• Phase I: Maximum tolerated dose (MTD) of vorinostat/isotretinoin (cRA), carboplatin (CBT)/cRA and vorinostat/cRA/CBT [ Time Frame: 3 Years ]
• Phase II: Efficacy of vorinostat/cRA versus CBT/cRA versus vorinostat/cRA/CBT [ Time Frame: 3 Years ]

• Phase II: Radiological response, progression free survival at 6 months, overall survival and unexpected toxicity [ Time Frame: 3 Years ]
• Phase II: Obtain exploratory data regarding histone 3 and 4 acetylation and p21 levels in tumor tissue and peripheral monocytes [ Time Frame: 3 Years ]
• Phase II: Evaluate the occurrence of symptoms and correlate to disease progression and tolerance to treatment [ Time Frame: 3 Years ]

Primary Objective (Phase I):

1. To determine the maximum tolerated dose (MTD) of vorinostat/isotretinoin (cRA), carboplatin (CBT)/cRA and vorinostat/cRA/CBT combinations in adult patients with recurrent glioblastoma multiforme (GBM) and anaplastic gliomas.

Primary Objective (Phase II):

- To determine the efficacy of vorinostat/cRA versus CBT/cRA versus vorinostat/cRA/CBT in patients with recurrent GBM as determined by time to progression (TTP) using an adaptive randomization phase II trial design.

Secondary Objectives (Phase II):

• To determine the radiological response, progression free survival at 6 months, overall survival and unexpected toxicity in the three treatment arms.
• To obtain exploratory data regarding histone 3 and 4 acetylation and p21 levels in tumor tissue and peripheral monocytes in a subset of surgical patients and in non-surgical patients with available tissue from previous surgical procedures.
• To evaluate the occurrence of symptoms and correlate to disease progression and tolerance to treatment using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool.

Carboplatin is designed to kill tumor cells by damaging their DNA. Isotretinoin is designed to decrease the growth rate of gliomas and may decrease the blood supply to the tumor. Vorinostat is designed to change the levels of production of several proteins in the tumor cells and either kill or stop their growth. Researchers hope that it may improve the effects of isotretinoin and carboplatin on malignant gliomas.

Before you can start treatment on this study, you will have what are called "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. You will have a complete medical history and physical exam, including measurement of your height and weight. Blood (about 1-2 tablespoons) will be drawn for routine tests and to check how well your blood clots. You will have a magnetic resonance imaging (MRI) scan to measure the tumor. Women who are able to have children must have a negative blood (about 1 teaspoon) pregnancy test.

There are 2 phases to this study. In Phase 1, researchers are trying to find the highest tolerable dose of the study drugs that can be given together in each of the 3 study groups. Up to the first 54 participants enrolled in this study will be enrolled in Phase 1. If you have an anaplastic glioma you are only allowed to participate in the Phase I part of this study. In Phase 2, researchers will be trying to find out which of the 3 groups is best for the treatment of gliomas.

If you are found to be eligible to take part in this study and you are enrolled in Phase 1, you may be assigned to either Group 1 or Group 2. Group 1 will receive vorinostat and isotretinoin. Group 2 will receive carboplatin and isotretinoin. If you enter the study after the highest tolerable doses for Groups 1 and 2 are found, you will be assigned to Group 3 and will receive vorinostat, isotretinoin, and carboplatin. No matter which group you are assigned to, every 28 days will be called a study "cycle. During Days 21-28, you will not receive any study drugs. This is called the "rest" period.

The first 3 participants in each study group will receive the lowest dose levels of the study drugs. If there are no intolerable side effects seen at that dose level after 4 weeks (or, 1 study "cycle"), the next 3 participants enrolled to each study group will receive a higher dose of the study drugs. If there are no intolerable side effects at that second dose level, 3 more participants will be enrolled in each study group at the next (higher) dose level. In any study group, if 1 participant has intolerable side effects, another 3 participants will be enrolled at the same dose level. If a second participant at that dose level has intolerable side effects, another group of 3 participants will then be enrolled in that study group at the earlier (lower) dose level, to make sure that it is the highest safe dose combination that can be given.

Once the phase I portion of the study is completed, the Phase II portion will begin. If you are found to be eligible to take part in this study and are 1 of the first 30 participants in Phase II, you will be randomly assigned (as in the roll of dice) to 1 of the same 3 groups as participants in the Phase I portion of the study.

If you are found to be eligible to take part in this study and you are not one of the first 30 participants assigned to Phase II, you will be assigned to a study group based on how well each group is performing. If each group is about as effective as the other groups, you may still have an equal chance of being assigned to each group. If 1 or 2 groups appear to be more effective, you will have a higher chance of being assigned to the more effective group(s).

If you are eligible to participate in the Phase II portion of the study but your doctor has recommended that you have surgery to remove a tumor that has come back, you would have the surgery before being assigned to a study group. This part of the study is done to learn the effects of vorinostat on tumor tissue and blood cells. Up to 10 participants will take part in this portion of the study.

If you participate in this part of the study, you will be given vorinostat by mouth once daily for 3 days in a row before your surgery. The last dose of the drug will be given the morning of surgery. After the surgery, a portion of the remaining tumor tissue will be used to measure the drug levels and the effects of vorinostat on the tumor. Blood (about 1 teaspoon) will be drawn before and after the first dose of vorinostat, and at the same time as the tissue removal during surgery. This blood will be used to study the drug levels and the effects of the drug in normal blood cells and to match these findings with that in the tumor.

After you have recovered from the effects of surgery (about 2 weeks), you will then be randomly assigned or assigned based on known effectiveness as all other members of the Phase II portion.

All participants, regardless of being assigned to Phase 1 or 2, will receive the same study drugs (based on the group they are assigned to) and the same procedures and testing.

• If you are assigned to Group 1, you will take vorinostat by mouth once a day during Days 1-14. You will also take isotretinoin by mouth 2 times a day on Days 1-21.
• If you are assigned to Group 2, you will take isotretinoin by mouth 2 times a day on Days 1-21. You will receive carboplatin through a needle in your vein on Day 1 over 30 minutes.
• If you are assigned to Group 3, you will take vorinostat by mouth once a day during Days 1-14. You will also take isotretinoin by mouth 2 times a day on Days 1-21. You will also receive carboplatin through a needle in your vein on Day 1 over 30 minutes.

About every week during Cycle 1 and about every 2 weeks after that, blood (less than 1 tablespoon) will be drawn for routine tests. Blood (about 2 tablespoons) will also be drawn about every 2 weeks during Cycle 1 and then at the end of every cycle to check your liver and kidney function and to see how well you blood clots.

At the end of Cycle 1 and the at the end of every odd numbered cycle (Cycles 3, 5, 7 and so on), blood (about 1 teaspoon) will be drawn for lipid testing (a check of different types of fat in the blood, such as cholesterol).

Women who are able to have children must have a negative blood (about 1 teaspoon) pregnancy test before each new cycle. If at any point during the study your treatment is delayed, you will also have a pregnancy test before restarting therapy.

You will have an MRI scan and a complete physical and neurological exam at the end of Cycle 1 and then at the end of every other cycle (Cycles 3, 5, 7 and so on). These tests may be performed more often if your doctor thinks it is necessary.

You will receive the treatment for up to 1 year, after which you will continue to be monitored on the study provided your disease does not get worse. You may continue to receive treatment beyond 1 year and remain on study if your doctor decides that it is in your best interest.

Once you are no longer receiving the study drugs, you will have an end-of-study visit. At this visit, you will have another complete physical exam. Blood (less than 2 tablespoons) will be drawn for routine tests, to check your liver and kidney function, to check your bloods ability to clot, and for lipid testing. You will have an MRI.

After you have your end-of-study visit, you will have a follow-up evaluation (a clinic visit or telephone call) about every 3 months to find out how you are feeling. These visits/calls will continue indefinitely. The phone calls will take about 15 minutes.

THIS IS AN INVESTIGATIONAL STUDY. Isotretinoin, carboplatin, and vorinostat are FDA approved drugs and commercially available. The use of these drugs in this combination is investigational. Up to 189 patients will take part in this study. All will be enrolled at M. D. Anderson.

• Glioblastoma Multiforme
• Anaplastic Glioma

• Drug: Vorinostat
• Drug: Carboplatin
• Drug: Isotretinoin
• Other: No Surgery
• Procedure: Surgical Resection

• Other: Non-Surgical
• Other: Surgical Arm

Inclusion Criteria:

• Patients with histologically proven supratentorial glioblastoma multiforme, gliosarcoma or anaplastic glioma will be eligible for the Phase I component of this protocol. Anaplastic gliomas include anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma, or malignant glioma NOS. Patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a malignant glioma is made. Only patients with histologically proven supratentorial glioblastoma multiforme or gliosarcoma will be eligible for the Phase II component.
• Patients must have shown unequivocal evidence for tumor recurrence or progression by MRI scan and should have failed radiation therapy. The scan done prior to study entry documenting progression will be reviewed by the treating physician to document changes in tumor dimension to confirm recurrence. Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis.
• Patients may have had up to 2 prior relapses provided the functional status and other eligibility criteria for enrollment are met.
• All patients must sign an informed consent indicating that they are aware of the investigational nature of this study in keeping with the policies of this hospital.
• The baseline on-study MRI should be performed within 14 days (+ 3 working days) prior to registration and on a steroid dosage that has been stable or decreasing for at least 5 days. If the steroid dose is increased between the date of imaging and the initiation of therapy (or at that time), a new baseline MRI is required. The same type of scan, i.e., MRI, must be used throughout the period of protocol treatment for tumor measurement.
• Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as they have recovered from the effects of surgery. Evaluable or measurable disease following resection of recurrent tumor is not mandated for eligibility into the study. To best assess the extent of residual measurable disease post-operatively, a MRI should be done no later than 96 hours in the immediate post-operative period or 4-6 weeks post-operatively.
• Patients must be 18 years old or older.
• Patients must have a Karnofsky performance status equal or greater than 60.
• Patients must have recovered from the toxic effects of prior therapy to < grade 2 non hematological or grade 2 or lesser hematological toxicity per CTC ver 3 (except deep vein thrombosis): 4 weeks from prior cytotoxic therapy and/or at least two weeks from vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine administration, and 1 week for non-cytotoxic agents, e.g., interferon, tamoxifen, cis-retinoic acid, etc. (radiosensitizer does not count). Patients who receive anticancer agents for non-therapeutic purposes unrelated to this study
• (9. continued) (such as presurgically for obtaining pharmacology data for the agent) will be eligible to enter the study provided they have recovered from the toxic effects of the agent if any. Because the trial is based on the hypothesis that the combination of agents used will be synergistic in their effects, and that HDAC inhibition will potentially overcome resistance to retinoids, prior treatment with cRA is allowed. Any questions related to the definition of non-cytotoxic agents should be directed to the Study Chair.
• Patients must have adequate bone marrow function (ANC = or > 1,500/mm^3 and platelet count of = or > 100,000/mm^3), adequate liver function (SGPT = or < 3 times normal and alkaline phosphatase = or < 2 times normal, bilirubin = or <1.5 mg/dl), adequate renal function (BUN and creatinine = or <1.5 times institutional normal) and normal serum amylase and lipase prior to starting therapy. Elevated cholesterol and triglycerides are not a contraindication to study enrollment, but should be managed as clinically appropriate.
• Patients must be willing and able to comply with the FDA mandated iPLEDGE program for treatment with isotretinoin (cRA). Patients must sign specific informed consents for treatment with cRA, as mandated by iPLEDGE guidelines. Women of childbearing potential must not be pregnant, must not be breast-feeding and must practice adequate contraception during and one month after participation in the study. Male patients on treatment with vorinostat must agree to use an adequate method of contraception for the duration of the study, and for 30 days after the last dose of study medication.
• Prior treatment with carboplatin is not allowed.

Exclusion Criteria:

• Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix or bladder), unless in complete remission and off of all therapy for that disease for a minimum of 3 years.
• Patients must not have: a) active infection; b) disease that will obscure toxicity or dangerously alter drug metabolism, especially liver disease; c) serious intercurrent medical illness; d) prior recurrence with other HDAC inhibitors. However, patients who have received anticancer agents for non-therapeutic purposes (for eg., as part of a pharmacology study without therapeutic intent) will remain eligible; e) grade 2 or higher peripheral neuropathy.
• Pregnant and breast feeding women.
• Patients receiving valproic acid (VPA), an anticonvulsant drug with HDAC inhibitor properties, will be excluded, unless they are switched to an alternative agent prior to treatment initiation. No wash out period is required.
• Patients on previous treatment with carboplatin.
• Patients with a known allergy to any component of vorinostat, or a known allergy to carboplatin and/or isotretinoin.
• Patient must be able to tolerate the procedures required in this study including periodic blood sampling, study related assessments, and management at the treating institution for the duration of the study. Inability to comply with protocol or study procedures (for example, an inability to swallow tablets) will be an exclusion criteria.