Vorinostat, Isotretinoin and Temozolomide in Adults With Recurrent Glioblastoma Multiforme (GBM)

Phase I / II Adaptive Randomized Trial of Vorinostat, Isotretinoin and Temozolomide in Adults With Recurrent Glioblastoma Multiforme

The goal of this clinical research study is to learn if vorinostat when given with isotretinoin and temozolomide can help to control glioblastoma or gliosarcoma. The safety of these drug combinations will also be studied.

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 3 groups. If you are on of the first 30 participants in the study, you will be randomly assigned to a group. If you are enrolled after the first 30 participants, you will be more likely to be enrolled in the group that is showing better results.

• If you are in Group 1, you will take vorinostat and isotretinoin.
• If you are in Group 2, you will take isotretinoin and temozolomide.
• If you are in Group 3, you will take vorinostat, isotretinoin and temozolomide.

Study Drug Administration:

Each study cycle is 28 days.

You will take vorinostat by mouth once a day during Days 1-7 and Days 15-21 of each cycle. You should take vorinostat by mouth in the morning, at about the same time each day. Vorinostat capsules should be swallowed whole and should not be opened. If a capsule is damaged or broken, spills of powder from vorinostat capsules should be cleaned up carefully. If you come in contact with the powder, you should wash your hands thoroughly. If the spill is on a surface, the area must be washed at least 3 times with rubbing alcohol, followed by water. Vorinostat capsules should be stored at room temperature (59°-86°F [15°-30°C]) in a dry area. You should take vorinostat with food, but not a high fat meal.

You will also take isotretinoin by mouth 2 times a day on Days 1-21 of each cycle.

You will take temozolomide by mouth once a day on Days 1-7 and Days 15-21 of each cycle. You should take temozolomide by mouth at bedtime, at about the same time each day. You should swallow the temozolomide capsules whole, one right after the other, without chewing them. They should be taken on an empty stomach (at least 2 hours after eating) with 1 cup (about 8 ounces) of water.

If you vomit while taking vorinostat, isotretinoin and/or temozolomide, you should not "make up" the dose. You should wait until the next scheduled dose.

Study Visits:

At Week 2 of every cycle:

° Blood (about 1 teaspoons) will be drawn for routine tests.

At Week 4 of Cycles 1:

• Blood (about 2 teaspoons) will be drawn for routine tests and to check how well your blood clots,.
• If you are able to become pregnant, you will have a blood (about 1/2 teaspoon) pregnancy test.

At Week 4 of Cycle 2 and then every other cycle after that (Cycles 4, 6, 8, and so on):

• You will have a physical exam, including a neurological exam.
• Blood (about 2 teaspoons) will be collected for routine tests. This routine blood draw will also include a pregnancy test if you can become pregnant.
• Blood (about 2 teaspoons) will be drawn to check how well your blood clots, your pancreas function and the amount of fats in your blood.
• You will have a brain MRI scan to check the status of the disease.

At any time during the study, extra tests may be performed if the doctor thinks they are needed for your safety. The study doctor will tell you more about any extra tests.

Length of Study:

You may take the study drug(s) for up to 1 year. You may continue to receive the study drug(s) beyond 1 year if your doctor decides that it is in your best interest. You will be taken off study early if the disease gets worse or you have intolerable side effects.

Long-Term Follow-Up:

After your last dose of the study drug, every 2 months after that, you may be called and asked how you are feeling. This phone call should take about 5-10 minutes.

If you stop the study drugs because of intolerable side effects, you will visit the clinic every 2 months, unless the disease gets worse. At these visits, You will have a physical exam, including a neurological exam.

• Blood (about 2 teaspoons) will be collected for routine tests. This routine blood draw will also include a pregnancy test if you can become pregnant.
• Blood (about 2 teaspoons) will be drawn to check how well your blood clots, your pancreas function and the amount of fats in your blood.
• You will have a brain MRI scan to check the status of the disease.

This is an investigational study. Isotretinoin, temozolomide, and vorinostat are FDA approved drugs and commercially available. The use of these drugs in this combination is investigational.

Up to 135 patients will take part in this study. Up to 30 will be enrolled at MD Anderson.

Inclusion Criteria:

1. Patients with histologically proven supratentorial WHO grade IV glioma (glioblastoma or gliosarcoma) will be eligible for the study.
2. 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.
3. (2. continued) Patients with prior therapy that included interstitial brachytherapy, Gliadel wafers or stereotactic radiosurgical procedures must have confirmation of true progressive disease rather than radiation necrosis. Such confirmation may be using advanced imaging studies (e.g. PET scans, diffusion-perfusion MRI, SPECT etc) or if available, surgical sampling and histological confirmation (surgery is not required).
4. Patients may have had up to 2 prior relapses.
5. All patients must sign an IRB approved informed consent indicating their awareness of the investigational nature of this study. Patients must have signed an authorization for the release of their protected health information.
6. 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.
7. Patients who have 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.
8. Patients must be 18 years old or older.
9. Patients must have a Karnofsky performance status equal or greater than 60.
10. 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 4 (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
11. (10. 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. Any questions related to the definition of non-cytotoxic agents should be directed to the Study Chair.
12. 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 upper limit of normal and alkaline phosphatase = or < 2 times upper limit of normal, bilirubin = or <1.5 mg/dl), adequate renal function (BUN and creatinine = or <1.5 times upper limit of 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 by the treating physician.
13. 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 and Female 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.
14. Prior treatment with dose dense regimens of temozolomide is not allowed (e.g, 7 days on/7 days off, 21 day/28 day and daily low dose continuous dosing). However, prior treatment with standard day 1-5 dosing in the adjuvant setting and low dose daily dosing as part of chemoradiation therapy are allowed
15. Prior treatment with isotretinoin is allowed because the trial is based on the hypothesis that HDAC inhibition will potentially overcome resistance to retinoids.

Exclusion Criteria:

1. 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.
2. 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 treatment with 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 for enrollment into the study.
3. Prior treatment with bevacizumab is not allowed.
4. 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.
5. Patients on previous treatment with carboplatin.
6. Patients with a known allergy to any component of vorinostat, or a known allergy to temozolomide and/or isotretinoin.
7. 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 criterion.
8. Patients receiving treatment with other antiepileptic medications will not be excluded. Vorinostat is not metabolized by cytochrome P450 3A4 (CYP 3A4). However, vorinostat may potentially suppress CYP 3A4 activity. Therefore, patients should preferably be treated with non-enzyme inducing anti-epileptic medications to avoid any potential interactions with vorinostat.
9. (8. continued) However, the use of non-enzyme inducing anti-epileptic medications is not mandatory. If enzyme-inducing antiepileptic drugs are used, monitoring of drug levels should be considered, as considered clinically appropriate by the treating physician.