CTLA-4 Blockade and Low Dose Cyclophosphamide in Patients With Advanced Malignant Melanoma

Inclusion Criteria: 1. Men \& women, ages ≥18 2. Willing/able to give written informed consent. 3. Histologic diagnosis of unresectable AJCC Stage III/IV malignant melanoma 4. At least 2wks must have elapsed since last chemotherapy, immunotherapy, hormonal therapy, radiotherapy or major surgery \& beginning of protocol therapy. At least 6wks for nitrosoureas, mitomycin C, \& liposomal doxorubicin 5. Toxicity related to prior therapy must either have returned to ≤ grade 1 or baseline. 6. Two punch tumor biopsy at Screening and Wk12 (4mm diameter) must be provided for immune analysis/staining if patients have accessible disease. Biopsies are optional during the Maintenance Period.Site of tumor biopsy s/n be only site of measurable disease. Minimum of 5 out of 1st 10 patients in stage I of the protocol must have biopsy accessible disease. 7. Patients must have measurable disease defined as @ least 1 lesion that can be accurately measured in @ least 1 dimension (longest diameter to be recorded) as \>20 mm with conventional techniques or as \>10 mm with spiral CT scan. 8. Required values for initial laboratory tests: 1. WBC ≥ 2000/uL 2. ANC ≥ 1000/uL 3. Platelets ≥ 50 x 103/uL 4. Hemoglobin ≥ 9.5 g/dL 5. Creatinine ≤ 3.0 x ULN 6. AST/ALT ≤ 2.5 x ULN for patients without liver metastasis, ≤ 5 x ULN for patients with liver metastasis 7. Bilirubin ≤ 3.0 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL) 9. Life expectancy of at least 4mos 10. Patients w/stable, treated central nervous system (CNS) metastasis are eligible 11. ECOG Performance Status Score 0-1 12. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout study \& for up to 26wks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal. Post-menopause is defined as: * Amenorrhea ≥ 12 consecutive months w/o another cause, or * For women with irregular menstrual periods and taking hormone replacement therapy (HRT), documented serum follicle-stimulating hormone (FSH) level ≥ 35 mIU/mL. * Women who are using oral contraceptives, other hormonal contraceptives (vaginal products/skin patches/implanted/injectable products), mechanical products such as an intrauterine device or barrier methods (diaphragm/condoms/ spermicides) to prevent pregnancy,are practicing abstinence or where their partner is sterile (eg vasectomy) should be considered to be of childbearing potential. * WOCBP must have a negative urine or serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) w/in 72hrs before the start of ipilimumab. 13. Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study \[and up to 26wks after last dose of investigational product\] in a way that risk of pregnancy is minimized. Exclusion Criteria: 1. Any other malignancy from which patient has been disease-free for less than 5yrs, with the exception of adequately treated \& cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix. 2. Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (eg rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[eg Wegener's Granulomatosis\]); motor neuropathy considered of autoimmune origin (eg Guillain-Barre Syndrome and Myasthenia Gravis). 3. Any underlying medical or psychiatric condition, which in the opinion of investigator will make administration of ipilimumab hazardous or obscure interpretation of AEs, like a condition associated with frequent diarrhea. 4. Uncontrolled or significant cardiovascular disease 5. Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1mo before/after any dose of ipilimumab). 6. History of prior treatment with ipilimumab or prior CD137 agonist or CTLA 4 inhibitor or agonist. 7. Concomitant therapy with any of following: IL 2, interferon, other non-study immunotherapy regimens; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids (\>60mg prednisone/day). 8. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg infectious) illness. 9. Women of childbearing potential (WOCBP), defined above who: 1. are unwilling/unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 26wks after cessation of study drug, or 2. have a positive pregnancy test at baseline, or 3. are pregnant or breastfeeding. 10. Persons of reproductive potential who are unwilling to use an adequate method of contraception throughout treatment \& for at least 26wks after ipilimumab is stopped.