The purpose of this research study is to test an experimental combination of drugs to determine if they can cause shrinkage or even complete disappearance of your melanoma. The two drugs being tested in combination are Rituxan and Abraxane

Rituxan and Abraxane are approved for the treatment of other cancers, but not for melanoma. Candidates for this study have melanoma that has spread to their lymph nodes or internal organs and that cannot be removed by a surgical procedure.

The safety of this combination of drugs will also be looked at throughout this study.

Rituxan will be administered IV at weeks 1 and 3 of each cycle. Abraxane will be administered IV weekly for 3 consecutive weeks. This is followed by 1 week of rest after which, the cycle is repeated. Following the second cycle, there will be a 4-week period of rest. Evaluation of response will occur on day 71 +/-3 days. If either disease stabilization or clear evidence of clinical response is observed two additional cycles of treatment will be administered. Lesions will be measured on the scan (CT or PET/CT), x-ray

Inclusion Criteria:

• Patients must have inoperable stage III and IV melanoma.

Patients will be included in the trial based on the following criteria:

Patients previously treated with no more than 1 non-abraxane containing chemotherapy regimen or patients with the B-Raf mutation, who have received vemurafenib or the combination of Dabrafinib and trametinib (or similar compound on clinical trial) and progressed, who have documented surgically inoperable stage III or IV metastatic melanoma on pathologic examination of tissue. Previous treatment with immunotherapy is allowed. Patients who have been treated with either immunotherapy or chemotherapy must have be either 4 weeks from their last treatment or have fully recovered from all previous treatment.

Measurable or evaluable non-CNS disease required as defined:

• Uni-dimensionally measurable lesion as determined by physical exam, X-ray, CT scan, MRI, or other radiographic procedure.
• Lesion that can be seen on a radiologic test but is not uni-dimensionally measurable
• Previously irradiated lesion allowed only with documentation of progression if no other metastatic site present.

No active brain metastases Patients with previously treated brain metastases that have responded to therapy will be allowed on study assuming there is measurable disease outside of the CNS. Active therapy for the CNS disease must be completed a minimum of 3 weeks for chemotherapy and 6 weeks for radiation therapy (prior to enrollment on this study).

Prior/ Concurrent therapy

Biologic therapy No concurrent biological therapy with the exception of growth factors for anemia, neutropenia or thrombocytopenia.

Chemotherapy No greater than 1 previous non-abraxane containing chemotherapy treatment allowed

Radiotherapy At least 6 weeks since completion of radiotherapy

Patient characteristics Age and ability to give informed consent Patients must be 18 years of age or older. Patients must have the ability to give informed consent.

Performance status ECOG 0-2 Life expectancy of at least 3 months

General Medical Concerns:

• Normal organ function, except if abnormal due to tumor involvement.
• Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months after completion of treatment.
• Subject has provided written informed consent.

Rituximab-Specific Concerns:

• ANC: > 1200/mm3
• Platelets: > 100,000/mm3
• Hemoglobin: > 9 gm/dL
• Adequate renal function as indicated by serum creatinine measurement < 1.5 x the upper limit of normal or GFR > 50 ml/min.
• Adequate liver function, as indicated by bilirubin < 3.0
• AST or ALT <2x Upper Limit of Normal unless related to primary disease.
• AST or ALT <5x Upper limit of Normal if evidence of liver metastasis.

Exclusion Criteria:

• Life expectancy less than 3 months

Untreated brain metastasis

Previous treatment with Abraxane containing regimen