Doxycycline, Temozolomide and Ipilimumab in Melanoma

Inclusion Criteria:

1. Patient must be age >/= 18 years.
2. Patients must have histologically or cytologically confirmed diagnosis of malignant (unresectable Stage III or Stage IV) melanoma, not amenable to resection with curative intent.
3. Patients must have metastatic melanoma which has >25% of melanoma cells stained positive for iNOS expression by CLIA-certified immunohistochemistry assay. However, in phase I portion of the study, the requirement of >25% of melanoma cells stained positive for iNOS expression does not apply.
4. Patients must be at least 21 days since surgery, radiation therapy and 6 weeks after immunotherapy with regimens including vaccines, interferon, IL-2, etc. and fully recovered from adverse effects of these therapies.
5. Patients must have evaluable disease for response.
6. There is no limit on the number of prior therapies for Phase I portion. For Phase II portion only, patients may have received less than or equal to 1 prior chemotherapy regimen for metastatic melanoma. There is no limit on prior immunotherapies or kinase inhibitors. Patients with prior ipilimumab therapy will be excluded during the phase II portion.
7. Patient must have an ECOG performance status of 0 or1.
8. Patient must have adequate liver and renal function as documented by the following laboratory test results within 14 days prior to starting therapy: • total bilirubin less than or equal to 1.5 x upper limit of normal (ULN); • AST (SGOT) and ALT (SGPT) less than or equal to 2.5 X ULN or less than or equal to 5 X ULN if liver metastasis is present; • serum creatinine less than or equal to 1.2 X ULN
9. Patient must have adequate bone marrow function as documented by the following laboratory test results within 14 days prior to starting therapy: • platelets greater than 100,000/mm3; • absolute neutrophil count (ANC) greater than 1500/mm3; • hemoglobin greater than 9.0 g/dL;
10. Patient must have completed any prior chemotherapy, immunotherapy, radiation therapy, biological therapy, or other investigational cancer therapy at least 4 weeks prior to starting the study drug(s) and must have recovered from all acute side effects (to CTCAE less than Grade 1) prior to initiation of the study drug(s). Patients who were receiving mitomycin C or nitrosoureas must be 6 weeks from the last administration of chemotherapy. For a prior BRAF inhibitor, the washout period is 7 days.
11. Patient (man or woman) must agree to practice effective contraception during the entire study period, unless documentation of infertility exists, and for at least 4 weeks after the last dose of the study drug(s).
12. Patient must be willing and able to sign the informed consent form.
13. Patient must be willing and able to self-administer orally and document all doses of doxycycline ingested.
14. Patients must be willing to have iNOS expression assay test done on disease easily amenable to biopsy or suitable tissue obtained within the last 3 months.

Exclusion Criteria:

1. Patients who have received doxycycline or other tetracycline-analogs within the 4 weeks prior to the first dose of the study drug.
2. For Phase II portion only, patients with a diagnosis of ocular melanoma will be excluded.
3. Patients with an inability to swallow tablets or capsules.
4. Patients with a symptomatic malabsorptive disorder (eg, Crohn's Disease) or removal of either the terminal ileus or more than 2/3 of the small intestine.
5. Patients with active brain metastases or primary central nervous system (CNS) malignancies; patients with previously treated brain metastasis may be included, provided that no requirement for steroids and no evidence of progression for greater than or equal to 8 weeks after a local brain treatment.
6. Patients with an active second malignancy.
7. Patients who are pregnant or breastfeeding.
8. Patients with clinically significant illnesses which could compromise participation in the study, including, but not limited to:uncontrolled diabetes;active or uncontrolled infection; acute or chronic liver disease (i.e., hepatitis, cirrhosis);confirmed diagnosis of HIV infection; or, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, or uncontrolled cardiac arrhythmia.
9. Patients with history of autoimmune disease.