Doxycycline, Temozolomide and Ipilimumab in Melanoma

Study Groups: If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Up to 5 groups of 3-6 participants will be enrolled in the Phase I portion of the study, and up to 28 participants will be enrolled in Phase II. If you are enrolled in the Phase I portion, the dose of doxycycline you receive will depend on when you joined this study. The first group of participants will receive the lowest dose level of doxycycline. Each new group will receive a higher dose of doxycycline than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of doxycycline is found. If you are enrolled in the Phase II portion, you will receive doxycycline at the highest or most clinically active dose that was tolerated in the Phase I portion. All participants will receive the same dose level of temozolomide and ipilimumab. Study Drug Administration: You will start taking doxycycline on Day -6 of Cycle 1 (1 week before Day 1 of Cycle 1 starts) by mouth 2 times a day by itself for 1 week. You should fast (not eat or drink anything but water) for at least 2 hours before and 1 hour after you take the study drug. After that, on Day 1 of Cycle 1, you will start taking the combination of temozolomide and ipilimumab. You will receive ipilimumab by vein over 90 minutes every 3 weeks. On Day 1 of Cycle 1, you will start taking temozolomide by mouth with about 1 cup (8 ounces) of water on Days 1-4 of each cycle. You should fast for at least 2 hours before and 2 hours after you take the study drug. You will continue taking doxycycline by mouth 2 times a day throughout the study. Each study cycle is 3 weeks except the first cycle, which is 4 weeks. This is because it includes 1 week of doxycycline given by itself. You will be given a study drug diary to record the times and doses that you take the study drugs. You should bring the diary to each study visit. You should also bring any leftover study drug with you to each study visit. Study visits: At every study visit, you will be asked about any drugs you may be taking, how you are feeling, and if you have had any side effects. On Day -6 of Cycle 1: * You will have a physical exam if not done in the past 8 days. * Your weight and vital signs will be measured. * Your performance status will be recorded. * Blood (about 1 tablespoon) will be drawn for routine tests if this was not done in the past 8 days. * Blood (about 4 tablespoons) will be drawn for biomarker testing. Biomarkers are found in the blood and tissue and may be related to your reaction to the study drugs. On Day 1 of Cycles 1 and 2: * You will have a physical exam, including measurement of your weight and vital signs. * Your performance status will be recorded. * Blood (about 5 tablespoons) will be drawn for routine tests and biomarker testing. * You will have an ECG. * On Day 1 of Cycle 1, if you are in Phase II of the study, you will have a tumor biopsy performed to test if doxycycline is able to block the iNOS protein. This biopsy is optional if you are in Phase I. On Day 8 of Cycle 1, if you are in Phase I: * Blood (about 5 tablespoons) will be drawn for routine tests and biomarker testing. * Your vital signs will be measured. * Your performance status will be recorded. On Day 15 of Cycle 1, if you are in Phase I, blood (about 5 tablespoons) will be drawn for routine tests and biomarker testing. On Day 1 of Cycles 3 and beyond: * You will have a physical exam, including measurement of your weight and vital signs. * Your performance status will be recorded. * Blood (about 1 tablespoon) will be drawn for routine tests. Every 6 weeks (2 cycles), you will have a CT scan, an MRI scan, and/or a bone scan to check the status of the disease. Length of Treatment: You may continue taking doxycycline for as long as the doctor thinks it is in your best interest. You may continue receiving temozolomide and ipilimumab for up to 4 cycles. You will no longer be able to take the study drugs if the disease gets worse, if you start having other health problems, if intolerable side effects occur, or if you are unable to follow study directions. Your participation on the study will be over once you have completed the end-of-treatment visit. End-of-Treatment Visit: Within 4 weeks after your last dose of study drugs: * You will have a physical exam, including measurement of your weight and vital signs. * Your performance status will be recorded. * Blood (about 5 tablespoons) will be drawn for routine tests and biomarker testing. * You will have an ECG. * You will have a tumor biopsy performed to test if there is any change in the level of iNOS protein. This is an investigational study. Temozolomide is FDA approved and commercially available to treat advanced brain tumors. It is commonly used to treat advanced melanoma but is not FDA approved for it. Ipilimumab is FDA approved and commercially available to treat advanced melanoma. Doxycycline is FDA approved and commercially available to treat various infections, but using it to treat cancer is investigational. Up to 58 patients will take part in this study. All will be enrolled at MD Anderson.