods must use highly effective contraception throughout the trail and for 6
                  months after last study treatment

          -  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